University of Pennsylvania

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Publicly Accessible Penn Dissertations

Fall 2011

Patterns of Weight Change in infants With Congenital Heart

Disease Following Neonatal Surgery: Potential Predictors of
Growth Failure
Sharon Y. Irving
University of Pennsylvania, [email protected]

Follow this and additional works at: https://repository.upenn.edu/edissertations

Part of the Critical Care Nursing Commons, Dietetics and Clinical Nutrition Commons, and the
Pediatric Nursing Commons

Recommended Citation
Irving, Sharon Y., "Patterns of Weight Change in infants With Congenital Heart Disease Following Neonatal
Surgery: Potential Predictors of Growth Failure" (2011). Publicly Accessible Penn Dissertations. 443.
https://repository.upenn.edu/edissertations/443

This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/443

For more information, please contact [email protected].
Patterns of Weight Change in infants With Congenital Heart Disease Following
Neonatal Surgery: Potential Predictors of Growth Failure

Abstract
Abstract

Patterns of Weight Change in Infants with Congenital Heart Disease Following Neonatal Surgery:
Potential predictors of growth failure

Sharon Y Irving

DISSERTATION SUPERVISOR: BARBARA MEDOFF-COOPER, RN, PhD

Congenital heart disease (CHD) is reported to have an incidence of 9 to 14 per 1000 live births with a
prevalence estimated between 650,000 and 1.3 million persons in the United States (US). It is a structural
malformation(s) of one or more heart chamber(s) and/or deformity of one or more of the major
intrathoracic blood vessel(s) and the ensuing malady occurring during embryonic development. Up to
one-third of infants with CHD, require surgical intervention. Improved surgical technique over the last
several decades has seen an increased survival of neonates with CHD. Concomitantly there has been an
emergence of co-morbidities. Growth failure is a common co-morbidity following neonatal surgery for
CHD. More than 30% of these infants fall below the third percentile for weight early in their lives.
Postsurgical physiology, disease severity, feeding dysfunction, and a hypermetabolic state may all
contribute to growth failure, which has been associated with deficits in cognitive development, intellectual
ability and neurodevelopment, effecting maturation and school performance. Early recognition and
intervention of growth failure can improve health outcomes. The objective of this work is to identify
patterns of growth and growth failure in infants with CHD and explore potential predictors that may be
modifiable to mitigate growth failure and prevent the associated untoward consequences.

Degree Type
Dissertation

Degree Name
Doctor of Philosophy (PhD)

Graduate Group
Nursing

First Advisor
Barbara Medoff-Cooper, RN, PhD

Second Advisor
Martha A.Q. Curley, RN, PhD

Third Advisor
Virginia A. Stallings, MD

Keywords
growth failure, growth, energy expenditure, congenital heart disease, growth velocity
Subject Categories
Critical Care Nursing | Dietetics and Clinical Nutrition | Pediatric Nursing

This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/443

 PATTERNS OF WEIGHT CHANGE IN INFANTS WITH CONGENITAL HEART

DISEASE FOLLOWING NEONATAL SURGERY: POTENTIAL PREDICTORS OF

GROWTH FAILURE

SHARON Y IRVING, CRNP

A DISSERTATION

In

Nursing

Presented to the Faculties of the University of Pennsylvania

In

Partial Fulfillment of the Requirements for the

Degree of Doctor of Philosophy

2011

Dissertation Supervisor: ___________________________________

Barbara Medoff-Cooper, RN, PhD, FAAN

Ruth M. Colket Professor of Pediatric Nursing

Graduate Group Chairperson: _______________________________

Marilyn S. Sommers, RN, PhD, FAAN

Lillian S. Brunner Professor of Medical-Surgical Nursing

Dissertation Committee:

Martha Curley, RN, PhD

Professor of Nursing

Charlene Compher, RD, PhD

Associate Professor of Nutrition Science

Virginia A Stallings, MD
Professor of Pediatrics
PATTERNS OF WEIGHT CHANGE IN INFANTS WITH CONGENITAL HEART

DISEASE FOLLOWING NEONATAL SURGERY: POTENTIAL PREDICTORS OF

GROWTH FAILURE

COPYRIGHT

2011

Sharon Y Irving
 DEDICATION

To my parents:
You lived by the mantra “It takes a village”, and raised me in that way. Thank
you for placing me in the “right village” and always believing and supporting
even when you did not agree. I love you both. Mom, I wish you could see me
now.

To my close and my extended family:

You believed when it was unbelievable. Thank You.

To my very first nursing preceptors: Brenda, Rose and Miss Mary and Mrs. J:
Thank you for the tireless hours of teaching, repeating, answering questions,
and showing me how. You gave me the space to learn from you – look at what I
have learned.

To my many mentors along the way:

Each of you has helped me walk this journey. Thank You.

“I would like to be a scholar in whatever I do, a scholar is never finished, he is always

seeking and I am always seeking”.

Ahmad Jamal

iii
 ACKNOWLEDGEMENTS

First always in my life is God.

To my family:

There are no words that can ever thank you enough for all the love and the
support and more love. Through the smiles and the tears, thank you, thank you, and
thank you. I pray I make you proud.

To my “Cultural Heritage” sistahs:

Danica, Margo, Bridgette – thank you for ‘Paying it Forward’. I learned from
your learning, your teaching and just by being in your presence. Thank you for
welcoming me with open arms, big hearts and lots of love. Each of you are a part of the
fabric that I am.

To my committee:

Thank you Barbara, Martha, Charlene and Ginanne. Each of you have inspired,
you taught, you mentored, you pushed, you pulled and in the end – you nurtured.

iv
 ABSTRACT

PATTERNS OF WEIGHT CHANGE IN INFANTS WITH CONGENITAL HEART

DISEASE FOLLOWING NEONATAL SURGERY: POTENTIAL PREDICTORS OF

GROWTH FAILURE

SHARON Y IRVING

DISSERTATION SUPERVISOR: BARBARA MEDOFF-COOPER, RN, PhD

Congenital heart disease (CHD) is reported to have an incidence of 9 to 14 per

1000 live births with a prevalence estimated between 650,000 and 1.3 million persons

in the United States (US). It is a structural malformation(s) of one or more heart

chamber(s) and/or deformity of one or more of the major intrathoracic blood vessel(s)

and the ensuing malady occurring during embryonic development. Up to one-third of

infants with CHD, require surgical intervention. Improved surgical technique over the

last several decades has seen an increased survival of neonates with CHD.

Concomitantly there has been an emergence of co-morbidities. Growth failure is a

common co-morbidity following neonatal surgery for CHD. More than 30% of these

infants fall below the third percentile for weight early in their lives. Postsurgical

physiology, disease severity, feeding dysfunction, and a hypermetabolic state may all

contribute to growth failure, which has been associated with deficits in cognitive

development, intellectual ability and neurodevelopment, effecting maturation and

school performance. Early recognition and intervention of growth failure can improve

health outcomes. The objective of this work is to identify patterns of growth and growth

failure in infants with CHD and explore potential predictors that may be modifiable to

mitigate growth failure and prevent the associated untoward consequences.

v
 TABLE OF CONTENTS

INTRODUCTION…………………………………………………………………….1

CHAPTER 1

The Problem: Growth Failure……………………………………………. 4

Methods……………………………………………………………………. 11

Purpose and Specific Aims ………………………………………………13

Conclusion…………………………………………………………………. 15

References……………………………………………………………….…16

CHAPTER 2

Part 1: “Growth Velocity over the First Year of Life Following

Neonatal Surgery for Congenital Heart Disease”

Abstract …………………………………………………………….30

Definition of Terms ……………………………………………….. 31

References……………………………………………………….…44

Part 2: “Resting Energy Expenditure at 3-Months of Age in

Infants following Neonatal Surgery for
Congenital Heart Disease”

Abstract …………………….…………………………….………..59

Definition of Terms ………………………………………………. 60

References…………………………………………………………71

CHAPTER 3

National Institutes of Health Award Application……………………….... 83

“The Use of Indirect Calorimetry (IC) to Measure Energy
Needs in Mechanically Ventilated Children with
Acute Lung Injury”

References……………………………………………………………….…119

vi
CHAPTER 4

Summary and Conclusions……………………………………..……….. 127

Growth Monitoring ………………………………………………………...127

NIH Directors Early Independent Investigator Award Application ……133

References……………………………………………….…………………137

CLOSING…………………………………………………………………………… 140

“LOOK AT US NOW”

vii
 LIST OF TABLES

CHAPTER 1

Table 1 Definition of Terms ………………………………………………26

Table 2 Comparison of infants with Congential Heart Disease

enrolled versus not enrolled……………………………………...27

Table 3 Manuscripts and Specific Aims………………………………… 28

CHAPTER 2

Part 1

Table 2 Primary diagnosis of infants with Congenital Heart Disease... 50

Table 3 Study sample demographics…………………………………… 51

Table 4 Mean (SD) growth parameters,

healthy females and males……………………………………… 52

Table 5 Mean (SD) growth parameters,

females and males with CHD…………………..……………….. 53

Table 6 Mean (SD) growth parameters,

healthy males and males with CHD……………………………..54

Table 7 Mean (SD) growth parameters,

healthy females and females with CHD…………………….…..55
.
Part 2

Table 1 Terms and Definitions………………………………….……….. 60

Table 2 Congenital Heart Disease diagnoses of

study sample………………………………………..…………..... 7

Table 3 Growth, body composition and resting energy expenditure

in all subjects at 3 months of age……………………………….79

Table 4 Regression model of covariates with strongest

Contribution to REE kcal/day……………………………………80

CHAPTER 3

Table 1 Inclusion and exclusion criteria……………………………....... 99

viii
 Table 2 Sample characteristics of healthy infants and infants with
Congenital Heart Disease………………………………………… 78

Table 3 Growth, body composition and resting energy expenditure

in all subjects at 3 months of age………………………………… 79

Table 4 Regression model of covariates with strongest contribution

to REE kcal/day

CHAPTER 3

Table 1 Inclusion and exclusion criteria…………………………………….99

Table 2 Study measurements…………………………….………………..104

Table 3 Estimated Timeline of study activity…….………………………..113

ix
 LIST OF ILLUSTRATIONS

CHAPTER 1

Figure 1 Conceptual Model of Potential Influences on

Growth in CHD…………………………………………………… 29

CHAPTER 2

Part 1

Figure 1 Weight velocity z-score by gender……………………………… 56

Figure 2 Length velocity z-score by gender……………………………….57

Figure 3 Head circumference velocity z-score by gender………………..58

Part 2

Figure 1 Box plot graph of growth measures at 3 months of age………..81

Figure 2 Regression line of REE kcal/day for fat-free mass (FFM), kg

from TOBEC

CHAPTER 3

Figure 1 Randomization schema……………………………………………96

CHAPTER 4

Figure 1 Modified conceptual model………………………………………139

x
INTRODUCTION

Congenital heart disease (CHD) is defined as the structural malformation(s) of

one or more heart chambers and/or deformities of the major intrathoracic blood vessels

and the ensuing malady that occurs during embryonic development. The incidence of

CHD reported to be 9 to 14 per 1,000 live births,1-3 has a prevalence estimated

between 650,000 and 1.3 million persons in the United States (US).1,4,5 CHD accounts

for as much as 50% of neonatal infant mortality and is considered to be the most

common cause of infant death from a birth defect in the US.6 Up to one third of infants

born with CHD require surgical intervention early in their lives.7 The Consortium of the

Society of Thoracic Surgeons of Congenital Heart Surgery reported more than 60% of

infants born between July 2004 and June 2008 presented for surgical intervention in

the neonatal period (first 30 days of life).8 As a disease entity, CHD contributes not only

to the rate of infant mortality and to the prevalence of infant morbidity, but also to

chronic childhood health conditions and the associated healthcare costs.

With improvement in surgical technique, medical treatment, and nursing care

over the last few decades, there has been marked increase in the survival rate of

neonates with CHD. Between 1979 and 1997, CHD-related mortality declined more

than 39% in the US.1 Along with improved survival of neonates and infants undergoing

surgery for CHD, there has been a parallel emergence of co-morbidities in the

survivors. Although non-cardiac concomitant conditions requiring services from

pediatric subspecialists such as neurologists, pulmonologists, and orthopedics are

frequently seen,9 growth failure is one of the more common sequelae observed in

infants with CHD.10-12 More than 50% exhibit poor growth early in life and 30% fall

below the third percentile for weight on standard growth charts for age and gender

1
during infancy.13,14 The high prevalence of CHD, its contribution to infant morbidity and

mortality and the association with poor growth in infancy are ongoing challenges in

caring for these infants.

Growth is fundamental to pediatric care and often used as a gauge to measure

the infant’s health and well-being. For postsurgical infants with CHD, growth,

particularly weight gain, may also be a measure of surgical success and disease

management. Poor growth is common and well documented in infants with CHD both

before and after surgical intervention.10-12,14-18 Historically, poor growth also described

as growth failure has been ascribed to the population sample studied, making it difficult

to quantify and more difficult to generalize.19,20 Recent data suggest suboptimal

monitoring of growth measures, chronic medical problems that present with poor

growth, and socioeconomic factors may all be associated with growth failure but are

under-appreciated for their contribution to this condition.21,22 This may in part be

responsible for lack of an all-encompassing definition for growth failure adding to the

difficultly of diagnosis and treatment. Growth failure in infants with CHD can be the

result of feeding dysfunction resulting in inadequate nutrient intake, hemodynamic

alterations related to the underlying cardiac physiology, alterations in body

composition, neurologic immaturity, intercurrent illnesses, or disease severity.

There is no consensus on the definition of growth failure for infants and young

children with CHD. The same primary cardiac diagnosis can present differently based

on physiology and degree of hemodynamic impairment. This variability affects weight

gain and adds to the complexity of defining and identifying growth failure in this

population.

2
 Regardless of the etiology, growth failure can have a long-lasting effect on

overall health. Poor growth has also been associated with poor cognitive development

and deficits in neurodevelopmental outcomes that extend well into childhood and

adolescence.23-27 Further investigation into potential contributing factors, physiologic

associations, and possible modifiable elements that will lead to development of

strategies and interventions to prevent and/or minimize growth failure in these infants

will augment continued advances in surgical approach and improvements in care. A

better understanding of growth failure and its contributing factors can lead to

interventions to minimize or prevent its occurrence and improve health outcomes for

these infants. An investigation into the pattern of growth in infants with CHD compared

to healthy infants and exploring energy expenditure as a potential contributing factor to

the poor growth often seen is the focus of this dissertation. For the purposes of this

work, the terms ‘growth failure’ and ‘poor growth’ are synonymous and define the less

than adequate growth described throughout. Table 1 is a definition of terms.

3
CHAPTER 1
The Problem: Growth Failure

Understanding Growth and Growth Failure

Whereas growth is fundamental to pediatric health and is often a measure of

overall well-being, poor growth, evidenced by a decrease in previously attained weight

and/or a negatively altered pattern of weight gain, is often associated with poor health,

chronic illness, and acute or chronic malnutrition. The first year of life is the time of the

most rapid ex utero growth. In infancy, lack of adequate energy, protein, and other

nutrient intake will likely result in adverse effects on growth and has potential to affect

neurodevelopmental maturation and behavior.24,28,29 Numerous studies have linked

poor growth in infancy with diminished intellectual ability, lower than average

Intelligence Quotient (IQ) and negative cognitive and behavioral outcomes in childhood

and adolescence.29-32

The typically developing infant gains between 20 to 30 grams per day in the first

6 months of life following an expected physiologic weight loss that may reach and can

exceed 10% of birth weight; in months 6 thru 12, weight gain slows to between 10 to 20

grams per day.13,33,34 Adequate nutrient intake in infancy is crucial to promote a positive

energy balance to support best potential for brain growth, neurologic development, and

physical maturation. In the second year of life, physical development changes and

weight gain further slows down to approximately 8 grams per day, while brain growth,

estimated by head circumference measurement is expected to increase an average of

0.33 centimeters (cm) per week and continue development late into childhood.24,35

Incremental gains in crown-to-heel length average 0.66 cm per week in the first 6

months of life, slowing to approximately 1.2 cm per month between 6 and 12 months of

age.13,24 Many neonates with CHD do not meet these parameters despite being born
4
full term and within the normal weight range for age and gender at birth.36,37 The

inability to attain and maintain growth parameters within an acceptable range for age

and gender, and/or a significant decrease from an established pattern of growth are

indicators of growth failure and if not corrected can lead to associated physical and

neurodevelopmental consequences.23,28-32,38

The definition of growth failure in the pediatric medical and/or nursing literature

is ambiguous and lacks a uniformly accepted approach to identify those infants at risk

for and who exhibit poor growth. In general, growth failure, most often called failure to

thrive (FTT), is defined as a disruption of the expected rate of growth, and can be the

prelude to significant morbidity and mortality.39 The most common description of FTT is

weight-for-age at or below the third to fifth percentile on more than one consecutive

weight-for-age assessment, or weight-for-age measurements that descend two or more

percentiles on a standard growth chart for age and gender.39-41 The definition of FTT

can also be specific to the infant, by describing weight gain that negatively deviates

from an established pattern of growth.41 Terms such as FTT, growth deficiency, growth

failure, growth faltering, poor growth, protein energy malnutrition, and under-nutrition,

are used interchangeably to describe less-than-adequate weight gain and poor

physical development seen in infancy and early childhood.13,41-44

Consequences of Growth Failure

Researchers have investigated prolonged, inadequate growth in early infancy

and its effect on cognitive and neurodevelopmental maturation. Bhoomika and

colleagues30 found growth failure, the result of poor nutrition, to be associated with

cognitive impairments, decreased acquisition of intellectual processes and poor

development of executive functions, including visual-spatial skills, working memory and

5
attention span. Dykman et al31 related deficits in growth measurements to deficiencies

in cognitive development, poor school achievement and adverse behavior in school-

aged children. In a population study of over 1,800 infants, McDougall and colleagues29

found growth failure in the first two months of life to be a risk factor for decreased

intellectual ability, lower IQ and developmental delay. Black et al45 reported cognitive

deficiencies inclusive of poor work habits, deficient math skills and behavioral problems

in 130 children with a known diagnosis of growth failure. These researchers also

describe attenuation of the cognitive and neurobehavioral impairments they observed

with early sustained intervention for both the child with growth failure and the primary

parental caregiver.45 Collectively these studies provide evidence of a strong association

between inadequate nutrient intake in early infancy and growth failure that have

implications for negative cognitive, neurodevelopmental and behavioral outcomes in

childhood.

Growth Failure in CHD

For the infant with CHD who has undergone neonatal surgery, poor growth is a

common co-morbidity that may have multiple factors contributing to its etiology. Factors

presumed to affect weight change and contribute to poor growth in these infants can

singularly or in combination include hemodynamic abnormalities related to cardiac

physiology and disease severity,13,32,46 inadequate nutrient intake,1,5,45 gastrointestinal

malabsorption,12,47-50 neurologic insults,12,36,47,51 and presumed increase in energy

expenditure.11,33,52-55 Additionally, these infants may have fluid losses as high as 10% to

15% compared to healthy infants, losses that can be attributed to tachypnea, poor fluid

intake, and the necessary use of diuretics for fluid regulation related to the underlying

cardiac disease.13,14,36,56 The dynamics of these factors and the impact they can have

6
pre- and/or postsurgical intervention may contribute to the growth failure often

exhibited by these infants. Figure 1 conceptualizes potential influencing factors on

growth for infants with CHD who have undergone neonatal surgery.

The relationship between growth failure and cardiac physiology has long been a

topic of discussion and investigation. The literature is robust with studies demonstrating

that infants with cyanotic lesions and postoperative single-ventricle (SV) physiology

exhibit more significant growth failure than infants with acyanotic disease or those with

two normally functioning ventricles.14,15,17,48,57-60 The degree of growth failure has been

associated with severity of hemodynamic impairment and/or the presence of heart

failure.13,60 A right-to-left or left-to-right shunt between either the atria or the ventricles

affects the infant’s hemodynamics and presumably has a negative effect on weight

gain contributing to growth failure in this population. Cyanotic defects, such as

Tetralogy of Fallot, Tricuspid Atresia and Hypoplastic Left Heart Syndrome are

associated with right-to-left shunting of blood flow at the ventricular level, resulting in

hypoxemia, often causing disturbances in both weight gain and attainment of

stature.13,60,61 Alternatively, acyanotic lesions, Aortic Stenosis, Coarctation of the Aorta

and Ventricular Septal Defect that manifest left-to-right shunting of blood at the atrial or

ventricular level affects weight rather than stature in the pre-operative stage of

disease.14,62 Regardless of the cardiac anatomy, growth failure for neonates and infants

with CHD is a significant challenge and warrants further investigation to identify causal

factors that if corrected may decrease morbidity and improve health outcomes.

In addition to growth measures of weight, length and head circumference, there

is high interest among healthcare providers and families in the behavioral,

neurodevelopmental and cognitive outcomes following surgical intervention for CHD.

7
An association has been established between growth failure and increased infant

irritability.63 Previous work from the parent study of this dissertation, reported infants

with CHD, particularly those with postoperative SV physiology were more likely to

exhibit growth failure, and have an increased level of irritability and negative

behaviors.64 Limperopoulos et al27 reported a combination of preoperative,

perioperative and postoperative factors influenced neurodevelopmental outcomes they

observed in infants 12 to 18 months after neonatal surgery for CHD. These

researchers found infant weight to be a significant predictor of motor and cognitive

deficits at 2 years of age.27 The Boston Circulatory Arrest Trial, a large longitudinal

study evaluated the neurodevelopmental status of participants at one, four and eight

years of age following infant surgery for CHD in which the participants were

randomized to either cardiac arrest or low-flow cardiopulmonary bypass for

intraoperative organ support.37,65-67 Study findings demonstrated moderate neurologic

deficits in motor coordination, and visual-motor integration, with mild deficits in speech

and language, thought to be associated with the use of cardiac arrest versus the low

flow cardiopulmonary bypass option during infant surgery.35,64-66 In a review of eight

studies, Snookes and colleagues68 reported consistent delay in cognitive and motor

development following surgery for CHD in early infancy. In an extensive review of the

literature reflecting progressive changes in cardiac surgery conducted by Shillingford

and Wernovsky23 a number of consistent themes regarding neurologic outcomes for

children with CHD who had undergone surgery in infancy were discovered. The

authors cite common themes of: 1) prevalence of attention deficits and behavior

problems; 2) deficits in visual-motor integration, visual-spatial challenges, and

abnormalities in speech and language development; 3) impaired development of

8
executive functioning; and 4) an association between intraoperative use of hypothermic

cardiac arrest and/or cardiopulmonary bypass with neurodevelopmental abnormalities

as sequela of surgery during infancy for cardiac disease.23 Predictors of these post

surgical deficits may or may not include the primary underlying cardiac defect, the

surgical approach, the decision for repair versus palliation, use of, type and duration of

intraoperative organ support, and/or the existence of an unknown pre-surgical

neurologic or genetic abnormality.25,38,68-71 Collectively, the evidence points to the need

for close, repeated assessment of growth measures and incremental

neurodevelopmental testing in infants and young children following surgical

intervention for CHD to promote early identification of neurodevelopmental problems

that may be minimized with prompt intervention(s).

Other factors that potentially influence weight gain and growth in infants with

CHD following neonatal surgery include metabolic rate and energy balance. A positive

energy balance, the direct result of energy intake that exceeds energy utilization, is

necessary to support somatic growth, neurobehavioral development, and long-term

health.72-74 The utilization of energy is divided between that required for basal metabolic

functions, thermal effects of digestion, requirements for tissue accretion, weight gain,

and the cost of physical activity.73 In general, neonates have a higher metabolic rate

compared to older children and adults, they require more kcal/kg of body weight.24,75 It

is postulated that infants with CHD, particularly those with heart failure, require an

increased energy intake to attain and maintain growth measurements within an

acceptable range for age and gender. This increased requirement is thought to be from

an increased oxygen consumption and inadequate caloric intake related to poor

feeding ability, gut dysmotility, and/or gastrointestinal malabsorption.14,76 Infants with

9
heart failure may be in a fixed hypermetabolic state prior to and/or immediately

following surgery, secondary to an increase in cardiopulmonary work and postoperative

stress.52,60 This hypermetabolic state, whether or not it is fixed, may affect the infants’

energy intake and energy utilization. Growth failure often seen in infants with CHD

following surgery may be the result of an imbalance between energy intake and energy

utilization, however, available data do not consistently support this

hypothesis.10,14,17,48,55,60 To date, studies suggesting an association between increased

energy expenditure and poor growth in infants and children with complex CHD have

yielded mixed results and are inconclusive due to study design, sample size, and a

heterogeneous participant group.52,61,73,77,78

Research endeavors specifically directed at examining energy intake and

utilization by neonates and infants with CHD prior to, immediately following, and at an

extended postsurgical time may elucidate the role energy balance and alterations in

have on weight gain and the subsequent growth of infants with CHD. With the known

association between growth failure and poor neurodevelopmental and cognitive

outcomes, it is essential to improve knowledge and understanding of factors

contributing to poor growth in this population. This will better prepare healthcare

providers to identify signs of growth failure, develop strategies toward decreasing the

incidence of poor growth in infants with CHD, and increase their ability to achieve

maximal growth, neurodevelopmental and intellectual potential.

10
 Methods

Parent Study: “Feeding Behaviors and Energy Balance in Infants with Congenital Heart

Disease”

The current body of work stems from a large, prospective study entitled:

“Feeding Behaviors and Energy Balance in Infants with Congenital Heart Disease”

(NIH/NINR R01 NR002093; MO1-RR00240; UL1-RR-024134), Principal Investigator:

Barbara Medoff-Cooper, PhD, RN, FAAN, heretofore known as the “parent study.”

Study approval was obtained from both Institutional Review Boards of The Children’s

Hospital of Philadelphia (CHOP) and the University of Pennsylvania, Philadelphia.

Study Design

The parent study design was a prospective, longitudinal design, from a single

center convenience sample.

Study Setting

The parent study is a single-institution investigation conducted at CHOP, a 430-

bed tertiary care facility serving the metropolitan Philadelphia area. During the study

period, March 2003 through May 2007, more than 1,100 neonates were admitted to the

Cardiac Intensive Care Unit (CICU) for evaluation of cardiac disease. The CICU staff

consists of surgeons, physicians, nurses, respiratory therapists and ancillary staff

specially trained in the intervention and therapeutic care of infants and children with

congenital and acquired cardiac disease.

Sample Population

Infants were screened following surgery and if eligible parents/guardians were

approached for enrollment. During the study period, 667 neonates in the CICU met

criteria; of these, 502 families were approached with 164 enrolled, a 33% consent rate.

11
The low rate of consent is multi-factorial and reflects challenges faced in this research

effort. These included absence of parent or guardian for consent, parental refusal to

participate, parental perceived study burden and inability or unwillingness to return to

CHOP for study visits. Additionally there were simultaneous ongoing studies in the

CICU competing for enrollment of the same group of infants. Many infants who met

criteria were from referral institutions where they would return for continued care and

thus be unavailable for study visits. Demographic characteristics of infants with CHD

who were not enrolled were similar to the enrolled group for gender, age, race,

ethnicity and post-operative physiology (Table 2). Healthy infants that served as the

control group were recruited from primary care practices affiliated with CHOP and self-

referral from surrounding communities. Demographic information on healthy infants not

enrolled was not available. Total enrollment in the parent study was 242 combined

cardiac and healthy infants. Race and ethnicity of the infants was assigned by parental

self-identification. Families unwilling or unable to return to CHOP for study visits were

not enrolled.

Eligibility criteria for all infants included >36 weeks post-menstrual age and birth

weight >2,500 grams. Infants with CHD who underwent surgical intervention during the

first 6 weeks of life, and did not have known multiple congenital, facial, chromosomal

and/or complex gastrointestinal anomalies or congenital and/or acquired neurologic

diagnoses were eligible for enrollment. Postoperative classification as SV or BV

physiology was completed in keeping with established standards.79

Data Acquisition

The study protocol commenced following hospital discharge when the infant

was 3-months of age. All data was obtained during study visits in the outpatient Clinical

12
and Translational Research Center and the Nutrition and Growth Lab at CHOP, by

trained research staff. The study protocol did not include assessment of type, amount,

or caloric density of daily nutrient intake or the rate of feeding advancement, the only

distinction referred to oral and device or device-assisted feedings. Dietary recall

diaries were provided to families as part of the study protocol, with instruction to record

nutrient intake for 3-days prior to or immediately following each study visit. The

research staff phoned families bi-monthly to inquire on the infant’s status and to

maintain interest in study participation.

Purpose and Specific Aims

The aim of the parent study was to develop a model to predict poor growth in

postsurgical infants with CHD through a over the first year of life. Sub-analyses of data

from the parent investigation has culminated in two studies that focus on examination

of factors related to growth and growth failure in infants with CHD who underwent

surgery in the first six weeks of life. These studies are presented in chapter two. The

first is a descriptive examination of the pattern of growth velocity over the first year of

life. This is a novel approach to describing growth as the study uses the new World

Health Organization (WHO) child growth velocity standards.80 The aim of this study

was to examine the pattern of growth velocity, inclusive of weight, length, and head

circumference for infants with CHD physiology compared to healthy controls. Growth

velocity, defined as the change in measure over time, is considered a superior

assessment of growth and more accurate than attained measures.80 Assessment of

growth velocity allows early detection of poor growth which can indicate alterations in

health and well-being or inadequate nutrient intake thereby facilitating early

identification of infants at risk for growth failure.80,81

13
 The second study in chapter two examines resting energy expenditure (REE) in

infants with CHD compared to healthy infants at 3-months of age. There were two aims

to this study, 1) to examine differences in REE between infants with CHD compared to

healthy infants at 3 months of age and 2) to investigate if differences exist among

infants with CHD having SV versus BV physiology. This study uses WHO82 child

growth standards for weight, length and head circumference for children from birth to 5

years of age. These standards represent the best physiologic description of growth for

infants and children living in ideal environments.73,80,82

In chapter three, a grant application was developed and submitted for

consideration of an Early Independent Investigator award in response to a call from the

National Institutes of Health for educational-institution sponsored candidates. This

proposal embraces a modified approach to the principle of translational research.

Applying knowledge and skills gained through the course of this dissertation work in

the measurement and analysis of energy expenditure the goal of this proposal was to

identify differences between measured energy expenditure and the use of prediction

equations to prescribe caloric intake for children with acute lung injury requiring

mechanical ventilation. Using indirect calorimetry to measure energy expenditure will

allow tailored prescriptions for energy intake for critically ill children, in whom good

nutrition has a vital role in the process of recovery. Outcome measures for this

proposal include: 1) increased number of ventilator-free days, 2) decreased weight

loss, 3) decreased loss of lean body mass and 4) decreased length of stay. Table 2

describes the subject for each manuscript, and the grant proposal with the related

specific aim.

14
 Conclusion

Multiple factors have an influence on growth in infants with CHD following

neonatal surgery. Postsurgical physiology, severity of illness, feeding ability, neurologic

status, and energy expenditure may all contribute to growth failure that many of these

infants exhibit. The overall aim of this body of work is to explore the pattern of weight

change and investigate factors that contribute to or influence growth or growth failure in

the postsurgical infant with CHD. Monitoring growth velocity and understanding energy

needs and the relationship they share with adequate growth will enable first-line care

providers to better assess and intervene if growth failure is evident. Early recognition

and intervention of growth failure can potentially improve patient outcomes and overall

health. This work aims to initiate thoughtful collaboration among healthcare providers

to address the challenge(s) of growth failure in neonates and infants with CHD who

have undergone surgical intervention early in infancy.

15
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25
Table 1 Definition of Terms

Term Definition

Acyanotic Absence of cyanosis; oxygenated blood in

systemic circulations

Bi-ventricle (BV) Normal two ventricle cardiac physiology; right

ventricle receives blood from the systemic
circulation pumps to the pulmonary circulation;
left ventricle receives blood from the pulmonary
circulation pumps to the systemic circulation

Congenital Heart Disease (CHD) Anatomic or physiologic abnormality of the

heart occurring in utero

Congestive Heart Failure (CHF) The heart cannot deliver adequate cardiac
output to meet the metabolic demands of the
body

Cyanotic Deoxygenated blood in the systemic

circulation; pale or blue discoloration to skin,
face, hands, mucous membranes; related to
type of cardiac defect and resulting physiology

Growth Failure Weight attainment or weight change velocity is

significantly below that of other infants of same
sex and age, based on a prescribed reference
standard

Infant Child from 1 month to 12 months of age

Neonate Newborn infant from birth to 30 days of life

Postsurgical physiology Functional and anatomic physiology of blood

flow following surgical intervention for
congenital heart disease

Single Ventricle (SV) Cardiac defect with one functioning ventricle for
pulmonary and systemic blood flow

Weight Attainment Weight measured at a point in time; may be

assessed as kilogram or z-score

Weight Change Velocity Weight measured over specified time

increments; may be assessed as kilograms, z-
score, or percentiles over time

26
Table 1 Comparison of infants with Congenital Heart Disease enrolled versus not
enrolled.*

Total Enrolled Not Enrolled

Characteristics
% of n = 242 % of n = 338
Gender
Male 61 76
Female 39 57

Post Operative Physiologya

SV 33 22
BV 33 18

Healthy Controlsb 33 -

Racec
African-American 18 9
Asian 1 <1
Caucasian 69 54
More than 1 Race 6 -
Unknown/No Response 6 8

Ethnicityc
Non-Hispanic 64 40
Hispanic 7 5
Unknown/No Response 29 4

*Rounded % of total for each characteristic;

a
Physiology data for not enrolled subjects not confirmed
b
Comparable information on the unrecruited healthy infants was not available
c
Data for race and ethnicity in the not enrolled participants is incomplete; race and ethnicity is
assigned based on parent self-identification after enrollment

27
Table 2 Manuscripts and Specific Aims

Chapter Specific Aim

Chapter 2

Section 1
Growth Velocity over the First Year of Life To examine the pattern of growth
Following Neonatal Surgery for Complex velocity of weight, length, and head
Congenital Heart Disease circumference for infants with
postsurgical classification as SV
physiology compared to healthy age-
matched controls over the first year of
life.
Section 2
Resting Energy Expenditure at 3 Months of To investigate differences in energy
Age in Infants with Complex Congenital expenditure between infants with CHD
Heart Disease Following Neonatal Surgery who have a postoperative classification
as single-ventricle or two-ventricle
physiology as compared to healthy
age-matched controls at 3 months of
age.

Chapter 3

The Use of Indirect Calorimetry (IC) to Use of IC derived measurements of -

Measure Energy Needs in Mechanically energy expenditure to prescribe
Ventilated Children with Acute Lung Injury nutrient intake specific to energy needs
in critically ill, mechanically ventilated
pediatric patients to increase
ventilation-free days, decrease hospital
stay, and improve overall outcome
following critical illness in a specific
patient population.

Description of manuscripts of the dissertation

28
Figure 1 Conceptual Model of Potential Influences on Growth in CHD

Potential Influences on Growth

Infant Severity of Disease Growth
with complex Weight Change Velocity
CHD Weight for age z-score
Length for age z-score
HC for age z-score
Cardiac hemodynamic factors
Nutrient intake
Influencing Malabsorption
Factors Neurologic factors
Surgical factors
Postoperative Course / Severity of Illness

Potentially
Modifiable Energy Balance
Factor

Conceptualization of the potential components and processes having an effect on growth in

infants following neonatal surgical intervention for CHD

29
CHAPTER 2

Part 1

Growth Velocity over the First Year of Life Following Neonatal Surgery for

Congenital Heart Disease

Abstract

Background: Growth failure is well documented in infants with CHD. Poor growth in
infancy has an effect on cognitive and neurobehavioral development. Assessment of
growth velocity will identify infants at risk for growth failure.

Objective: To assess growth using World Health Organization (WHO) growth velocity
standards.

Study Design: A descriptive, a sub-analysis from a prospective, longitudinal study in a

large, metropolitan, cardiac center.

Methods: Infants with CHD were recruited following surgery. Healthy infants were from
primary practices and surrounding community. Growth measures were every 3 months.
WHO velocity z-scores were calculated. Student’s t-test was used to assess
differences between the groups.

Results: A total of 120 infants were included, 69 with CHD, 45% had SV physiology
and 55% with BV. There were 65% males, and 80% were Caucasian. Males and
females had statistically significant lower weight velocity z-score (males and females
p<0.001) for the birth to 3-month interval. In subsequent intervals there was no
difference in weight. Head circumference were different in velocity z-score only at the
birth to 3-month interval for males (males p<0.001; females (p<0.05). Other velocity z-
scores were not different.

Conclusion: Infants with CHD demonstrate poor growth velocity early in infancy. There
was no difference in growth velocity after the birth to 3-month interval. WHO growth
velocity standards are useful and may be more appropriate to assess growth patterns
for infants with CHD.

30
Definition of Terms

Term Definition

Bi-Ventricle (BV) Normal two-ventricle cardiac physiology

Congenital Heart Disease (CHD) Anatomic and/or physiologic abnormality

of the heart occurring in utero, present at
birth

Growth Failure Weight attainment or weight change

velocity that is significantly below
reference standards for age and gender

Growth Velocity Weight, length, head circumference

measured over time; assessed as
centimeters, grams, kilograms, or z-
score

Infant Child from 30 days to end of 12 month

Neonate Newborn child from birth to 30 days of

life

Postsurgical physiology Functional and anatomical physiology of

blood flow following surgical intervention
for congenital heart disease

Single Ventricle (SV) Cardiac defect with one functioning

ventricle for pulmonary and systemic
blood flow

Weight Attainment Weight measured at a point in time;

assessed as centimeters, grams,
kilograms

31
 Growth Velocity over the First Year of Life Following Neonatal Surgery for

Congenital Heart Disease

Introduction

Growth is often a gauge of an infant’s health, well-being and ability to thrive; it is

fundamental to pediatric healthcare. In the US, current American Academy of

Pediatrics guidelines recommend growth measurements at specified intervals to

monitor an infant’s growth progress.1,2 The first year of life is a period of rapid growth,

adequate nutrient intake is necessary to ensure acceptable weight gain, appropriate

increase in stature and support best potential for brain development. Alterations in

growth that occur during the first year and cause the infant to fall below reference

standards, may indicate growth failure and can have long-reaching consequences for

neurobehavioral development, cognitive function and school performance.3-6 Infants

with congenital heart disease (CHD), who have undergone surgery in the neonatal

period, often fall short of growth measurements that meet gender- and age-specific

reference standards, putting them at risk for consequences of the poor

neurodevelopment that can result from growth failure in early infancy.7-10

In 2006, the World Health Organization (WHO) introduced international child

growth standards consisting of z-scores and percentile curves for male and female

children aged 0 to 5 years.11 These standards describe how children should grow

versus a depiction of attained growth at a point in time. Experts agree that the WHO

standards represent the best physiologic growth for children under optimal

environmental conditions, with adequate nutrition, free of psychological, socio-

economic and ethnicity biases.11 As an adjunct to the growth standards, WHO

researchers developed growth velocity standards, introduced in 2009.12 Growth velocity

32
defined as the change in measure over time, accounts for the normal individual pattern

of variability characteristic of saltatory, catch-up or slow-down growth.12 Growth

velocity can be highly variable, despite this it is considered a superior assessment and

may prove to be more appropriate than attained growth values. It allows for early

detection of infants and children at risk of falling below reference growth trajectories.

To better understand growth and growth patterns of infants with CHD following

surgery in the neonatal period, we examined growth velocity using the WHO

standards.12 The aim of this study is to describe the velocity of growth for weight,

length, and head circumference over the first year of life in 3-month intervals for infants

with CHD following neonatal surgery as compared to healthy infants of similar age and

gender. Table 1 is a definition of terms and abbreviations.

Study Design and Setting

This is a descriptive sub-analysis from a convenience sample of a prospective,

longitudinal study conducted at The Children’s Hospital of Philadelphia (CHOP),

between March 2003 and May 2007. Study approval was obtained from the CHOP

Institutional Review Board, and informed consent was obtained prior to

commencement of study procedures.

Study Sample

Neonates were recruited from the Cardiac Intensive Care Unit at CHOP.

Healthy infants from primary care practices affiliated with CHOP and the community at

large served as the control group. Eligible participants were 36 weeks post-menstrual

age with birth weight of > 2,500 grams. Birth data were extracted from records that

accompanied the infant to CHOP or by parental report for healthy infants. Infants with

known or overt chromosomal abnormalities, multiple congenital and/or facial

33
anomalies, or complex gastrointestinal or congenital and/or acquired neurologic insults

were not eligible as these factors are associated with poor growth. Infants with CHD

were classified as single ventricle (SV) or biventricular (BV) physiology in the usual

manner.13 Race and ethnicity were assigned based on parent self-identification.

Study Methods

All study visits were conducted at CHOP in the Clinical and Translational

Research Center and the Nutrition and Growth Lab. Study measurements were

obtained by research personnel using standard protocol.14 Design of the larger study

included study visits in 3-month intervals beginning at 3-months of age through 12

months. Goal timing of study visits was set within 2 weeks before or after the infant’s

birth date. Infants who attended a minimum of two of five study visits, one being the 3-

month visit and had birth weight data were included in this analysis.

Weight was measured in kilograms (kg) using a Scale-Tronix (Scale-Tronix,

White Plains, NY, USA) infant pan scale, accurate to 5 gm. Recumbent length

measured in centimeters (cm) was obtained using an infant length board (Holtain

Limited, Crymuch, UK) accurate to 0.1 cm. Head circumference was measured using

a non-stretchable tape and measured to 0.1 cm (McCOY Health Science Supply,

Maryland Heights, MO, USA). Measurements were obtained in triplicate, and the

calculated mean used for analysis. Using WHO standards,11,15 measures of weight,

length, and head circumference were converted to z scores. Calculations for weight

growth velocity were calculated in four, 3-month intervals. Velocities for length and

head circumference were calculated for three intervals owing to incomplete birth data

for these measures.

34
Statistical Analysis

All analyses were completed using the SAS V9.2 (SAS Institute, Cary, NC)

statistical analysis program. Statistical significance was determined at the p<0.05 level.

Descriptive statistics of the means, standard deviations, medians, and minimum and

maximum values for each measure were calculated. Distribution plots were used to

assess normality of the data.

Velocity for each growth parameter for each infant for each time interval was

calculated using the equation:

unit of measure/day = Δ in growth parameter ÷ length of interval in days,

where the change (Δ) in growth parameter is the difference between the measured

weight, length or head circumference obtained at two contiguous study visits. That

change was then divided by the time interval in days between study visits. The result is

the unit of measure/day. An example of calculation for weight velocity is:

20.8 gm/day = 5800 gm – 3550 gm ÷ 108 days,

where 5800 gm is the 3-month visit weight, 3550 gm is the birth weight, 108 days is the

number of days between birth and the 3-month study visit, resulting in 20.8 gm/day

weight change over 108 days.

The next step was to correct the velocity to the specified 3-month interval of the

study protocol. This was done by multiplying the derived unit of measure by 91.2 to

account for months with 30 and 31 days. The result is a value representing the change

specific to a 3-month interval. Using the example above:

1897 gm over 3 months (total weight change) = 20.8 gm/day x 91.2 days.

The same procedures were repeated to calculate the velocity of length and head

circumference for each infant for each time interval.

35
 Velocity z-score for each growth parameter was then calculated using the WHO

equations12 based on 3-month intervals, 0 – 3, 3 – 6, 6 – 9, and 9 – 12, as specified in

the larger study protocol. To enable comparison of the groups, z-scores were

calculated using the lambda (L), mean (M), standard deviation (S), and delta values

specified in the WHO procedure for the 3-month intervals indicated.12 The WHO

velocity z-score was calculated using the equation:

12
,

where represents the growth parameter increment (weight, length or head

circumference) for t, the visit age interval; LMS values are from the WHO tables for 3-

month intervals by gender. Once velocity z-scores were calculated for all parameters,

two-sided Student’s t-test was used to compare differences at each interval between

healthy infants to infants with CHD by gender.

Results

There were 130 infants who met inclusion criteria. Three infants with CHD died

prior to study completion due to complications of their cardiac disease. Five healthy

infants did not have birth weight data and two families withdrew from study

participation. There were 120 infants included at the initiation of this analysis. Of these,

69 were infants with CHD, 31 (45%) with SV physiology, 38 (55%) with BV physiology;

51 were healthy infants. The distribution of diagnoses for infants with CHD is presented

in Table 2. Data are presented by gender with healthy infants compared to infants with

CHD, as small sample size did not permit examination of the data in infants with CHD

by physiology. The number of participants at each visit, for each measure and each

interval was determined. Study sample demographics are presented in Table 3. The

data are grouped and presented by growth parameter, illustrating the group mean,

36
WHO z-score, parameter measurement change over time and WHO velocity z-score

(Tables 4, 5, 6, and 7).

Birth weight in grams and z-score were not different among the groups. The

mean attained weight was significantly less for males with CHD compared to healthy

males (5517 gm, z-score -1.4, p<0.001) at 3-months, with a statistically significant

decreased weight change in the birth to 3 month interval (2015 gm, p<0.001). The

weight velocity z-score further demonstrated this decreased weight change, z-score

-1.82, p<0.001 compared to healthy males. This trend of decreased mean attained

weight continued and remained negative and statistically significant in males for each

time point (Table 6). There was a 20% drop in attendance from the 3-month to 6-month

visit and a 22% drop from the 6-month to 9-month visit. At 12 months, males with CHD

had 89% attendance, a 40% increase from the 9- month visit. The attained weight at 12

months although still significantly less than healthy in males (9398 gm, p=0.04) showed

improvement. There was no difference in weight change or weight velocity z-score

after the birth to 3-month interval.

Females with CHD demonstrated a statistically significant decrease in attained

weight (5422 gm, p=0.02) at the 3-month visit compared to healthy females. The birth

to 3-month interval weight change (1764 gm) and weight z-score velocity (-1.8) were

also significantly lower (p<0.001) than for healthy females. Attained weight, weight z-

score, weight change, and weight velocity z-score were not different between females

with CHD and healthy females at any other time point or interval. Females with CHD

represented the smallest number of participants at each study visit. Table 7 compares

healthy females to females with CHD for each growth parameter.

37
 Males with CHD demonstrated significantly lower attained length at each study

visit compared to healthy males; the length z-score, length change and length velocity

z-score were not different (Table 6). Head circumference showed a similar pattern to

weight in males with CHD compared to healthy males, with the exception of the 12-

month visit where attained head circumference was not different between the groups.

The head circumference velocity z-score for males (0.1) was negatively significant at

the birth to 3-month interval, p<0.01. No other intervals were different from those in

healthy males.

Length for females with CHD was not different from healthy females at any visit

or any time interval. The attained measure for head circumference in females with CHD

was significantly lower (39 cm, p<0.05) than in healthy females at the 3-month visit, no

difference was demonstrated in attained measurement, head circumference z-score,

head circumference change or head circumference velocity z-score for any other time

point or time interval. Females with CHD demonstrated a drop in attendance of 26%

from the 3 to 6-month visit, 29% from the 6 to 9-month visit and an increase of 43%

from the 9 to 12-month visit, which has a critical impact on the findings. In addition,

there was more than 20% missing data for each measurement across the study

critically affecting the findings and limiting the conclusions that can be derived.

Discussion

In this study, using the new WHO growth and growth velocity standards to

evaluate infants with CHD compared to healthy infants of similar age and gender, we

demonstrate decreased attained weight, decreased interval weight change and

negative weight velocity z-scores in both males and females with CHD at 3-months of

age. The small sample size and missing data necessitate cautious interpretation of

38
these findings. Despite this, these data give promise for better understanding of the

pattern of growth in infants with CHD who have undergone neonatal surgery.

Infants are expected to gain between 20 and 30 grams/day in the first 6

months of life following a physiologic weight loss in the first days of life up to and

exceeding 10%.16-18 This rate of growth is different in exclusively breastfed infants.17

From these data, it appears that on average infants with CHD are at the lower end of

this expected range for weight gain or do not meet it, particularly in the first 3-months of

life. In our study, males with CHD showed a mean weight change in the birth to

3- month interval of 2015 gm, approximately 22gm/day; the mean weight change in

healthy males was approximately 29 gm/day. Using the WHO growth velocity

standards, this change is equal to a weight velocity z-score of -1.82 and corresponds to

the 3rd to 5th percentile of weight velocity for age and gender. In the same birth to 3-

month period, females with CHD demonstrated a weight change of 19 gm/day

compared to 27 gm/day in healthy females; they too are in the 3rd to 5th percentile with

a corresponding weight velocity z-score of -1.8. For the birth to 3-month interval, both

females and males with CHD demonstrated growth velocity below the 5th percentile by

WHO standards. Although these are the mean values of the respective groups, it is the

low weight velocity z-scores in conjunction with low attained weight that are of concern.

These values represent significant growth failure at this time interval, supporting the

existing evidence that describes poor weight gain in infants with CHD in early infancy.

The attained weight in males with CHD remained statistically significant and below that

of healthy males throughout the study period. Following the birth to 3-month interval

weight change and weight velocity z-scores were not different for males or females

39
with CHD compared to healthy infants of the same gender, suggesting catch-up growth

occurs subsequent to 3-months of age.

Attained length for males with CHD was significantly below that of healthy

males at each study visit (Table 6) however, the change in length and length velocity z-

score were not different, suggesting that although length at 3-months of age is lower

than that in healthy infants, the rate of increase is the same. Length for female infants

with CHD was not different from healthy females in our study sample. Several studies

of infants with CHD report linear growth delay in early infancy, with catch up growth for

length commencing later in infancy and progressing at a slower rate than weight catch

up growth.10,19,20 These studies suggest that delayed attainment of length in infants with

CHD following neonatal surgery is reversible.

Head circumference is the best determinant of brain growth.21,22 In males with

CHD in our study sample, attained head circumference was decreased from that of

healthy males with no difference by 12 months of age. Females with CHD

demonstrated a negative statistically significant difference only at 3-months and only

for the attained head circumference measurement (39 cm, p=0.01); this finding is likely

skewed due to small sample size. Research suggests that prenatally, infants with CHD

have smaller brain volume and decreased brain growth; this low volume presents at

birth as small head circumference and may indicate global neurologic immaturity.21-23

This decreased brain volume and the potential for slow brain growth can have a direct

effect on neurodevelopment, cognition, and behavior in childhood.22,24

Monitoring growth parameters is an important component of care for infants and

young children, particularly infants with CHD who have undergone neonatal surgery.

Although limited, the data presented show significantly decreased growth in males and

40
females at 3-months of age with promise for catch up in late infancy. We used WHO

standards for growth11 and growth velocity12 to evaluate these data as it is believed

these standards provide a more precise assessment of how growth is occurring over

time compared to how it has occurred at a point in time. Ross and colleagues25

demonstrated a downshift or poor weight attainment in early infancy, at 2 to 4 months

of age, and found to be predictive of later poor growth despite an interval period of

growth recovery. These researchers suggest that healthcare providers use

acceleration and deceleration standards to identify patterns of growth in infants at risk,

initiate stringent monitoring procedures and provide early interventions for those infants

whose pattern of growth in early infancy suggests growth failure.25

Poor growth in early infancy has been associated with infant irritability, cognitive

impairments, delayed development of executive functions, developmental delay, poor

school achievement, and deficits in motor, speech and language skills.4,5,26,27 In a

population based study, Gale et al28 reported prenatal head growth and head growth

during infancy to be particularly important determinants for subsequent intelligence,

further, they found head growth after infancy did not appear to compensate for

decreased growth during infancy. McDougall et al4 studied over 1800 infants with

documented poor growth in the first months of life and found an association to

decreased intellectual ability and lower IQ at school age. These studies present

evidence of an association between poor growth in infancy and negative impact on

neurodevelopment and intelligence in childhood.

The data presented here, demonstrate growth failure in the infants with CHD.

Contributing factors that may have a role in poor growth evidenced in infants with CHD

include inadequate energy intake to promote a positive energy balance,29-32

41
gastrointestinal tract abnormalities,33,34 neurologic immaturity,21,23,35 and feeding

dysfunction.36-38 Regardless of the etiology, the potential short and long-term

consequences of poor growth can be detrimental to the infant and are a focus of

interest. Reviews of studies investigating neurobehavioral and neurodevelopmental

outcomes following surgery for CHD have consistently found reports of delay in

cognitive and motor development, attention deficits and altered development of speech

and language skills.6,39-41 These documented consequences of growth failure and the

impact they can exert on growth and long-term intellectual development are ample

cause to further investigate contributors to poor growth in this population and seek

viable interventions to minimize its occurrence.

Study Limitations

Limitations include this being a convenience sample from a single center with

high illness acuity of cardiac disease. There was a large amount of missing data

resulting in small sample size. Dietary intake records were not available to assess

energy intake simultaneously with growth in these infants. All birth data were parent

report or extracted from the transfer record that accompanied the infants with CHD.

Some bias may exist in that families who enrolled were motivated to participate in a

complex study protocol.

Conclusion

Poor growth is a common morbidity in infants with CHD who have undergone

neonatal surgery. In this study, the use of the WHO growth and growth velocity

standards presents a novel approach to examine growth in our cohort of infants with

CHD. We found a pattern of poor growth in the birth to 3-month interval across gender,

a time usually associated with rapid growth and development. From these limited data,

42
growth in all measures appears to begin catch-up following the initial interval of poor

growth. Further study with a larger sample is and fewer missing data points is

necessary for a better evaluation of these findings. However, these data are important

and may be the first to use the WHO growth velocity standards to evaluate growth in a

cohort of chronically ill infants. Use of this methodology may assist providers in early

identification of poor growth in infants with CHD following surgery in the neonatal

period and facilitate timely interventions to prevent or minimize growth failure,

decreasing the risk for and potential of negative cognitive and neurodevelopmental

sequelae associated with poor growth in early infancy, particularly in infants with CHD.

43
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49
Table 2 CHD Primary diagnosis of infants with Congenital Heart Disease

Primary Diagnosis Postsurgical Physiology

Single Ventricle Bi-Ventricle

% of N = 31 % of N = 38

Hypoplastic Left Heart Syndrome 59

Tricuspid Atrestia 16

Double Inlet Left Ventricle 6

L-Transposition of Great Arteries 3

D-Transposition of Great Arteries 6 47

Double Outlet Right Ventricle 3 3

Valvular Pulmonary Atresia 6 3

Coarctation of the Aorta 21

Tetrology of Fallot 11

Interrupted Aortic Arch 5

Truncus Arteriosus 2

Aortopulmonary Window 2

Valvular Aortic Stenosis 2

Total Anomalous Pulmonary Venous 3

Return

Distribution of diagnoses across sample of infants with CHD, with postsurgical cardiac
classification

50
Table 3 Study sample demographics

Healthy Infants Infants with Congenital Heart Disease

Single Ventricle Bi-Ventricle

N 51 31 38

Gender
Female 19 8 15
Male 32 23 23

Race
AA 13 4 -
Asian 1 - -
Caucasian 33 26 37
>1 2 - 1
Not Reported 2 1 -

Ethnicity
Hispanic 2 2 3
Non-Hispanic 42 21 25
Not Reported 6 8 9

Gender, race, and ethnicity distribution of study sample.

51
Table 4 Mean (SD) growth parameters, healthy females and males

Healthy Females Healthy Males

Time Birth 3 6 9 12 Birth 3 6 9 12

n 19 19 19 17 19 32 32 32 24 27

Age 98 194 270 374 93 191 276 370

0 0
(d) (15) (18) (11) (17) (9) (15) (14) (17)

Wta 3304 5984 7379 8376 9195 3576 6272 7969 9213 9952
gm (0.5) (0.8) (0.8) (1.0) (1.1) (0.6) (0.6) (1.0) (0.7) (1.0)

z- 0.1 -0.1 -0.1 0.1 0.1 0.4 -0.2 -0.1 0.3 0.2
score (1.1) (1.0) (0.9) (1.0) (0.9) (1.1) (0.8) (1.0) (0.6) (1.0)

Wt Δ, 2461 1419 903 918 2653 1570 1194 875

b (562) (393) (460) (303) (601) (404) (546) (377)
gm

Wt -0.3 -0.2 -0.2 0.6 -0.6 -0.1 0.5 0.3

c (1.1) (1.0) (1.3) (0.9) (1.1) (1.0) (1.7) (1.1)
z-vel

a
Lt 61 66 70 73 62 69 73 77
cm (2.8) (2.1) (2.3) (1.2) (2.4) (2.8) (3.0) (3.0)

z- -0.31 -0.0 0.3 -0.3 0.3 -0.0 0.6 0.3

score (1.3) (0.9) (1.3) (0.8) (1.1) (1.0) (1.3) (1.2)

Lt Δ, 5.5 -0.1 3.7 5.5 4.6 3.4

b
Gm (2.1) (1.0) (1.4) (2.1) (1.5) (1.3)

Lt -0.5 -0.3 -0.2 -0.2 0.3 -0.5

c
z-vel (2.0) (1.6) (1.5) (1.1) (1.5) (1.5)

a
HC 40 43 45 45 41 44 46 47
cm (1.4) (1.1) (1.3) (1.0) (1.3) (1.2) (1.1) (1.3)

z- 0.5 0.5 0.8 0.4 0.4 0.3 0.5 0.5

score (1.0) (0.8) (1.0) (0.7) (1.1) (0.8) (1.0) (1.0)

HC Δ, 2.7 1.8 0.7 2.7 1.7 1.2

b
Gm (0.5) (0.7) (1.3) (0.6) (0.6) (0.5)

HC -0.5 -0.3 -0.2 -0.2 0.3 -0.5

c
z-vel (2.0) (1.6) (1.5) (1.1) (1.5) (1.5)
*Weight for birth data only; Parameter means (SD), Parameter interval Δ (SD), Parameter
a b c

interval velocity z-score

52
Table 5 Mean (SD) growth parameters, females and males with CHD

Females with CHD Males with CHD

Time Birth 3 6 9 12 Birth 3 6 9 12

n 23 23 17 12 21 46 46 37 29 41
Age 99 192 272 375 96 189 277 380
0 0
(d) (16) (17) (12) (17) (13) (15) (16) (19)
a § ‡ ¥ ‡ §
Wt 3491 5422 6982 8217 9119 3396 5517 7257 8303 9398
gm (0.5) (0.7) (0.9) (1.0) (1.1) (0.5) (0.9) (1.0) (1.1) (1.1)

z- 0.0 -0.9 -0.6 -0.1 0.0 0.1 -1.4 -1.0 -0.7 -0.4
score (1.0) (1.0) (1.1) (1.0) (1.0) (1.0) (1.2) (1.1) (1.2) (1.1)

Wt Δ,
‡ ‡
1764 1524 1056 901 2015 1607 1080 833
b
gm (545) (246) (296) (424) (606) (347) (493) (506)
‡ ‡
Wt -1.8 0.1 0.3 0.5 -1.82 0.0 0.2 0.2
z- (1.3) (0.7) (0.8) (1.2) (1.2) (1.0) (1.4) (1.5)
c
vel
a ‡ ¥ ‡ §
Lt 60 66 71 74 60 66 70 75
cm (2.5) (3.4) (2.8) (3.0) (2.8) (2.5) (2.9) (2.8)

z- -0.4 -0.6 0.3 0.0 -0.4 -0.7 -0.8 -0.6

score (1.2) (1.4) (1.2) (1.1) (1.2) (1.1) (1.2) (1.2)

Lt Δ, 6.5 4.8 3.8 6.4 4.7 3.3

b
gm (1.3) (1.5) (1.2) (1.5) (1.0) (2.0)

Lt 0.5 0.4 -0.1 0.1 0.4 -0.2

z- (1.2) (1.5) (1.3) (1.3) (1.0) (1.4)
c
vel
a § ‡ § §
HC 39 43 45 46 40 43 45 46
cm (1.1) (1.0) (1.6) (1.6) (1.7) (1.4) (1.7) (1.6)

z- -0.34 -0.2 -0.4 0.0 -0.9 -0.3 -0.3 -0.0

score (1.1) (0.9) (1.3) (1.2) (1.4) (1.1) (1.4) (1.3)
§
HC 3.0 1.6 1.3 3.3 1.7 1.4
Δ, (0.4) (1.0) (0.7) (0.7) (1.0) (0.8)
b
gm
¥
0.5 0.4 -0.1 0.10.4 -0.2
HC (1.2) (1.5) (1.3) (1.3)
(1.0) (1.4)
c
z-vel
*Weight for birth data only; Parameter means (SD), Parameter interval Δ (SD), Parameter
a b c
§ ¥ ‡
interval velocity z-score; Student’s t-test significance levels p<0.05, p<0.01 p<0.001
53
Table 6 Mean (SD) growth parameters, healthy males and males with CHD

Healthy Males Males with CHD

Time Birth 3 6 9 12 Birth 3 6 9 12

n 32 32 32 24 27 46 46 37 29 41
Age 93 191 276 370 96 189 277 380
0 0
(d) (9) (15) (14) (17) (13) (15) (16) (19)
‡ ¥ ‡
Wta 3576 6272 7969 9213 9952 3396 5517 7257 8303 9398
§
gm (0.6) (0.6) (1.0) (0.7) (1.0) (0.5) (0.9) (1.0) (1.1)
(1.1)
z- 0.4 -0.2 -0.1 0.3 0.2 0.1 -1.4 -1.0 -0.7
score (1.1) (0.8) (1.0) (0.6) (1.0) (1.0) (1.2) (1.1) (1.2) -0.4
(1.1)
‡
Wt Δ, 2653 1570 1194 875 2015 1607 1080
b (601) (404) (546) (377) (606) (493) 833
gm (347)
(506)
‡
Wt -0.6 -0.1 0.5 0.3 -1.82 0.0 0.2
c (1.1) (1.0) (1.7) (1.1) (1.2) (1.4) 0.2
z-vel (1.0)
(1.5)
a ‡ ¥ ‡ §
Lt 62 69 73 77 60 66 70 75
cm (2.4) (2.8) (3.0) (3.0) (2.8) (2.5) (2.9) (2.8)

z- 0.3 -0.0 0.6 0.3 -0.4 -0.7 -0.8 -0.6

score (1.1) (1.0) (1.3) (1.2) (1.2) (1.1) (1.2) (1.2)

Lt Δ, 5.5 4.6 3.4 6.4 4.7 3.3

b
gm (2.1) (1.5) (1.3) (1.5) (1.0) (2.0)

Lt -0.2 0.3 -0.5 0.1 0.4 -0.2

c
z-vel (1.1) (1.5) (1.5) (1.3) (1.0) (1.4)

a ‡ § §
HC 41 44 46 47 40 43 45 46
cm (1.3) (1.2) (1.1) (1.3) (1.7) (1.4) (1.7) (1.6)

z- 0.4 0.3 0.5 0.5 -0.9 -0.3 -0.3 -0.0

score (1.1) (0.8) (1.0) (1.0) (1.4) (1.1) (1.4) (1.3)

HC Δ,
§
2.7 1.7 1.2 3.3 1.7 1.4
b
gm (0.6) (0.6) (0.5) (0.7) (1.0) (0.8)
¥
HC -0.2 0.3 -0.5 0.1 0.4 -0.2
c
z-vel (1.1) (1.5) (1.5) (1.3) (1.0) (1.4)
*Weight for birth data only; Parameter means (SD), Parameter interval Δ (SD), Parameter
a b c
§ ¥ ‡
interval velocity z-score; Student’s t-test significance levels p<0.05, p<0.01 p<0.001

54
Table 7 Mean (SD) growth parameters, healthy females and females with CHD

Healthy Females Females with CHD

Time Birth 3 6 9 12 Birth 3 6 9 12

n 19 19 19 17 19 23 23 17 12 21
Age 0 98 194 270 374 0 99 192 272 375
(d) (15) (18) (11) (17) (16) (17) (12) (17)

§
Wta 3304 5984 7379 8376 9195 3491 5422 6982 8217 9119
gm (0.5) (0.8) (0.8) (1.0) (1.1) (0.5) (0.7) (0.9) (1.0) (1.1)

z- 0.1 -0.1 -0.1 0.1 0.1 0.0 -0.9 -0.6 -0.1 0.0
score (1.1) (1.0) (0.9) (1.0) (0.9) (1.0) (1.0) (1.1) (1.0) (1.0)
‡
Wt Δ, 2461 1419 903 918 1764 1524 1056 901
b (562) (393) (460) (303) (545) (246) (296) (424)
gm
‡
Wt -0.3 -0.2 -0.2 0.6 -1.8 0.1 0.3 0.5
c (1.1) (1.0) (1.3) (0.9) (1.3) (0.7) (0.8) (1.2)
z-vel

a
Lt 61 66 70 73 60 66 71 74
cm (2.8) (2.1) (2.3) (1.2) (2.5) (3.4) (2.8) (3.0)

z- -0.31 -0.0 0.3 -0.3 -0.4 -0.6 0.3 0.0

score (1.3) (0.9) (1.3) (0.8) (1.2) (1.4) (1.2) (1.1)

Lt Δ, 5.5 -0.1 3.7 6.5 4.8 3.8

b
Gm (2.1) (1.0) (1.4) (1.3) (1.5) (1.2)

Lt -0.5 -0.3 -0.2 0.5 0.4 -0.1

c
z-vel (2.0) (1.6) (1.5) (1.2) (1.5) (1.3)

a §
HC 40 43 45 45 39 43 45 46
cm (1.4) (1.1) (1.3) (1.0) (1.1) (1.0) (1.6) (1.6)

z- 0.5 0.5 0.8 0.4 -0.34 -0.2 -0.4 0.0

score (1.0) (0.8) (1.0) (0.7) (1.1) (0.9) (1.3) (1.2)

HC Δ, 2.7 1.8 0.7 3.0 1.6 1.3

b
Gm (0.5) (0.7) (1.3) (0.4) (1.0) (0.7)

HC -0.5 -0.3 -0.2 0.5 0.4 -0.1

c
z-vel (2.0) (1.6) (1.5) (1.2) (1.5) (1.3)

*Weight for birth data only; Parameter means (SD), Parameter interval Δ (SD), Parameter
a b c
§ ‡
interval velocity z-score; Student’s t-test significance levels p<0.05, p<0.001
55
Figure 1 Weight velocity z-score by gender

Graph illustrating weight velocity z-score by gender in 3-month intervals.

Student’s t-test to compare healthy to infants with CHD of same gender: males -1.82, p<0.001;
females -1.80, p<0.001

56
Figure 2 Length velocity z-score by gender

Graph illustrating illustrating length velocity z-score by gender in 3-month intervals. Birth
length data not available. No difference between the groups. Student’s t-test to compare
healthy to infants with CHD of same gender.

57
Figure 3 Head circumference velocity z-score by gender

Graph illustrating head circumference velocity z-score by gender in 3-month intervals.

Birth length data not available. No difference between the groups. Student’s t-test to
compare healthy to infants with CHD of same gender.

58
CHAPTER 2

Part 2

Resting Energy Expenditure at 3-Months of Age in Infants Following Neonatal Surgery

for Congenital Heart Disease

Abstract

Background: Growth failure is well recognized in infants with Congenital Heart Disease
(CHD). Poor growth can impact physiologic and neurodevelopmental outcomes.

Study Aim: To determine resting energy expenditure (REE), body composition and
weight at 3-months of age in infants with CHD. A secondary aim was to identify
predictors of REE.

Design and Methods: Sub-analysis of a prospective, single center cohort with single
ventricle (SV) and bi-ventricle (BV) physiology. Anthropometric measurements, REE,
and body composition were obtained at 3-months. Analysis included chi-square for
association between categorical variables, t-tests, ANOVA and ANCOVA to compare
differences. Pearson’s correlation was used to examine linear relationships.

Results: Of the 44 infants with CHD, 18% had SV physiology. Infants with SV and BV
physiology had lower weight for age z scores compared to healthy infants -1.1 for SV
(p=0.001) and -1.0 for BV (p<0.005). Infants with SV and BV physiology had lower %
body fat compared to healthy controls (SV 23.7%; BV 22.7%) but had similar REE as
the control group. Fat free mass and infant age were positively correlated with REE.

Conclusion: Cardiac physiology was not a predictor of REE kcal in this study sample.
Infants with CHD had lower weight for age z score and decreased % body fat at 3
months of age. These data suggest that inadequate caloric intake contributes to growth
failure in infants with CHD.

59
Table 1 Definition of Terms

Abbreviation Term

BV Biventricular Physiology

CHD Congenital Heart Disease

FM Fat Mass, kg

FFM Fat Free Mass, kg

REE Resting Energy Expenditure, Kcal/day

%Sch Schofield equation percent predicted

SV Single Ventricle Physiology

%WHO WHO equation percent predicted

60
Introduction

Growth failure is well recognized in infants with Congenital Heart Disease

(CHD). Despite surgical intervention in the neonatal period, more than 50% of these

infants exhibit inadequate growth,1,2 with greater than 30% falling below the third

percentile for weight early in life.3 Poor somatic growth in infancy has the potential to

impact physiologic and neurodevelopmental outcomes well into childhood and

adolescence.4,5 The etiology of poor growth in infants following neonatal surgery for

CHD is likely multi-factorial and may in part result from inadequate energy intake or an

increase in energy expenditure, resulting in an energy imbalance. Strong correlations

have been demonstrated between growth failure early in life and long term cognitive

deficiencies, including poor arithmetic performance, attention deficit, aggressive

behavior and poor social and emotional development.4,5 We reported a high rate of

growth failure at hospital discharge in infants with both single ventricle (SV) physiology

and biventricular (BV) circulation following neonatal surgery.6,7 Poor weight gain in the

post-operative period prior to hospital discharge was associated with post-operative

complications, and timing of initiation of nutrient intake. These findings are similar to

other reports that suggest infants with CHD receive less than adequate caloric intake

to support normal weight gain and growth.8-14

There have been multiple investigations into the energy needs of infants with

CHD in the pre-operative and post-operative period. The results are mixed and may be

due to study design, small sample size, or a diverse sample of infants with cardiac

disease.15-23 The primary aim of this study was to determine whether there are

differences in resting energy expenditure (REE), body composition, and somatic

growth at 3-months of age in infants who have undergone neonatal surgery for CHD

compared to healthy infants, and whether differences are present among infants with
61
CHD classified postoperatively as SV versus BV physiology. A secondary aim was to

identify predictors of REE in infants with CHD compared to healthy infants.

Study Design and Setting

This is a sub-analysis from a prospective, cohort study investigating predictors

of growth in postoperative infants with CHD conducted at The Children’s Hospital of

Philadelphia (CHOP) from March 2003 through May 2007. Study approval was

obtained from the CHOP Institutional Review Board. Informed consent was obtained

from a parent or guardian of each participant prior to initiation of study protocol.

Sample Population

Study participants were recruited from the Cardiac Intensive Care Unit at

CHOP. Healthy infants served as the control group and were recruited from primary

care practices, and the community at large. Eligibility for all infants included post-

menstrual age > 36 weeks and birth weight > 2500 grams. Infants with CHD who

underwent cardiac surgical intervention during the neonatal period (first 30 days of life)

and did not have known multiple congenital, facial, chromosomal or complex

gastrointestinal anomalies or congenital and/or acquired neurological insults were

eligible. Infants were classified postoperatively as SV or BV physiology in accordance

with established standards.24 Race and ethnicity of the infants were assigned by the

parent’s self-identification. Families unable or unwilling to return to CHOP for study

visits were not enrolled.

Study Measurements

Measurements were obtained during the 3-month outpatient visit to the Clinical

and Translational Research Center (CTRC). The measurements were obtained by

research personnel according to standard protocol.25

Anthropometric Measurements
62
 Weight, length and head circumference measurements were obtained prior to

measurement of REE and body composition on all participants. Weight was measured

in kilograms (kg) using a scale accurate to 5 grams (Scaletronix, White Plains, NY,

USA). Infant recumbent length, was assessed using an infant length board (Holtain

Limited, Crymuch, UK) accurate to 0.1 cm and head circumference was measured

using a non-stretchable measuring tape accurate to 0.1 cm (McCOY Health Science

Supply, Maryland Heights, MO, USA). Measurements were obtained in triplicate, the

calculated mean was used in analysis. Birth weight was extracted from the transfer

records accompanying the infant to CHOP and by parental report for the control group.

All measurements were converted to z-scores using World Health Organization (WHO)

standards.26

Resting Energy Expenditure

REE was measured in the CTRC by open-circuit indirect calorimetry using a

canopy based computerized metabolic cart (Sensor Medic 2900 Z; Sensor Medics,

Yorba Linda, CA, USA) in a thermal-neutral, noise-restricted environment.

Measurements were performed during a minimum 30 minute period of infant sleep

following an ad libitum feeding of breast milk or the infant’s usual formula given within

one hour of the start of REE measurement. Infants who were device fed did not have

feeds infusing during REE measurement. In infants, sleeping energy expenditure is

used as a proxy for REE due to the practical considerations of measuring energy

expenditure.27-29 The metabolic cart measures infant respiratory gas exchange of

oxygen consumption (VO2) and carbon dioxide production (VCO2) in 1-minute intervals.

The initial period of infant adjustment and any period of significant movement that

altered REE were excluded from analysis. Studies with less than 15 minutes of usable

data were eliminated from analysis. The remaining data points were averaged and the
63
modified Weir equation30 was used to calculate the REE. The results of the measured

REE are expressed as kcal/day, and as a percent of the predicted values using

Schofield (%Sch)31 and WHO (%WHO)32 equations. The Schofield equation adjusts for

age, gender, weight and length, while the WHO equation adjusts for age, gender and

weight.

Body composition

Body composition was measured using the Total Body Electrical Conductivity

(TOBEC) instrument (TOBEC; model HP- Pediatric, 2 EM-SCAN, Springfield, IL), 33,34

TOBEC is based on a two-compartment model consisting of fat mass (FM) and fat free

mass (FFM). Infants were swaddled in a blanket to restrict movement with extremities

extended and held parallel to the trunk of the body. The swaddled infant was then

placed supine on the TOBEC sled. A minimum of five measurements were performed,

the mean FFM and FM in kg and % body fat are reported.

Statistical Analysis

Statistical analysis was performed using SAS V9.2 (SAS Institute, Cary, NC).

Infants with CHD were analyzed by SV and BV physiology classification to identify

differences between the groups. In addition, the SV and BV physiology groups were

compared separately to the healthy infants. Distribution plots were used to assess

normality of all variables. Chi-square was used to test the association between the

categorical variables. Descriptive statistics of the means, standard deviations, and

minimum and maximum values for the continuous variables and computation of

frequencies and percentages for categorical variables were calculated. Statistical

significance was determined at the p<0.05 level. Two sided t-tests were used to

compare mean differences in variables between the healthy and combined CHD

physiology group and between each of the CHD physiology groups and healthy infants.
64
In addition, the mean difference between the SV and BV CHD physiology groups were

compared using ANOVA. Possible linear relationships between all continuous

variables were examined using Pearson’s correlation coefficient. Additionally,

Pearson’s correlations were used to explore linear relationships between the

continuous variables and REE kcal/day, and to determine the independent variables to

be included in a model to predict REE kcal/day. Due to high correlation among many

of the independent variables, the number of covariates in the regression model was

restricted to minimize multicollinearity. ANCOVA models were constructed to examine

the differences in REE kcal/day for each CHD physiology group and among healthy

infants while controlling for particular continuous covariates. The least squares means

and the difference of the means were used to evaluate differences among the healthy

and the CHD physiology groups. The variance of inflation factor, a measure of the

degree of multicollinearity present in the model was used to assess collinearity among

the independent variables.35 All models tested had a variance of inflation factor <10,

indicating multicollinearity was minimal in the models constructed.

Results

The study group included 93 infants with REE and TOBEC measurements. Of

the44 infants with CHD, 17 (18%) had SV physiology and27 (29%) had BV physiology.

There were 49 (53%) healthy infants in the control group. The distribution of cardiac

primary diagnoses is presented in Table 1. Characteristics of the study sample are

presented in Table 2, and were similar between the control group, and the SV and BV

groups. Mean age was similar between the groups at the 3-month visit (Table 3).

Weight, length, head circumference (Table 3, Figure 1), and WHO z-score means were

all significantly lower (p<0.05) in both the SV and BV physiology groups when

compared to healthy infants, with the exception of length z-score of the BV physiology
65
group versus healthy infants (p=0.06). The SV and BV physiology groups only differed

in head circumference z-score; infants with SV physiology had smaller head size

(p=0.03).

The individual group means for REE kcal/day, %WHO REE, %Sch REE, FFM,

FM, and % fat are shown in Table 3. Compared to healthy infants (27%), infants with

SV (23.7%; p=0.04) or BV (22.7%; p<0.001) physiology had significantly lower % fat.

REE as %WHO predicted was significantly higher in infants with CHD than in healthy

infants (115, p=0.02). REE as %Sch predicted was higher in the BV group versus

healthy infants (112, p=0.02) but not in the SV versus healthy group. There were no

differences in REE or body composition between the SV and BV physiology groups.

From Pearson correlation analysis, REE kcal/day was significantly and

positively correlated with FFM (r=0.71, p<0.0001), FM (r=0.44, p<0.0001) and age in

days (r=0.31, p=0.003). From the multiple linear regression models, the best

predictors of REE kcal/day were FFM and infant age in days. The model that best

predicts REE kcal/day in this study sample includes FFM, age in days, and SV and BV

physiology and has an adjusted r2 =0.55 (Table 4). After adjusting for FFM and age in

days, the differences in REE kcal/day between infants with either SV or BV physiology

and healthy infants (reference group) were not significant. A model including FFM, FM,

age in days and physiology was examined; however, FM was not significant in the

presence of the other variables and did not contribute to the prediction of REE kcal/day

for infants with CHD.

Age was a significant covariate in each model tested. When age was removed,

retaining FFM, and SV and BV physiology, there was a decrease in variance from

r2=0.55 to r2=0.53 for predictors of REE kcal/day. An interaction term for SV and BV

physiology and FFM was tested but was not statistically significant, nor did these
66
interactions contribute to the prediction of REE kcal/day (data not shown). REE

kcal/day increased significantly with increasing FFM (kg) in this study sample, with no

significant difference found in the slope of this increase among the three groups

(healthy, SV, and BV).

Discussion

In this study, we evaluated REE at 3 months of age in infants who underwent

neonatal surgery for CHD compared to healthy infants. After adjusting for FFM and

infant age in days, there was no difference in REE kcal in infants with SV or BV

physiology compared to healthy controls. These findings do not support the clinically

held hypothesis that post-operative cardiac physiology is a primary factor causing an

increased REE kcal/day, contributing to delayed growth in infants with CHD. Instead,

these data demonstrate that body composition; specifically FFM and infant age were

strong predictors of REE kcal/day in our study sample.

As expected, the strongest and most consistent contributor to REE kcal in this

study was FFM. As the metabolically active component of body composition,

consisting of organs, muscles, skin, brain, bone, and supporting tissues, FFM is the

major contributor to REE kcal.36-38 An increased amount of FFM leads to an increased

REE per kg of body weight. The development of FFM during fetal life and early infancy

is environmentally regulated and is contingent on nutrient intake.39 In our study sample,

there was no difference in the mean FFM between the study groups. Despite its strong

positive correlation (r=0.44, p=<0.0001) to REE kcal, total FM in kg, the most variable

constituent of body composition in infancy was also not significant between the groups,

nor did FM significantly contribute to the model predicting REE after adjusting for FFM

and age.

67
 The rapid weight gain, common in early infancy is due in large part to an

increase in FM, which does not contribute significantly to REE kcal, likely related to the

modest metabolic activity of fat tissue.36,40 Although total FM in kg did not differ

between groups, % body fat was significantly lower in infants with CHD when

compared to healthy infants. At birth, full term neonates have approximately 14 - 15%

body fat.36 Fat accretion progresses rapidly in early infancy, and by 3 months of age,

male infants have 25-30% body fat, and female infants have as much 32%. .36,41 This

rapid increase in the typically developing infant results from a positive energy balance,

or energy intake that exceeds energy expenditure. Our data show the infants with CHD

to be below the expected % fat gains for age. The decreased weight z-scores in the

infants with CHD are primarily due to reduced FM rather than FFM suggesting

inadequate energy intake continues after hospital discharge.14 Insufficient energy

intake to support a positive energy balance will lead to loss of FM and a decreased

percentage of body fat per kg of body weight. This in turn commits a larger portion of

the infant’s body mass to metabolically active tissue, FFM, resulting in an increase in

REE kcal. Since the accretion of FM is directly related to energy intake, inadequate

caloric and nutrient intake in these infants was likely responsible for a reduced

accretion of fat and the decrease in % body fat. Our data show the infants with CHD

physiology to be below the expected % fat gains for age. Previous work reported poor

weight gain at hospital discharge,6,7 and findings of the current study demonstrate that

poor weight gain persists between hospital discharge and 3 months of age. Modest

improvement in caloric intake in infants with CHD will likely improve growth since there

is no demonstrated burden of an excessive use of energy related to cardiac

physiology.

68
 Interestingly, we found infant age to be highly significant in the regression

model (p=0.0006). The wide age range in this study sample across all groups (71 –

140 days) may account for the significance of age in the model. In multiple models

tested, infant age was consistently a significant covariate. These findings are similar to

those of Puhakka et al19 who also found age to be a significant predictor of REE kcal,

in their cohort of 25 subjects with CHD whose ages ranged from 2-months to 10 years.

In the last two decades, we identified nine studies examining REE kcal in

infants with CHD.15-23 A review of these studies and others by Nydegger and Bines42

identified poor growth as a common occurrence in this patient population. Our study is

unique in its approach to understanding energy expenditure in infants with CHD

following neonatal surgical intervention. We compared a healthy control group to

infants with CHD who underwent surgical intervention in the neonatal period, body

composition was measured in all subjectsat 3 months of age, and all subjects with

CHD were in their usual state of health at the time of study measurement.

Current clinical recommendations of energy requirements for healthy infants at

3 months of age are approximately 95 kcal/kg/day across gender irrespective of

formula or human milk intake.43 This recommendation is to provide a positive energy

balance in an infant of appropriate size and body composition to support growth and

activity compatible with good health.44,45 Our data demonstrate statistically significant

differences in kg weight and weight z-score at 3 months of age in infants with CHD

compared to healthy infants, this difference is primarily due to reduced percent body

fat. This deficit suggests that a moderate increase in caloric intake supporting the

accretion of FM may increase the% body fat to meet energy requirements in infants

with CHD, thus improving growth and development and decreasing the potential risks

69
of delayed neurobehavioral development, morbidity and mortality associated with poor

growth in infancy.45,46

Study Limitations

Study limitations included this being a single center cohort study our results

cannot be generalized. A major limitation of this study is lack of caloric and nutrient

intake data. Birth weight was obtained from the transfer record or from parent report

and are not as accurate or reliable as those obtained at 3 months of age in the

research setting. Lastly, there may be bias in that the families of infants who were

sicker did not return for testing.

Conclusion

Our findings refute the commonly held clinical view that postoperative cardiac

physiology is a major factor in determining the energy expenditure of infants with CHD

following neonatal surgical intervention. Infants with CHD had decreased weight z-

scores and percent body fat at 3 months, which is attributable to inadequate energy

intake and not post surgical cardiac physiology. These data suggest intermittent

measurements of body composition to accompany incremental growth measures may

provide better information on growth and have far-reaching implications for healthcare

providers to intercede in the nutritional support of those infants with CHD at risk for

growth failure.

70
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disease. Pediatr Crit Care Med. 2010;11(4):496 - 501.

16. Farrell AG, Schamberger MS, Olson IL, Leitch CA. Large left-to-right shunts

and congestive heart failure increase total energy expenditure in infants with

ventricular septal defect. The American Journal of Cardiology. 2001;87(9):1128-

1131.

17. Avitzur Y, Singer P, Dagan O, et al. Resting energy expenditure in children with

cyanotic and noncyanotic congenital heart disease before and after open heart

surgery. JPEN J Parenter Enteral Nutr. January 1, 2003 2003;27(1):47-51.

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18. Leitch CA, Karn CA, Peppard RJ, et al. Increased energy expenditure in infants

with cyanotic congenital heart disease. Journal of Pediatrics. 1998;133:755 -

760.

19. Puhakka K, Rasanen J, Leijala M, Peltola K. Metabolic Effects of Corrective

Surgery in Infants and Children with Congenital Heart Defects. British Journal of

Anaesthesia. 1993;70:149 - 153.

20. Gebara B, Gelmini M, Sarnaik A. Oxygen consumption, energy expenditure,

and substrate utilization after cardiac surgery in children. Critical Care

Medicine. 1992;20(11):1550 - 1554.

21. Ackerman I, Karn C, Denne S, Ensing G, Leitch C. Total But Not Resting

Energy Expenditure is Increased in Infants with Ventricular Septal Defects.

Pediatrics. 1998;102(5):1172 - 1177.

22. Li J, Zhang G, Herridge J, et al. Energy expenditure and caloric and protein

intake in infants following the Norwood procedure. Pediatr Crit Care Med.

2008;9(1):55 - 61.

23. Nydegger A, Walsh A, Penny DJ, Henning R, Bines JE. Changes in resting

energy expenditure in children with congenital heart disease. Eur J Clin Nutr.

2007;63(3):392-397.

24. Rhodes L, Colan S, Perry S, Jonas R, Sanders S. Predictors of survival in

neonates with critical aortic stenosis. Circulation. 1991;84:2325 - 2335.

25. Lohman TG, Roche AF, Martorell R. Anthropometric Standardization Reference

Manual. Champaign, IL: Human Kinetics Books; 1988.

26. World Health Organization. WHO Anthro (version 3.2.2, January 2011) and

macros. Child Growth Standards 2011. Accessed 5/6/2011.

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27. Reichman C, Shepherd R, Trocki O, Cleghorn G, Davies P. Comparison of

measured sleeping metabolic rate and predicted basal metabolic rate during the

first year of life: evidence of a bias changing with increasing metabolic.

European Journal of Clinical Nutiriton. 2002;56:650-655.

28. Butte N, Wong W, Ferlic L, Smith E, Klein P, Cutberto G. Energy Expenditure

and Deposition of Breast-Fed and Formula Fed Infants during Early Infancy.

Pediatric Research. 1990;28(6):631-640.

29. Wells JCK, Joughin C, Crisp JA, Cole TJ, Davies PSW. Comparison of

measured sleeping metabolic rate and predicted basal metabolic rate in the first

year of life. Acta Paediatrica. 1996;85:1013 - 1018.

30. Weir J. New methods for calculating metabolic rate with special reference to

protein metabolism. The Journal of Physiology. 1949;109:1 - 9.

31. Schofield W. Predicting Basal Metabolic Rate, New Standards and Review of

Previous Work. Human Nutrition: Clinical Nutrition. 1985;39C(Suppl):1, 5 - 41.

32. World Health Organization. FAO/WHO/UNU Expert Consultation. Energy and

protein requirements: technical report series #724. pp 71-112. Geneva1985.

33. de Bruin NC, Westerterp KR, Degehart HJ, Visser KHA. Measurement of Fat-

Free Mass in Infants. Pediatric Research. 1995;38(3):411 - 417.

34. Fiorotto M, Klish W. Total body electral conductivity measurements in the

neonate. Clinical Perinatology. 1991;18(3):611 - 627.

35. Robinson C, Schumaker RE. Interaction Effects: Centering, Variance Inflation

Factor, and Interpretation Issues. Multiple Linear Regression Viewpoints.

2009;35(1):6-11.

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36. Bechard LJ, Wroe E, Ellis K. Body Composition and Growth. In: Duggan C,

Watkins JB, Walker WA, eds. Nutrition in Pediatrics. Shelton, Connecticut:

People's Medical Publishing House; 2009:27 - 37.

37. Zemel BS, Barden E. Measuring Body Composition. In: Hauspie RC, Cameron

N, Molinari L, eds. Methods in Human Growth Research. Cambridge, UK:

Cambridge University Press; 2004:141 - 176.

38. Illner K, Brinkmmann G, Heller M, Bosy-Westphal A, Muller MJ. Metabolically

active components of fat free mass and resting energy expenditure in nonobese

adults. Am J Endocrinol Metab. 2000;278:E308 - E315.

39. Butte N, Wong W, Hopkinson J, Heinz C, Mehta N, Smith E. Energy

requirements derived from total energy expenditure and energy deposition

during the first 2 y of life. American Journal of Clinical Nutrition. 2000;72:1558-

1569.

40. Bresson JL. Energy Metabolism and Requirements in Health and Disease. In:

Duggan C, Watkins JB, Walker WA, eds. Nutrition in Pediatrics. Shelton,

Connecticut: People's Medical Publishing House-USA; 2009:417 - 430.

41. Roche AF, Shumei SS. Human Growth: Assessment and Interpretation. New

York: Cambridge University Press; 2003.

42. Nydegger A, Bines J. Energy metabolism in infants with congenital heart

disease. Nutrition. 2006;22:697 - 704.

43. Joint FAO/WHO/UNU Expert Consultation. Human energy requirements.

Rome: United Nations University; 2001.

44. Butte N. Energy requirements of infants. Public Health Nutrition.

2005;8(7A):953-967.

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45. Butte N. Energy Requirements of Infants and Children. Paper presented at:

Nestle Nutrition Workshop Series. Paediatric Programme2006.

46. Bjarnason-Wehrens B, Dordel S, Schickendantz S, et al. Motor development in

children with congenital cardiac diseases compared to their healthy peers.

Cardiology of the Young. 2007;17:487 - 498.

76
Table 1 Congenital Heart Disease diagnoses of study sample

Single-Ventricular Bi-Ventricular
% of n = 17 % of n = 27

Hypoplastic Left Heart Syndrome 76

Double Outlet Right Ventricle 12
Tricuspid Atresia 6
Valvular Aortic Stenosis 6
D-Transposition of Great Arteries 33
Coarctation of the Aorta 22
Tetralogy of Fallot 19
Valvular Pulmonary Atresia 7
Total Anomalous Pulmonary Venous
7
Return
Interrupted Aortic Arch 4
Ventricular Septal Defect 4
Double Inlet Left Ventricle 4

Primary diagnoses with post-operative physiology classification, depicted in percent of

total subjects for each category.

77
Table 2 Sample characteristics of healthy infants and infants with Congenital Heart
Disease.

Healthy
Infants with Congenital Heart Disease
Infants
Single
All Bi-Ventricle
Ventricle
n 49 44 17 27
Gender (%)
Male 63 61 71 56
Female 37 39 29 44
Race (%)
African American 27 7 6 7
Asian 2 0 0 0
Caucasian 65 91 94 89
Other 6 2 0 4
Ethnicity (%)
Latin/Hispanic 6 9 6 11
Non Latin/Hispanic 88 68 82 59
Other 6 23 12 30

Birth Weight
kg 3.4 ± 0.5 3.4 ± 0.4 3.5 ± 0.3 3.3 ± 0.5
z-score 0.2 ± 1.0 0.2 ± 1.0 0.5 ± 0.6 0.0 ±1.0

Sample distribution for gender, race and ethnicity with birth weight.

78
Table 3 Growth, body composition and resting energy expenditure in all subjects at 3
months of age. *

Healthy
Infants with Congenital Heart Disease
Infants
Single
All Bi-Ventricle
Ventricle
n 49 44 17 27

Age at visit, days 95 ± 13 96 ± 13 99 ± 15 93 ± 11

Weight
kg 6.1 ± 0.8 5.6 ± 0.9 ** 5.6 ± 1.0 ** 5.5 ± 0.7 **
z-score -0.3 ± 1.0 -1.1 ± 1.1 *** -1.1 ± 1.1 ** -1.0 ± 1.0 **
Length
cm 61.4 ± 2.8 59.8 ± 2.3 ** 60.1 ± 2.1 59.6 ± 2.5 *
z-score 0.0 ± 1.2 -0.7 ± 1.1 * -0.8 ± 0.9 * -0.6 ± 1.2
Head
Circumference
cm 40.8 ± 1.3 39.7 ± 1.5 *** 39.2 ± 1.6 *** 40.0 ± 1.3 **
z-score 0.3 ± 0.9 -0.6 ± 1.2 *** -1.1 ± 1.3 *** -0.2 ± 1.1 *§

Fat-free Mass, kg 4.4 ± 0.5 4.3 ± 0.5 4.2 ± 0.5 4.3 ± 0.5
Fat mass, kg 1.7 ± 0.5 1.3 ± 0.4 1.4 ± 0.5 1.3 ± 0.3
% Fat 27.0 ± 5.0 23.1 ± 5.1 ** 23.7 ± 5.5 * 22.7 ± 4.9 **

REE Kcal/day 328 ± 52 324 ± 55 325 ± 59 322 ± 54

Schofield, %
105 ± 13 112 ± 13 * 111 ± 14 112 ± 12 *
predicted
WHO, %
104 ± 13 115 ± 14 ** 115 ± 17 * 114 ± 12 *
predicted

*Results shown are means + SD. Significance levels *p<0.05, **p<0.01, ***p<0.001
show healthy infants compared separately to the combined and with each CHD
physiology group; §p<0.05 depicts significance comparing the SV and BV CHD groups.

79
Table 4. Regression model of covariates with strongest contribution to REE kcal/day

Parameter Standard Error t value p r2

Intercept -95.2 41.6 -2.3 0.02 0.55

FFM, kg 72.7 7.3 9.8 <0.0001
Age, days 1.6 0.3 3.6 0.0006
SV 7.6 10.3 0.7 0.5
BV 8.3 8.7 1.0 0.3

n = 93

Model depicting contribution of FFM, age and cardiac physiology to REE kcal/day.
Healthy infants are the reference group.

80
Figure 1 Box plot graph of growth measures at 3 months of age.

1
Z Score

-1

-2

-3

-4

SV BV Healthy SV BV Healthy SV BV Healthy

Weight Length Head Circumference

Legend:
N for each group: SV – 17, BV – 27, Healthy – 49.

81
 Figure 2 Regression line of REE kcal/day for fat-free mass (FFM), kg from TOBEC

550

500

450
d/l K EER

400

350

300

250

200
3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5

FFM, Kg

Legend:

Single Ventricle Biventricle Healthy

The predicted line is calculated from an ANCOVA model using REE kcal/day as the
dependent variable with FFM and physiology as independent variables.

82
CHAPTER 3

The Use of Indirect Calorimetry (IC) to Measure Energy Needs in Mechanically

Ventilated Children with Acute Lung Injury

(Submitted as NIH Director’s Early Independence Award Application)

Abstract

Acute Lung Injury (ALI) is associated with significant morbidity and mortality in

critically ill children. Annually, between 2,500 and 9,000 children are diagnosed with

ALI, a condition of lung injury marked by diffuse pulmonary inflammation that leads to

hypoxemia and respiratory failure. Characterized by acute onset, severe arterial

hypoxemia, and diffuse bilateral pulmonary infiltrates, ALI can quickly progress,

requiring mechanical ventilation for respiratory support and inciting a metabolic stress

response. If not halted, these physiologic reactions to stress prolong healing and

increase the risk for complications. In a critical illness such as ALI, optimal nutrition

support is essential to diminish the metabolic response, support immune function,

promote tissue repair, prevent loss of lean muscle mass, and eliminate weight loss.

Current clinical practice uses prediction equations derived from measurements of

healthy children and adults. These equations tend to over- or underestimate energy

needs and risk over- or underfeeding, threatening clinical outcomes. We purport that

the use of Indirect Calorimetry (IC) to measure energy needs is superior to prediction

equations and in fact, can help improve current nutrition management for critically ill,

mechanically ventilated children with ALI. Our study will test the efficacy of using IC to

accurately measure energy needs to the current practice of prescribing caloric needs

based on the use of prediction equation calculations in critically ill, mechanically

ventilated children with ALI. We hypothesize that compared to the use of standard

prediction equations, energy requirements derived from IC measurements will improve

83
clinical outcomes, measured by increase in ventilator-free days, decreased weight loss,

decreased loss of lean body mass, and decreased length of pediatric intensive care

admission with an overall reduction in the length of hospitalization.

Specific Aim

ALI is associated with significant morbidity and mortality in critically ill children.

Annually between 2500 and 9000 children are diagnosed with ALI,1 a condition of lung

injury marked by diffuse pulmonary inflammation that leads to hypoxemia and

respiratory failure.1-6 Characterized by acute onset, severe arterial hypoxemia, and

diffuse bilateral pulmonary infiltrates, ALI can quickly progress, requiring mechanical

ventilation for respiratory support and inciting a metabolic stress response.1 This

metabolic response uses endogenous energy stores to provide for basic metabolic

needs and support the ongoing stress response.7-10 If not halted, these physiologic

reactions prolong healing and increase the risk for complications. In a critical illness

such as ALI, optimal nutrition support is essential to diminish the metabolic response,

support immune function, promote tissue repair, prevent loss of lean muscle mass, and

eliminate weight loss.7,11 Research suggests that 16–20% and as high as 50% of

critically ill children demonstrate significant protein energy malnutrition (PEM) within 48

hours of admission, with continued deterioration during hospitalization.10-14 Current

clinical practice using prediction equations derived from measurements on healthy

children15,16 will likely over or underestimate energy needs, risking over or underfeeding

and threatening clinical outcomes.15 We propose the use of IC to measure energy

needs, which research suggests is superior to prediction equations to assess energy

requirements and improve current nutrition management for critically ill, mechanically

ventilated children with ALI. To improve clinical outcomes and decrease length of

hospital stay providing specific caloric goals are vital to counter the metabolic response
84
to critical illness, increase ventilator-free days, minimize loss of lean muscle mass, and

diminish weight loss for critically ill, mechanically ventilated children with ALI.17

Innovation and Impact

The caloric needs of critically ill children with ALI are related to the energy

burden imposed by the metabolic response to the inflammatory process and the

severity of illness.7,18 We suggest that measurement of energy expenditure by IC will

prove to be an accurate method to assess energy needs of critically ill children with

ALI. Current practice, the use of standard prediction equations with or without a stress

factor, are likely to over or underestimate energy requirements in critical illness,14,19-23

with the potential to prolong mechanical ventilation, increase the risk of infection, and

extend hospitalization due to prolonged recovery.24 To date, we are not aware of

clinical investigation assessing energy requirements for a specific disease in critically

ill, mechanically ventilated children in an intensive care unit. This study may reveal

energy requirements not previously acknowledged by critical care providers for

critically ill children with ALI. Indirect Calorimetry can provide precise information about

energy needs for children with ALI to optimize nutrition support and minimize the

caloric imbalances often incurred from use of prediction equations. This approach to

energy needs assessment has high potential for clinical implementation and has the

capability to shift clinical practice paradigms of nutrition management in the Pediatric

Intensive Care Unit (PICU) environment. Our study will test the efficacy of IC in

critically ill, mechanically ventilated children with ALI to assess energy requirements

and inform prescription for caloric goals. IC will be assessed during the acute, plateau,

and weaning phase of mechanical ventilation. In contrast to prediction equations,

accurate measurement of energy expenditure can provide more precise information to

determine specific caloric needs, inform clinical practice and assist decision-making for
85
nutrition support. This randomized, controlled clinical trial will compare IC

measurements to the current clinical practice, use of prediction equations to determine

energy needs, and examine outcomes specifically related to critical illness and

mechanical ventilation in children with ALI.

Primary Aim

To compare the effect of using Indirect Calorimetry to determine energy

requirements in critically ill, mechanically ventilated children with Acute Lung Injury to

the current clinical practice of prescribing energy needs by the use of prediction

equation calculations.

Hypothesis

Compared to the use of standard prediction equations, energy requirements

derived from Indirect Calorimetry measurements for critically ill, mechanically ventilated

children with Acute Lung Injury will improve clinical outcomes as evidenced by:

1) Increase in ventilator-free days

2) Decreased weight loss

3) Decreased loss of lean body mass

4) Decreased length of Pediatric Intensive Care Unit hospitalization

Background and Significance

Acute Lung Injury

Acute lung injury (ALI) is a condition marked by diffuse pulmonary inflammation that

leads to hypoxemia and respiratory failure in both children and adults.1-6 It is associated

with high mortality, morbidity, and an increased use of intensive care resources with

significant financial burden.1-3 Characterized by acute onset, severe arterial hypoxemia

resistant to oxygen therapy, and diffuse bilateral pulmonary infiltrates without evidence

of left atrial hypertension, ALI has a variety of triggers and risk factors, the most
86
common being infection in the pulmonary airways and parenchyma.1,25 In the United

States, between 2,500 and 9,000 children are diagnosed with ALI annually, constituting

between 1– 4% of all Pediatric Intensive Care Unit (PICU) admissions.1,26 The high

volume of children with ALI, severity of the disease, and potential for increased

morbidity make this a suitable illness to investigate energy needs for a subgroup of

critically ill children requiring mechanical ventilation. Approximately 63% of children

have more than one risk factor for developing ALI, a rate similar to that found in

adults.25 These factors include direct lung injury (51% pulmonary infection, 12%

pulmonary aspiration, 3% near drowning) and indirect lung injury (43% sepsis

syndrome, 40% multiple transfusions in close proximity, 10% post-bone-marrow

transplantation, 8% non-thoracic trauma). Mortality associated with ALI is reported to

be as high as 18–35% in children.5 Due to the severity of the pulmonary disease,

children with ALI often quickly progress to respiratory failure requiring endotracheal

intubation and mechanical ventilation. The disease process and respiratory failure

activate an acute alteration in metabolic status and trigger initiation of the stress

response and the ensuing catabolism inherent in the process. Characteristics of the

disease, the ensuing respiratory failure requiring mechanical ventilation, the metabolic

stress response, and decreased energy intake put these children at risk for alterations

in energy balance, PEM and its consequences leading to a prolonged PICU stay and

extended hospitalization.1,4 Despite its frequency as a diagnosis in the PICU population

and its severity, we have not found an investigation specifically designed to assess the

energy needs of critically ill, mechanically ventilated children with ALI. The severity of

illness, metabolic response to lung injury, alterations in caloric requirements, and

decreased energy intake are dynamic factors that potentially make the use of standard

prediction equations inconsistent with actual energy needs; the use of IC is a more
87
accurate method to assess energy needs and prescribe appropriate caloric intake. It

follows that children with ALI requiring mechanical ventilation and supportive care will

benefit from early, accurate assessment of energy needs and nutrient prescription for

appropriate caloric goals to decrease the harmful effects of catabolism resulting from

the metabolic response to critical illness.

Metabolic Alterations in Critical Illness

Metabolic alterations that accompany critical illness occur in proportion to the

magnitude of the illness and the pre-illness nutrition status. It is not always possible to

predict the child’s response to illness owing to the range of illness onset, its intensity,

and its duration. The metabolic response to critical illness is variable, and includes

hormonal and cytokine profiles that influence the overall energy burden.7,10,27

Characterized by an elevation of serum hormone levels of insulin, glucagon, growth

hormone, and cortisol and combined with the release of catecholamines and cytokines,

the stress response results in catabolism of endogenous supplies of protein, fat, and

carbohydrates. This process provides energy for both basal metabolism and the

metabolic requirements incited by the presenting illness.10 Typically, the metabolic

response to stress induces muscle protein breakdown that results in increased

circulation of free amino acids, some of which are used for tissue repair. Those free

amino acids not used in repair are redirected through the liver and become involved in

the production of glucose through gluconeogenesis. The increase in circulating serum

glucagon levels may deplete the limited endogenous stores, increasing reliance on

gluconeogenesis from non carbohydrate substrates (e.g. lactate).10,27 In addition,

cytokines mediate fat metabolism, causing increased fatty acid oxidation, resulting in

hypertriglyceridemia and lipid intolerance. Ketone production results from lipolysis to

provide energy and protection for the brain to maintain its uninterrupted and large
88
supply of glucose.27 It is common for children to have a delayed response to nutrition

support, this predisposes them to develop malnutrition from the metabolic response to

stress faster than adults.8 The administration of exogenous substrate of glucose does

not stop gluconeogenesis, and alteration in carbohydrate metabolism continues;27

however, the combined provision of glucose and protein may blunt the process by

supporting protein synthesis.7 The ability to utilize exogenous energy substrate and

synthesize new proteins is a critical aspect of recovery from critical illness and

resumption of normal metabolic processes. The capability to accurately assess caloric

needs and prescribe appropriate energy goals may facilitate early protein synthesis.

Given these alterations in the metabolic process with critical illness, and the severity of

illness seen in children with ALI requiring mechanical ventilation, it is conceivable that

PEM would complicate the disease process, delay recovery, and increase the length of

hospitalization.15 Overall, the metabolic response in ALI results in increased protein

breakdown and lipid and glucose intolerance. This combination of reactions, along with

suboptimal nutrition support, puts the critically ill child at high risk for weight loss, loss

of lean body mass, and an exacerbation of malnutrition that can worsen disease

progression.10,27

Suboptimal Nutrition Support in Pediatric Critical Illness

Nutrition support during critical illness such as ALI is challenging. The potential

risk of malnutrition and caloric imbalance can lead to PEM, which is associated with

altered physiologic response(s), impaired cell-mediated immunity, and loss of lean

body mass.9,22 Acute PEM in critical illness is multifactorial, owing to the dynamic range

of metabolic alterations, the child’s age, and severity of illness.7,12,28 It is difficult to

determine if the degree of illness contributes to a poor nutrition status or if a poor

nutrition status contributes to the severity of illness. The metabolic response to critical
89
illness cannot be prevented solely by nutrition support; however, suboptimal nutrition

accompanied by critical illness may contribute to prolonged alterations in metabolism

and exacerbate the stress response.

The effects of PEM in critically ill children were noted over two decades ago by

Pollack et al,29 who demonstrated acute PEM in 16% of their heterogeneous sample of

50 children admitted to the PICU; the condition was associated with clinical instability,

increased use of PICU resources, and higher rates of mortality. More recently, Hulst

and colleagues30 demonstrated a cumulative energy deficit of 100 kcal/kg and a

cumulative protein deficit of 10 gm/kg, which explained 39% and 40% of the respective

change in kilogram weight and lean body mass in their cohort of 98 mechanically

ventilated children. Despite advances in clinical care, the challenges of nutrition

support for children during critical illness identified in the 1980s persist.7-9,29,31,32

The lack of recognition and knowledge by care providers to the unique and

complex energy needs of the critically ill child add to the challenges of providing

adequate caloric intake during critical illness.7,29 In a recent study of 33 PICU subjects

with various diagnoses, Mehta and colleagues15 demonstrated failure of physicians to

accurately predict the metabolic status of the children studied, supporting the idea that

providers are unaware of metabolic requirements in critical illness. The researchers

deduced this was a contributing factor to overestimation of energy needs and

subsequent overfeeding in their study sample.15 This lack of accuracy in energy

assessment puts critically ill children such as those with ALI at risk for overfeeding or

underfeeding, either of which can contribute to acute PEM and potentiate infectious

and non-infectious complications, alterations in normal physiologic response to illness,

additional use of PICU resources, increased financial burden and can add to morbidity

and mortality.7,12,13,15,33,34
90
 Lack of energy intake or underfeeding has been associated with gastrointestinal

mucosal atrophy, heightening the subject’s susceptibility to infection, delayed wound

healing, muscle weakness prolonging the need for mechanical ventilation, diminished

cardiac reserve, and immune system dysfunction.7,9,12,14,33,35,36 Alternatively,

overfeeding can result in increased carbon dioxide production prolonging mechanical

ventilation, alteration in hepatic function, and variation in glycemic control.7,8,12,17,33,36

Either condition can be potentially life threatening for the mechanically ventilated child

with ALI who has a compromised respiratory status. Studies suggest that critically ill

children who receive adequate nutrition support experience early physiologic stability

and improved outcomes.8,35 The American Society for Parenteral and Enteral Nutrition

(A.S.P.E.N.) acknowledges that investigations specific to critically ill children are

necessary to guide nutrition support.18,22 Recently published guidelines for nutrition

support in critically ill children concede the inaccuracy of predictive equations to

estimate energy needs and suggest further investigation on the use of IC as a method

to accurately assess energy expenditure and guide energy prescription for critically ill

children.15,22

Determining Energy Needs: Predictive Equations and Indirect Calorimetry

Energy requirements in children are derived from standard prediction

equations. The equations frequently used in pediatrics include those developed by

Harris-Benedict, Talbot, Schofield, the Food and Agriculture Organization/World Health

Organization/United Nations University (FAO/WHO/UNU), and the Recommended

Dietary Allowance (RDA) predictions.6,17,37,38 The Harris-Benedict equation was based

on measurements in 97 infants under one month of age and more than 200

adolescents.20,39 Talbot developed energy estimates from data obtained through

repeated measures on healthy infants and children (the same participants) combined
91
with previously published studies.40 Schofield refined the initial predictive equations,

including those developed by Talbot, and constructed equations using weight, height,

and gender across age groups.41-43 The RDA is an estimate of the minimum average

daily intake necessary to meet nutrient requirements of healthy individuals across

gender and age.38

Studies conducted in heterogeneous PICU populations have shown

incongruence between measured energy expenditure and prediction equations.

Thomson et al44 demonstrated inaccuracies between the Harris-Benedict and Schofield

equations when compared to measured energy expenditure in both healthy and ill

infants. Coss-Bu et al45 found large differences between the Harris-Benedict and Talbot

equations, with and without use of a correction stress factor, when compared to IC

measurements in critically ill, mechanically ventilated children. Briassoulis and

colleagues17 found energy expenditure measured by IC to be significantly lower than

energy expenditure derived from prediction equations. Other researchers have found

under and overestimation of energy needs when using prediction equations and

endorse the use of IC to accurately assess energy needs and prescribe realistic caloric

intake goals for critically ill children.1,9,19,23,24,33,46,47 Many of the studies cited do not

address assessment of body composition as part of IC measurement. However,

determination of body composition is necessary for the judicious interpretation of

prediction equations and IC measurement. It is the variation in fat-free mass that may

explain a large component of energy needs, in that energy expenditure may be

decreased in children with a higher percentage of fat-free mass per kilogram of body

weight.48 The respiratory quotient (RQ) is another important marker obtained from IC

measurement. The RQ thought to be indicative of substrate use is a ratio derived from

carbon dioxide production (VCO2) to oxygen consumption (VO2) with an acceptable

92
range of 0.85 to 1.0 in children. Used to substantiate the validity of IC measurements,

an RQ above 1.0 may indicate overfeeding, while less than 0.85 may be a sign of

suboptimal energy intake. Applicability of the RQ in critical illness is limited owing to

alterations in metabolism, a compromised respiratory status, and its reported low

sensitivity and specificity in both adults and children.28,49 De Klerk et al35 found the RQ

in mechanically ventilated, critically ill children to indicate underfeeding in 45% of their

study sample and overfeeding in 15%. These researchers suggest RQ measurements

combined with IC measurements may be a better approach to assessment of energy

needs in critically ill children.35

Current Practice for Derived Energy Requirements

Investigations into energy requirements in critically ill children overwhelmingly

suggest inaccuracy of prediction equations to estimate energy needs.17,22-24,33,46,47,50 In

a recent study by Mehta and colleagues19 there was poor agreement between

equation derived energy needs and IC measured energy expenditure, resulting in a

high incidence of overfeeding and underfeeding, in their study sample, based on the

equations alone. Challenges with the use of these equations lie in the fact that they are

based on demographics from healthy children under conditions of usual environment

and physical activity16 and they do not account for the shifts in energy requirements

that accompany critical illness. Energy normally used for tissue accretion and growth is

used for tissue repair and glucose generation in critical illness; there is minimal

physical activity; and there is a transient cessation of growth during critical illness that

alters energy requirements.7,16,17,30 The metabolic response that is proportional to the

severity of illness can trigger changes in energy metabolism that work to counteract the

stress response while simultaneously lending support to basal metabolic function7;

prediction equations cannot adjust for these changes. This is particularly true for
93
critically ill children with ALI whose energy needs may be significantly altered, and in

whom inaccurate assessment of needs may lead to overfeeding or underfeeding and

affect an already compromised metabolic and respiratory status. In the PICU at The

Children’s Hospital of Philadelphia (CHOP), energy requirements are derived by

prediction equations. Dedicated PICU nutritionists primarily use the RDA for children

less than 1 year of age and the World Health Organization (WHO) equation for children

over 1 year. If the child is overweight and a length or height measurement is available

the Schofield equation is applied, lastly, in the case of an older adolescent or young

adult the Harris-Benedict equation is used to calculate energy requirements (personal

communication: M. Nagel RD, LDN, CNSD, S. Seiple, RD, LDN, CNSD; January 12,

2011). Based on calculations derived by one of the aforementioned equations,

prescriptions for caloric intake are generated. The child’s progress is followed and

adjustments for energy needs are made based on clinical status, laboratory results,

and respiratory progress. The decision to increase calories by use of a stress factor is

made by the clinical nutritionist in discussion with the critical care team based on age,

history,and severity of illness. Using IC to determine specific energy requirements and

prescribing such for critically ill, mechanically ventilated children with ALI can achieve

optimal nutrition support and avoid caloric imbalances often incurred with the use of

prediction equations.

Research Design and Methods

Study Overview

This study is a two-group randomized, controlled clinical trial that compares

energy requirements derived from IC measurement of energy expenditure to the

current practice of energy requirements derived from standard prediction equations.

After obtaining informed consent, subjects diagnosed with ALI will be randomized to
94
either the study or control group. The study group will receive IC measurements in

addition to prediction equation calculation for energy requirements, versus the control

group who will maintain the current practice of sole use of prediction equation

calculations to derive energy needs. Prediction equations, as described above, will be

calculated for all study participants to evaluate differences between IC measured

energy needs and energy needs derived from prediction equations. Those participants

who receive IC measurements will have their prescription for energy intake based on

the IC measurement and will receive caloric intake based on this measurement for the

duration of the study period. Participants whose energy needs are assessed by

prediction equation will have energy intake prescriptions generated accordingly. All

intake will be recorded and assessed daily for caloric content and total fluid volume for

each child participating in the study. This will include all intravenous fluids, glucose

containing base solutions for medications (enteral or intravenous), and enteral or

parenteral nutrition. All participants will have anthropometric measurements of weight,

supine length, and head circumference (if 5 years of age or younger). In addition, 4

skinfold measures including subscapular, tricep, bicep, suprailiac, and a mid upperarm

circumference will complete the anthropometric data set. These measurements will be

obtained upon study enrollment, prior to each IC measurement and at PICU discharge

or day 28 of study participation, whichever occurs first. Study participation will end at

28 days regardless of whether the participant remains mechanically ventilated or

remains in the PICU. The Acute Respiratory Distress Syndrome network defines

ventilator-free days (VFD) as the number of days from study enrollment to day 28

during which there is unassisted spontaneous breathing for 48 consecutive hours.51 All

participants will receive usual PICU care for ventilator and supportive management.

Usual PICU care includes extubation readiness testing (see appendix).

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Figure 1 Randomization Schema

Eligibility and Recruitment

Study Setting

The sample will be drawn from children admitted to the PICU at CHOP. This is

an internationally recognized clinical, critical care research center with a 54-bed

multidisciplinary intensive care unit that admits more than 3,000 critically ill children

annually. Age of children admitted to the PICU ranges from neonatal (28 days) to 18

years. The RESTORE clinical trial (U01HL086622; U01HL086649; Principal

Investigator: Martha A. Q. Curley, RN, PhD) is currently recruiting intubated and

ventilated participants with acute respiratory failure from the PICU at CHOP. In the

most recent 18 months, 108 participants consented and enrolled, 37% of whom had a

diagnosis of ALI. These data support the feasibility of recruitment for the current

proposal.

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Study Sample

Children admitted to the PICU and diagnosed with ALI will be screened for

study eligibility and participation. Parents or legal guardians will be approached for

consent if their child meets study criteria. All participants will be children with a

diagnosis of ALI requiring mechanical ventilation, who are at least 44 weeks post

conceptual age but have not yet reached their 19th birthday. Given that all participants

will be intubated and mechanically ventilated, it is anticipated that subjects will not be

able to provide assent to participate in the study. The exclusion criteria are designed to

eliminate potential participants with conditions known to alter basal metabolism and/or

conditions that can lead to inaccurate IC measurement results. Study exclusion criteria

include infants less than 44 weeks post conceptual age owing to typical physiologic

changes of the premature newborn that require increased energy, children with chronic

pulmonary disease and those with known chromosomal abnormalities. In addition,

children with illnesses that result in a compromised respiratory or pulmonary status

known to have alterations in energy requirements at baseline or the presence of air

leak through chest tube(s) causing inaccurate IC measurements are ineligible for

enrollment.52 Table 1 specifies inclusion and exclusion criteria.

Randomization

Once informed consent is obtained, study participants will be randomized at

enrollment to receive IC measurements in addition to having energy needs calculated

with prediction equations (intervention group) versus current practice for use of

prediction equations alone. Randomization will be performed using a permuted block

design with random block sizes53 to ensure an equal allocation of participants to both

the intervention and control groups throughout the study. Allocation will be concealed

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using serially numbered, opaque sealed envelopes containing study assignments. The

randomization schema is presented in Figure 1.

Table 1 Inclusion and Exclusion Criteria

Inclusion Criteria Exclusion Criteria

• At least 44 weeks • Chromosomal abnormalities
postconceptual age but have (known or suspected)
not yet had their 19th birthday • Metabolic disorders (known or
suspected)
• Diagnosis of acute lung injury: • Congenital heart disease
Intubated and mechanically • Severe brain injury
ventilated with a ratio of partial (Glasgow coma scale <8)
pressure of arterial • Presence of chest tube(s) with air
oxygen((PaO2) to the fraction leak
of inspired oxygen (FIO2) of • Supported on extracorporeal
300), bilateral pulmonary membrane oxygenation (ECMO)
infiltrates, and no clinical or High Frequency Oscillatory
evidence of left atrial Ventilation (HFOV)
hypertension • History of/presence of oxygen
and/or diuretic dependent chronic
• Intubated with a cuffed or lung disease
uncuffed entdotracheal tube • Upper airway diseases
with negligible air leak ≤ 5% (e.g. bronchial / tracheomalacia,
difference between inspired • Neuromuscular respiratory failure
and expired tidal volumes (e.g. spinal muscular atrophy)
• Chronic ventilator dependence
• Agreement that continued
treatment is futile
• Concurrent participation in any
other clinical trial

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Power Analysis

Based on preliminary data, we estimate the overall median numbers of

ventilator-free days (VFD) in the control group to be 21, recognizing that these data are

skewed consequential to assigning zero VFD to participants censored at the end of

their stay. As such, group sample sizes of 50 each will achieve 80% power to detect a

difference of 3 days between the groups (21 verses 24 VFD). The estimated group

standard deviations are assumed to be 4.0, along with a significance level (alpha) of

0.01 to account for multiple outcomes. This calculation is based on a two-sided Mann-

Whitney U test.

Attrition

Although attrition is expected to be minimal in this study, we will enroll 10

additional participants in each group to accommodate for participant dropout. Some

parents may opt to withdraw their child from the study. In addition, some participants

may improve rapidly and not provide 3 data points while other participants may

become too ill for 3 data points, or may not be able to tolerate the recommended

calories prescribed from IC measurement. Data will be analyzed with an intention-to-

treat analysis. Based on these assumptions, a completed data point is defined as one

completed IC assessment, with anthropometric measures and participant capability to

tolerate the caloric load recommended by the IC measurement. Nutrition support can

be delivered via either the enteral or the parenteral route; either route may be used for

the IC recommended caloric load to meet study completion criteria.

Study Procedures

The following section includes a discussion of the research protocol for the

proposed study. The major variables, their measurement, and the data analysis plan

are presented. Study measurements are outlined in Table 2.

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Participant PICU Measurements

Measurements of weight, length, and head circumference are obtained by the

Principal Investigator (PI) and /or Research Assistant (RA), the results will be shared

with the clinical staff. Weight measured in kilograms will be obtained on all potential

participants on admission to PICU in weigh bed scales (Stryker Medical, Portage, MI)

or infant weigh cribs (Hard Manufacturing Company, Buffalo, NY). If not admitted to a

weigh bed or crib, a weight will be obtained on the appropriate infant pan scale

(Scaletronix, White Plains, NY) or sling scale (Scaletronix, White Plains, NY) for age

and size. Head circumference is measured on subjects 5 years of age or less (protocol

of CHOP Nutrition and Growth Lab) using a non stretch, fiberglass tape measure.

Three measures are taken repositioning the tape between each measure; the mean of

the measures is recorded and used in analysis. Supine recumbent heel-to-crown

length will be measured on all subjects using flexible, non stretch measuring tape and

a stabilization board at the foot to optimize measurement.

Anthropometric Measures

Body composition, total fat-free mass, fat mass, and percent body fat will be

assessed by 4 skinfolds and a mid upper-arm and mid calf circumference using

prediction equations adapted for children and adolescents.54,55 All anthropometric

techniques will follow those described by Lohman et al56 and be performed by a trained

research anthropometrist. Anthropometric measurements will be assessed prior to or

following each IC measurement. Skinfold thickness to 0.1 mm will be measured at the

subscapular, tricep, bicep, and suprailiac sites with a skinfold caliper (Holtain,

Crymych, UK) to assess subcutaneous fat stores. Mid upper-arm and mid-calf

circumference will be measured with a non-stretch fiberglass tape to 0.1 cm (McCoy,

Maryland Heights, MO). All measurements will be taken and recorded in triplicate with
100
the mean used in analysis. Lange and Holtain skinfold calipers, sliding calipers,

abdominal caliper, and anthropometer, and a knee-height measuring device for

assessment of short-term growth are used for measurements. Anthropometric

equipment is checked and calibrated before every assessment to assure proper

operation.

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Table 2 Study Measurements

104
Prediction Equation Calculation

The PI and the clinical nutritionist will calculate energy needs based on an

appropriate equation for the participant’s age, gender, weight, stature and clinical

status. The Schofield,41 WHO,57 and RDA58 equations are used most often in our PICU

at CHOP and will be used for this study Parameters to use in the calculations are

specified by the equation.

Fluid and Nutrient Intake

All nutritional and non-nutritional intake will be retrieved from the clinical flow

sheet as documented by the bedside nurse and recorded daily for each enrolled

participant. Caloric and fluid intake and fluid balance will be followed daily for the 28-

day study period. Prescriptions for nutrient intake based on the recommendations of

the clinical nutritionist and prescribed by the provider clinically responsible will be

checked in the electronic medical record order system and documented by the RA in

the study clinical database. With few exceptions, nutrition support can be delivered to

critically ill children by either the enteral or the parenteral route or both. The enteral

route is preferred as it is the most physiologic, allowing stomach and bowel digestion

and absorption of nutrients. In the critically ill child, however, enteral intake may not be

possible for various reasons. Following IC measurements, the clinical nutritionist will

reassess the initially prescribed intake and make adjustments as indicated for

participants in the study group. The adjusted recommendations for energy intake made

in accordance with the IC measurements

will be communicated to the responsible prescriber and prescription changes made

accordingly. All energy intake inclusive of changes will be recorded daily for all

participants.

Indirect Calorimetry Measurement

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 Using IC, resting energy expenditure (REE) and the respiratory quotient (RQ)

will be assessed during the participant’s acute phase, plateau phase, and weaning to

extubation phase of illness. Individual time points allow the intervention to be driven by

the participant’s clinical status. In the acute phase of ALI, which commences with the

onset of respiratory insufficiency, measured by an increasing ratio of the partial

pressure of arterial oxygen to the fraction of inspired oxygen (PF ratio), equal to 300

mmHg or less and requires ventilator support, is when alterations in metabolism may

be heightened. During this time, accurate assessment of energy requirements is

necessary to provide adequate calories to minimize loss of lean body mass and

minimize the catabolic effects that can occur with the metabolic stress response.

During the plateau phase, when ventilator settings have not escalated in the previous

24 hours, metabolic requirements may change and adjustment of caloric goals will

minimize the potential to over- or underfeed. At the point of weaning ventilator support

(the weaning phase) characterized by a progressive reduction in ventilator settings in

the preceding 24 hours, energy needs may again change, and an adjustment in

calories may be necessary.59

IC measurements will be obtained using a portable computerized metabolic cart

(Vmax SPECTRA (29s), Viasys Healthcare/Sensormedics, Yorba Linda, CA). The PI, a

pediatric critical care nurse practitioner, or a critical care trained physician will assess

the participant for hemodynamic and respiratory stability prior to initiation of IC

measurements. For the purposes of this study, respiratory stability is defined as no

escalation in ventilation within 4 hours of IC measurement, no ventilation changes

within 1 hour prior to IC measurement, acceptable oxygen saturation and end tidal

carbon dioxide levels (based on preceding 4-hour trend), equal bilateral breath sounds

with equal aeration and chest rise, absence of retractions, and no overt signs of
106
respiratory distress (cough, excessive movement, pain, etc). Participants will be

assessed for a leak in the ventilator circuit that is 5% or less between measured

inspiratory and expiratory tidal volumes. Pain will be assessed by the PI using the

Faces, Legs, Activity, Cry and Consolability (FLACC) scale,60 cross-checked with the

bedside critical care nurse and both scores recorded. A score of 0–3 indicating none to

mild pain is necessary for the IC measurement to commence. If the FLACC scale score

is 3 or greater, the IC measurement will be postponed until the participant is in a

resting, comfortable state.

A registered respiratory therapist (RRT) trained in the care of critically ill,

mechanically ventilated children at CHOP will be present for the duration of each IC

measurement. In mechanically ventilated participants, an adapter is used to attach the

flow sensor of the metabolic cart to the exhalation outlet of the ventilator. This adapter

will be secured by the RRT and the participant will be reassessed for continued stability

and any changes in respiratory or ventilation status. Anticipating the possibility of lung

volume loss with attachment of the adapter, usual PICU procedures for managing lung

volume loss will be instituted and followed. For the entirety of each IC measurement on

each participant, a respiratory therapist, a critical care nurse specially trained in the

care of critically ill children requiring mechanical ventilation, the PI, and/or a critical-

care-trained physician will be in attendance. Should the participant exhibit any sign of

distress or clinical instability during IC measurement, the assessment will be

immediately aborted. Usual PICU care for safety will be maintained during IC

measurement, including but not limited to checking security and patency of the

endotracheal tube, continuous electronic hemodynamic monitoring and continuous

observed patient assessment. During each IC measurement, the environment will be

controlled in the usual manner as that used during an invasive or high-risk procedure in
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the PICU. Previous studies have not reported any serious adverse events associated

with IC measurements in mechanically ventilated children or adults.17,19,35,45,61

Following a well-established protocol from the Nutrition and Growth Laboratory

of Dr. Virginia Stallings at CHOP, an age-appropriate fast according to institution

standards will be instituted prior to each IC measurement. Every attempt will be made

to perform IC measurements between 6 a.m. and 10a.m. with the participant resting

and pain-free. Once the specified assessments are complete and the participant

determined clinically stable for IC testing, a 60-minute test will be performed. In

accordance with Dr Stallings’ protocol, 60 minutes is necessary to allow collection of an

adequate number of time points to ensure technical quality of the test, allow a period of

steady-state to commence, and have enough time measurements to assure quality

data collection for each IC measurement. Steady-state is defined as a period of time

after the start of the measurement with 10% or less variation in VO2 and VCO2 and a

5% or less variation in RQ measurements.62-64 Data from the first 10 minutes and

during periods of significant physical movement, coughing or agitation are eliminated,

with the remaining data averaged for the mean REE and RQ. REE is then

electronically calculated using the modified Weir equation and expressed in

kilocalories. REE from IC is then compared to values derived from prediction equation

calculations. The WHO equation adjusts for age, gender and weight,57 while Schofield

adjusts for age, gender, weight, and height.41 Fat-free mass will be assessed from

skinfold measures to determine its contribution to the REE.

Study Burden

We anticipate minimal study burden as all measurements are planned during

admission in the PICU. The degree of burden will be in a family’s decision to

participate. The study procedures will not interfere with any usual PICU care or
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procedures nor will it prevent participants transferring out of the intensive care unit

once they are clinically stable.

Study Safety

Safety of study procedures will be monitored for all study participants. There will

be strict adherence to study protocol with continuous electronic hemodynamic

monitoring in addition to continuous observation during the IC measurement by a

critical care provider (PI or critical-care-trained physician), critical care RRT, and the

critical care nurse. PICU precautions for maintenance of lung volume will include the

use of inline adapters and all usual maneuvers to minimize loss of lung volume when

the participant is disconnected from the ventilator circuit. Should a decrease in lung

volume occur, usual PICU maneuvers for re-recruitment will be employed. Participants

are monitored for respiratory and hemodynamic stability as well as environmental

safety throughout each IC measurement and throughout the study period.

Measurement of Study Outcomes

Study outcome is to compare the effect of using IC to determine energy

requirements in mechanically ventilated children with ALI to the current practice of

prescribing energy needs by the use of prediction equations. IC measurements as

proposed are useful for directing prescriptions for energy intake. This, we propose, will

result in:

1) Increase in ventilator-free days(VFD)

Ventilator-free days, is a composite outcome that reflects duration of mechanical

ventilation. For this investigation, VFD will be used to reflect appropriateness of energy

intake prescription. The numbers of consecutive days after the endotracheal tube has

been removed up to study day 28 constitute the absolute number of VFD. Removal of

the endotracheal tube will be calculated from the first time the tube is continuously
109
absent for a minimum of 48 hours, with success defined as spontaneous breathing for

24 hours without support of mechanical ventilation.61 We expect to see a difference

between those nutrient prescriptions derived from IC measurements compared to

prescriptions derived from prediction equation calculations. The difference we propose

will manifest in a 20% increase in ventilator-free days in the study group compared to

the control group.

2) Decreased weight loss

Adequate caloric intake should minimize weight loss. There is an association between

cumulative energy deficit and decrease in weight-for-age z-score (0.06; 95% CI: 0.01 –

0.1).30 Participant weight is obtained on admission to the PICU and followed throughout

the study period. Although it is difficult to obtain weights during the course of acute,

critical illness, we will follow the trend and determine change from admission through

PICU discharge or study day 28, whichever occurs first.

3) Decreased loss of lean body mass

Appropriate energy intake should minimize loss of lean muscle mass. We expect that

sustained, appropriate intake will result in minimal breakdown of endogenous protein

stores. Hulst and colleagues30 demonstrate an association between cumulative energy

deficit and decrease in mid-upper arm circumference z-score (0.07; 95% CI: 0.009 –

0.1). We will follow anthropometric measurements to determine change in muscle

mass during the 28-day study period.

4) Decreased length of PICU hospitalization

With the use of IC to direct prescription for energy needs, participants should receive

appropriate intake during the PICU stay and experience a decrease in overall length of

hospitalization. Research has demonstrated that critically ill children who receive

appropriate nutrition support demonstrate increased physiologic stability and an earlier

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return to baseline health status, shortening the duration of the illness and decreasing

the length of hospitalization.35 We hypothesize that critically ill children with ALI

requiring mechanical ventilation who have energy needs assessed through the use of

IC and nutrient prescription based on IC data will demonstrate improved physiologic

status due to optimization of nutrition support, resulting in improved clinical outcomes

and decreased length of hospitalization in comparison to those children whose nutrition

was determined using standard prediction equations.

Overall Analysis Plan

Preparation of the Analysis Data Set

All primary and secondary outcomes will undergo 100% data audit against the

medical record. The data audit includes visual screening for missing data and

inconsistencies. All out-of-range values, inconsistencies, and missing data will

generate a query that will require examination of the participant’s medical record for

resolution. Preplanned construction of new variables will be conducted in accordance

with the study hypotheses and analysis plans. Variable transformation may be required

for interpretation and statistical analysis purposes.

Analysis Plan

The primary outcome for this study is the number of VFD in the two groups.

Secondary outcomes include a decreased loss of lean body mass (LBM) with weight

maintenance (baseline to day 28) and length of hospitalization. The median number of

VFD will be compared using the nonparametric Wilcoxon rank-sum (Mann-Whitney U)

test. Categorical demographic variables will be analyzed using the Chi-square test,

while differences in continuous demographic and secondary outcome variables (loss of

lean body mass and length of hospitalization) will be assessed with the two-sample

111
Student t test (for normally distributed data) or the Wilcoxon rank-sum test (non-normal

data). Baseline analysis will include the following:

1. Comparison of the two groups using descriptive statistics (measures of central

tendency [means and medians] and dispersion [standard deviations and

interquartile ranges] for continuous variables with frequency counts and marginal

percentages for categorical variables) will be computed for all study variables and

examined for marked skewing, outliers, and any systematic missing data.

Transformations will be undertaken as required.

2. Pearson product intercorrelations will be computed and examined for

multicollinearity.

Statistical significance will be set at the 0.05 level based on the two-tailed alpha

test. Data analysis will be performed using SPSS (SPSS Inc., Chicago, IL) and

SAS (SAS Institute, Inc., Cary, NC) statistical programs.

Training of Study Personnel

In the start-up phase (first 9 months of study year 1), all members of the study

team will be trained on the study protocol. In addition, the PI will be trained and quality

tested for reliability on use of the metabolic cart to perform the REE measurements.

Both the PI and the RA will be trained and tested for reliability and reproducibility in

obtaining skinfold measurements, overseen by Dr. Stallings. Procedures for screening

of potential participants, family approach, and the consent and enrollment process will

be developed and evaluated for completeness with support from Drs. Medoff-Cooper,

Curley, and Srinivasan. The RA will be trained in participant screening, confirmation of

eligibility, family approach and consent, data abstraction, and data entry into a

password-secured database. RA activities will be directed and supervised by the PI.

Table 3 depicts the proposed training and study timeline.

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Table 3 Estimated Timeline of Study Activity

Year 1 Year 2 Year 3 Year 4 Year 5

Hire RA; Develop 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4
databases, operations
manual, case report
forms; Complete IRB
process

PI, RA training
Participant screening,
enrollment, initiate
protocol, data collection,
data entry

Complete data entry, data

cleaning; Preliminary data
analysis

Final Data analysis

Dissemination of results

Responsible Conduct of Research

The PI has received and will continue to receive training on the ethical conduct

of research through various resources available at the University of Pennsylvania. The

University recognizes and takes responsibility for training the applicant in the area of

responsible conduct of research. The format for the education in the responsible

conduct of research will vary. Members of the training team will be available for formal

and informal problem-focused meetings. The applicant will meet face-to-face monthly

with Dr. Barbara Medoff-Cooper, to assure the understanding of informed consent,

have the opportunity to observe and debrief the deliberations of two different IRBs and

observe the peer review process. In addition, the applicant will have face-to-face

meetings with Dr. Medoff-Cooper regarding the conduct of research with families and
113
vulnerable populations and to ensure protection of human subjects. The PI will

continue to participate in the University of Pennsylvania School of Nursing weekly

Research Colloquia, which is conducted though the Office of Nursing Research. In

addition, the PI will have access to monthly meetings in the Divisions of Family and

Community Health and Biobehavioral Research at the School of Nursing. Topics of

these hour-long sessions include, but are not limited to: conflict of interest (personal,

professional, and financial), policies regarding human subjects, mentor/mentee

responsibilities and relationships, collaborative research (including collaborations

with industry), peer review, data acquisition and laboratory tools, scientific integrity,

research misconduct (and policies for handling misconduct), responsible authorship

and publication, contemporary ethical issues in biomedical research, the scientist as

a responsible member of society, Federal Assurances, Internal Review Board (IRB)

basics, monitoring grant spending research with vulnerable populations, and

academic integrity.

The PI has completed on-line education on HIPAA certification and Protection

of Human Research Subjects- Biomedical, which satisfies the university’s requirement

for human subjects’ research training in the biomedical sciences. In addition, the PI has

completed the Subject Oriented Training in the School of Medicine. These modules

include information on informed consent, vulnerable populations, records research,

FDA regulated research, and conflicts of interest. In addition, the PI has completed

courses in clinical and research ethics. Issues of responsible conduct are included in

coursework of two research methods courses (quantitative and qualitative methods).

These courses are required of the applicant during doctoral education.

Protection of Human Subjects

The study will seek recruitment of a representative proportion of males and

114
females indicative of the ethnic and racial distribution common to the PICU at CHOP.

All participants will be children who are at least 44 weeks post-conceptual age, but

have not yet had their 19th birthday, with a diagnosis of ALI and require mechanical

ventilation. The entire primary research team is trained and has extensive experience

in the care and clinical management of critically ill infants, children and adolescents. A

member of the research team will be available to communicate with enrolled families

and the PICU staff at all times to answer questions and explain procedures as

necessary. Weekend and off-hours coverage will be on a rotating basis.

Potential risks which would involve loss of lung volume during the IC

measurement, will be minimized by strict adherence to the study protocol. Should the

participant exhibit signs of distress during IC measurement, the assessment will be

aborted immediately. A critical care provider, RRT and critical care nurse will be

present at all times during IC measurement. The patient will be continuously monitored

by observation and electronic hemodynamic monitoring.

Potential benefit to the participants randomized to the study group include

precise prescription of energy needs to meet actual energy requirements with the

potential to increase ventilator free days, decrease loss of lean muscle mass, maintain

weight through critical illness, improve overall outcomes and decrease length of

hospitalization. These potential benefits hold promise for clinical implementation and

shift of clinical practice paradigms related to nutrition management for critically ill

children with ALI requiring mechanical ventilation. Participants randomized to the

control group will receive usual PICU care. The alternative to IC measurements to

determine energy needs is usual PICU care and families can opt to withdraw from the

protocol at any time, however all effort to maintain participation will be employed.

There are no financial or legal risks for participation in this study.

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Confidentiality

To protect against any risk to participant confidentiality, all printed data forms

will be coded with a unique anonymous identifier. This unique identifier will be stored

separately from files with personal health information (PHI) to maintain confidentiality.

As part of the of the consent process, participants will be made aware that

circumstances exist (regulatory or legal) where the research team will have to provide

subject information to others. Signed consent forms and other participant specific

forms and documents will be labeled with the participant’s name, these forms along

with a master list of participants will be secured separate from any information with PHI

and identification numbers in locked cabinets away from the PICU. Access will be

limited to those directly involved with this study. Databases will be maintained on a

secured, password-protected research quality network drive and maintained by the PI

in accordance with the standards of the School of Nursing at the University of

Pennsylvania and CHOP. The scheduled back up procedures in accordance with each

institution will be followed. Every effort to maintain participant information confidentiality

will be employed. All identifying data will be removed from files prior to electronic

transfer to the biostatistician. No individual subjects will be identifiable from written or

oral dissemination of the results of this study.

Data Safety Monitoring

There will be two levels of data and safety monitoring. The first level will be on-

site, a study monitor (PI or other member of the study team) will verify data integrity,

compliance to the protocol and review source data and medical records, case report

forms and regulatory documents for completeness, accuracy and legibility.

Discrepancies will be discussed between the PI and study team as appropriate. The

study team will collect all data and perform initial data entry. A verification of data entry
116
will then be performed by another member of the team. The second level of data and

safety monitoring will be the establishment of a Data and Safety Monitoring Board

(DSMB), which consists of individuals responsible for study oversight. The DSMB

members will be appointed by the PI with approval of the funding agency. The

Research Institute at CHOP and the University of Pennsylvania will be provided

names, and a summary of the background and expertise of the DSMB board members.

The DSMB members will consist of three faculty members independent of the research

team, two with expertise in pediatric critical care and one with expertise in

interpretation and analysis of energy expenditure measurements.

All DSMB members will be appointed for the five study years. They must disclose any

conflict of interest with the present study. The DSMB board will have a Chair and

Executive Secretary appointed. The DSMB will monitor study regulatory files,

enrollment tracking logs, informed consent forms, case report forms and overall study

protocol. The board will meet at least annually for these activities. The PI will be

responsible for scheduling the meetings and selecting items to be reviewed.

Inclusion of Women, Minorities, and Children

All participants in the study are children between post-conceptual age of 44

weeks and prior to their 19th birthday. The anticipated sample will be racially diverse as

CHOP serves a large local, regional, national and international community. Bi-weekly

meetings with the research team will include discussions surrounding recruitment and

retention of minority children. Concurrently, the PI and RA will participate in the

University of Pennsylvania, School of Nursing’s Culture and Diversity seminars. In the

over 3000 annual admissions in the PICU at CHOP in the preceding year, the diversity

distribution was 54% non-Hispanic White, 6.4% Hispanic, 28% African-American, 1.7%

117
Asian/Pacific Islanders, < 1% Native American and 10% Other / Unknown / Decline to

Claim. Gender distribution was 58% to 42% male to female respectively.

Consortium Agreement

The Pediatric Intensive Care Unit (PICU) at The Children’s Hospital of

Philadelphia (CHOP) is a clinical, research facility were this randomized clinical trial

would be conducted.

Invertebrate Animals

There is no use of animals or collection of data from animals in this study.

118
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3. Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus

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5. Santschi M, Joumet P, Lederc F, et al. Acute lung injury in children: Theraputic

practice and feasibility of international clinical trials. Pediatric Critical Care

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the Pediatric Intensive Care Unit: Role of Targeted Indirect Calorimetry. JPEN J

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usefulness of the respiratory quotient in critically ill children. Nutrition.

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30. Hulst JM, van Goudoever JB, Zimmermann LJ, et al. The effect of cumulative

energy and protein deficiency on anthropometric parameters in a pediatric ICU

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Ventilated Critically Ill Children: Within-and Between-Day Variability. JPEN J

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Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, DC:

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of measured sleeping metabolic rate and predicted basal metabolic rate during

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Resting energy expenditure and prediction equations in young children with

failure to thrive. J Pediatr. 2000;136:345-350.

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energy expenditure in infants: A need for reappraisal. J Pediatr. 1995;126:21 -

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energy expenditure in children in a pediatric intensive care unit: comparison of

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46. Verhoeven JJ, Hazelzet JA, van der Voort E, KFM J. Comparison of measured

and predicted energy expenditure in mechanically ventilated children. Intensive

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JT. Energy expenditure in critically ill children. Pediatr Crit Care Med.

2007;8(3):264 - 267.

48. Illner K, Brinkmann G, Heller M, Bosy-Westphal A, Muller MJ. Metabolically

active components of fat free mass and resting energy expenditure in nonobese

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49. McClave SA, Lowen CC, Kleber MJ, McConnell W, Jung LY, Goldsmith LJ.

Clinical Use of the Respiratory Quotient Obtained From Indirect Calorimetry.

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50. Martinez JLV, Martinez-Romillo PD, Sebastian JD, Tarrio FR. Predited versus

measured energy expenditure by continuous, online indirect calorimetry in

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51. Curley MAQ, Arnold JH, Thompson JE, et al. Clinical trial design - effect of

prone positioning on clinical outcomes in infants and children with acute

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Measurements. Arch Dis Child. 1971;46(246):182 - 187.

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Manual. Champaign, IL: Human Kinetics; 1988.

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58. Institute of Medicine. Dietary Reference Intakes for Energy, Carbohydrate,

Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, DC:

National Academies Press; 2005.

59. Curley MAQ, Fackler JC. Weaning from mechanical ventilation: patterns in

young children recovering from acute hypoxemic respiratory failure. Am J Crit

Care. Sep 1998;7(5):335-345.

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Clin Pract. 2004;19:622-636.

64. Bines JE, Truby HD. Measurement of resting energy expenditure in infants. J

Paediatr Child Health. 2004;40:380-383.

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Chapter 4

Summary and Conclusions

There is abundant evidence associating growth failure and infants with

Congenital Heart Disease (CHD). This body of work further examines this relationship

through an investigation of growth velocity and energy expenditure in a sample of

infants with CHD following surgical intervention in early infancy. Although there is

debate clinically and in the literature on what constitutes growth failure in these infants,

the studies presented in this dissertation illustrate a negative statistical difference in

growth between infants with CHD and healthy infants. In addition, this data offers one

potential explanation – inadequate energy intake. Use of the newly developed World

Health Organization (WHO) child growth and growth velocity standards,1,2 make the

studies presented here novel in their approach to investigate growth in these infants.

Illustrating a difference in growth velocity compared to healthy infants and

demonstrating that energy expenditure in infants with CHD is not different from healthy

infants of the same age and gender, make this work is timely and important to the

clinical care of these infants. The following is a summation of the research findings and

their contribution to better understand growth failure in infants with CHD following

surgery in the neonatal period.

Specific Aims and Manuscript Review

Growth Monitoring

Growth Velocity

Growth velocity is the change over time in a given measure of physical

development. It can have high variability reflecting a naturally occurring pattern of

saltatory growth and catch-up or slow-down to account for a normal pattern of attained

growth reflected on standard growth charts.2 The first study of this dissertation, “Growth
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Velocity over the First Year of Life Following Neonatal Surgery for Congenital Heart

Disease” is a descriptive study describing the pattern of growth velocity for weight,

length and head circumference in a sample of infants with CHD following neonatal

surgery compared to healthy infants of similar age and gender. These data

demonstrate decreased growth velocity in infants with CHD compared to healthy

infants. Calculating and monitoring growth velocity growth is a more accurate way to

assess short and long-term changes in growth measures based on the time intervals

instead of a point in time.2,3 Using the WHO standards, which define growth based on

international child health standards, weight, length and head circumference, z-scores

and velocity z-scores were calculated. The standardized z-score measures clearly

exhibited a difference at 3-months of age, depicting lower z-scores and a decreased

rate of growth in infants with CHD. Despite the decreased rate of growth seen at 3

months of age, there was no difference in velocity z-scores for weight, length or head

circumference for the remaining time intervals, suggesting that the growth disparity of

early infancy is modifiable and that improved growth in infants with CHD is attainable.

These data provide a foundation on which to build a definition of growth failure in

infants with CHD. However, small sample size and missing data prevent development

of a definition based on this sample.

Although we measured growth velocity in 3-month intervals, the WHO growth

velocity standards allow for surveillance in weekly intervals in early infancy.2 The use of

these standards with close observation beginning at birth of attained growth and the

rate of change in growth parameters are a means for early identification of infants at

risk for poor growth. With early identification, early intervention is possible which can

prevent or minimize the degree of growth failure and decrease the potential for long-

term morbidities that can result from poor growth in infancy.

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 These data provide the platform for the design of strategies and interventions

aimed at increased caloric intake to assess if growth failure demonstrated in this study

by poor growth velocity is in fact modifiable. A program of feeding strategies that

supports an increase in energy intake may be the not so simple solution to this

persistent problem.4-8 Ongoing concentrated efforts in nutrition support aligned with

medical and nursing care may improve the rate of growth in infants with CHD to mirror

that of healthy infants. Further, this study may be the prologue of an intervention study

to develop and longitudinally test an intervention aimed at providing increased caloric

intake and monitoring infant response through feeding tolerance and attained growth

and growth velocity patterns. This may be a step at mitigating growth failure in infants

with CHD following neonatal surgery.

Energy Expenditure

The identification of differences in growth between infants with CHD and

healthy infants demonstrated in the study on growth velocity, presents a logical

progression to identify predictors of poor growth in these infants. Increased energy

expenditure related to cardiac physiology and the associated hemodynamic and

metabolic status is hypothesized to be a contributing factor in growth failure in infants

with CHD. This is the focus of the second study presented in chapter 2, “Resting

Energy Expenditure at 3-Months of Age in Infants Following Neonatal Surgery for

Congenital Heart Disease”. The primary aim of the study was to determine differences

in resting energy expenditure (REE), body composition and weight at 3-months of age

in infants with CHD compared to healthy infants. A secondary aim was to identify

predictors of REE in the same population.

Findings from this investigation reject the hypothesis that post surgical cardiac

physiology is the primary component driving energy expenditure. Further, no difference

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in REE was demonstrated between infants with CHD compared to healthy infants. In

fact, fat free mass (FFM) and infant age were the strong predictors of REE Kcal/day in

the study sample. Not only was cardiac physiology was not a primary causal factor, it

was not a major contributor to REE kcal in this study sample.

As expected, data from this study demonstrate FFM to be the primary predictor

of REE kcal. There was no difference in REE kcal between infants with CHD and

healthy infants, eliminating it, FFM, as contributing to poor growth in infants with CHD.

Instead, this study demonstrated % body fat to be lower in infants with cardiac disease,

which like accounts for their lower body weight in this study. This finding suggests

energy intake is inadequate in infants with CHD since FM and therefore % body fat is

directly related to caloric intake. Studies have shown poor nutrient intake during

hospitalization, poor weight gain at hospital discharge, and reports of inconsistent

feeding tolerance once home.4,9-11 The decreased accretion of fat demonstrated in this

study at 3-months of age suggests that poor weight gain continues post hospital

discharge. This was an interesting finding as it further supports the hypothesis that

consistent energy and nutrient intake are a challenge for infants with CHD and may be

the basis for poor weight gain and subsequent growth failure. It was striking that the

infants with CHD showed an increased REE difference of only 8 kcal/day compared to

healthy infants, however, kg weight and WHO weight z-scores were significantly

different between the groups. This is most likely explained by the significantly lower %

body fat these infants exhibited. Clinically, these findings suggest poor attained weight

at 3-months of age is related to inadequate caloric intake and the inability of these

infants to attain and sustain a positive energy balance that is necessary for fat and lean

body mass accretion.

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 It is important to note that these findings did not indicate cardiac physiology to

be a predictor for REE kcal in infants with CHD. This dispels the commonly held view

that cardiac disease is the basis for growth failure these infants often exhibit. In

addition, these findings support that idea that with focused concentrated nutrition

support along with medical and nursing care, growth failure seen in early infancy is

reversible and it is possible for these infant to attain their genetic growth potential.

Similar to the study on growth velocity, these findings present a platform for a program

of research investigating the unique feeding, energy and nutrient intake needs of

infants with CHD. Further, this study supports the idea of incremental measurements

of body composition in these infants to assess their nutrition status by the amount of

lean body mass compared to body fat mass, which can direct prescriptions for energy

and nutrient intake.

These studies examined questions focused on growth and nutrition status in

infants with cardiac disease following neonatal surgery. They present important data

that can be used as a platform for further inquiry and clinical practice. The introduction

of the WHO growth and growth velocity standards for infants and children, provide

excellent tools to further the inquiry surrounding growth and nutrition in clinical practice

and research endeavors.12 The WHO standards have indices for weight, length, head

circumference and growth velocity that have proven successful in the studies

presented to evaluate growth. 1,2 The child growth and growth velocity standards can

be useful for designing protocols and to identify specific parameters that can be used

to define growth failure in infants with chronic illness such as CHD, however the

studies presented suggest poor growth seen in early infancy is reversible and normal

growth patterns for infants with CHD attainable.

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 These investigations of growth and growth failure in infants with CHD are

important not only for somatic growth and its association with child health, but also for

the sequela that is associated with poor growth. Numerous associations exist between

cognitive, neurodevelopmental and neurobehavioral deficits in children who have

experienced poor growth in infancy. In both the general pediatric literature and the

pediatric cardiac literature, poor growth in infancy has the potential to have residual

effects well into childhood. The work of this dissertation has elucidated information that

potentially can intervene in growth failure in early infant and may in turn thwart the

associated untoward cognitive and neurologic outcomes seen in childhood.

Study Limitations

The limitations presented here are relevant to both studies presented in

Chapter 2. These include both studies are single center cohorts. This limits the

generalizability of the findings but lays the groundwork for replication of each of the

study protocols as larger clinical trials to determine reproducibility and generalizability

of the study results. The study setting, The Children’s Hospital of Philadelphia (CHOP),

may have a higher acuity of cardiac disease than that seen and treated in other

centers. Therefore, study findings may not be applicable in all pediatric cardiac

settings. Recruitment for both studies occurred approximately 8 years prior, with the

changes in surgical approach and technology these study findings may have a

decreased impact in the research community. Assessment of dietary intake was

attempted but the Neither investigation had reliable dietary intake data available for

analysis, which would have strengthened the results. Birth data was extracted from the

transport record that accompanied the infant to CHOP leaving question to its reliability,

and reducing any inference that can be made regarding growth and growth velocity

between birth and 3-months of age. Information learned from the 3-month data in both
132
studies, indicate the time between hospital discharge and 3 months of age in infants

with CHD may be crucial to better understanding growth issues in these infants. There

may be bias in that the families that enrolled and participated were motivated and

actively participated in the rigorous research protocol. Data is not available to address

familial educational or socioeconomic status and whether this reflects or impacts study

enrollment. Lastly, the study sample may not completely represent families with infants

that had the most challenging hospital course and were therefore not willing to consent

to study participation. These issues singularly or in combination, they may influence

study results.

NIH Director’s Early Independence Award Application

To move the science forward and to ‘translate’ the knowledge and skills

obtained over the course of this dissertation work, a grant proposal was prepared and

submitted to the National Institutes of Health (NIH) as a candidate for an Early

independent Investigator award. This proposal entitled: “The Use of Indirect

Calorimetry (IC) to Measure Energy Needs in Mechanically Ventilated Children with

Acute Lung Injury”, represents a modified approach to translational research,

addressing the adoption of best practice.13 As part of this dissertation, this proposal

serves to demonstrate the importance of translation of knowledge to support the idea

of best practice in the care of children. Through knowledge gained from the testing and

analysis of energy expenditure in postsurgical infants with complex CHD, this

application, designed as a clinical trial proposes to measure energy expenditure in

critically ill children requiring mechanical ventilation. The goal of this proposed trial was

to assess energy needs through the use of indirect calorimetry in children with acute

lung injury requiring mechanical ventilation. The specific aim of the proposed study is

to measure energy expenditure using indirect calorimetry to assess and prescribe

133
caloric intake specific to energy needs as compared to standard current practice of

prescribing energy intake from the use of prediction equation calculations. Research

has shown that prediction equations often under or overestimate energy requirements,

which can threaten clinical outcomes14-16. In this dissertation work, the investigation of

energy expenditure in infants with cardiac disease demonstrated the inaccuracy of

prediction equations to estimate energy needs when compared to measured energy

expenditure. This proposal exemplifies the need to further study measurement of

energy expenditure and its impact on participant outcomes versus the use of

equations.

Many of the current therapies and much of our understanding of disease

progression and appropriate treatment for children are derived from adult science.

This practice can be challenging as knowledge is gained about differences between

adults and children in their presentation and response to illness and treatment.

This proposal exemplifies the importance of conducting research specific to infants and

children to better understand pediatric response to illness, treat the unique needs of

the pediatric population and improve care delivery and overall outcomes. This is

particularly true in regards to energy needs, which can influence response to illness

and has long-reaching consequences for optimal health.

Future Research

The current body of work can move forward in two directions. The first would be

to replicate the research presented to a larger sample and follow the cohort for a longer

period. This would allow serial monitoring of growth measures, and the collection of

more data points to better examine and understand growth and growth velocity in both

healthy infants and those with CHD. Data on nutrient intake during the study period

will also improve understanding of growth and growth failure and can provide for
134
recommendations for caloric and nutrient intake, improve prescriptions for energy

needs based on actual energy intake and expenditure, and provide for a better

assessment of growth measures. This will better define growth, growth velocity and

growth failure in infants with complex CHD relating their nutrient intake, nutrition status

and growth parameters. This trajectory of research will establish a foundation to

develop nutrition support programs for infants are at risk for growth failure. Initiating

nutrition support programs can establish another tier of continued research to monitor

program success with incremental assessments of growth, growth velocity, body

composition and energy expenditure.

A second direction for future research would parallel the ideas outlined in the

grant proposal. There is much to understand the nutritional needs of infants and young

children during critical illness. With ongoing evidence that the prediction equations are

inadequate, it follows that a more accurate method is necessary to address energy

needs and prescription of appropriate energy and nutrient intake during critical illness.

Measurement of caloric needs with prescription and delivery specific to those needs

can be an adjunct to care in critically ill children and has potential to improve outcomes.

In pediatric critical care, appropriate provision of energy and nutrients remains a

challenge, both researchers and clinicians acknowledge meeting nutrition needs to be

an important aspect of care during and immediately following hospitalization. Accurate

nutrition prescriptions based on measured energy expenditure can decrease

complications associated with inadequate nutrient intake in critical illness, i.e. weight

loss, alteration in body composition, and length of hospitalization.

Based on work throughout this dissertation, the conceptual model introduced at

the outset can be modified. This work suggests energy balance is modifiable, and that

modification can effect growth in infants with cardiac disease who have undergone
135
surgical intervention in the neonatal period. The possibilities for future nutrition and

growth research born from this dissertation work abound and provide an exciting

outlook for the direction of investigations in the care of infants and young children.

136
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9. Schwalbe-Terilli C, Hartman DH, Nagel ML, et al. Enteral Feeding and Caloric

Intake in Neonates After Cardiac Surgery. Am J Crit Care. 2009;18(1):52 - 57.

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functionally univentricular heart: from surgical intervention to hospital discharge.

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11. Anderson JB, Marino BS, Irving SY, et al. Poor post-operative growth in infants

with two-ventricle physiology. Cardiol Young. 2011;21:421 - 429.

12. Van den Broeck J, Willie D, Younger N. The World Health Organization child

growth standards: expected implications for clinical and epidemiological

research. Eur J Pediatr. 2008;168:247 - 251.

13. What is Translational Research. 2007; http://ccts.uth.tmc.edu/what-is-

translational-research. Accessed May 3, 2011, 2011.

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Nutritional goals, prescription and delivery in a pediatric intensive care unit. Clin

Nutr. 2007;27:65 - 71.

15. Mehta NM, Bechard LJ, Dolan M, Ariango K, Jiang H, C D. Energy imbalance

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138
Figure 1 Modified Conceptual Model

Potential Influences on Growth

Growth
Infant Weight Change Velocity
with complex Severity of Disease Weight for age z-score
CHD Length for age z-score
HC for age z-score

Cardiac hemodynamic factors

Nutrient intake
Influencing Malabsorption
Factors Neurologic factors
Surgical factors
Postoperative Course / Severity of Illness

Energy Balance

Potentially Modifiable
Factors

Modified schematic of the concept of potential influences on growth in infants with CHD
following surgical intervention in the neonatal period

139
CLOSING

Commencement May 16, 2011

PhD Student Speaker Address:
University of Pennsylvania,
School of Nursing
Kimmel Center, Philadelphia, PA

LOOK AT US NOW

Good Afternoon. To Dean Meleis, Ms Greco, Dr Savard, Dr Shalala, esteemed faculty,

honored guests, fellow graduates, family and friends:

LOOK AT US NOW

LOOK AT US. To my graduating colleagues, you remember year “1”. We were all
sitting in Dr Julie Fairman’s class on the “Philosophy of Science in Nursing”. You
remember – we were told that we were about to have our brains unpacked, scrambled
and then by graduation – sometime in the future, we would re-packed our brains with
some of the same but also with enhanced and new knowledge. Who knew we would
learn the language of post-modernism, empiricism, feminism, relativism and the
like…Well – LOOK AT US NOW, the repacking has been a journey, but much easier
than we thought…

LOOK AT US NOW. Remember - “Concept Analysis” – some of us had to stretch,

because to conceptualize we thought, was well beyond our reach, we provided care, it
was tangible, not a concept… but, concept building, it was a part of the unpacking and
the scrambling; we had yet to reach the repacking stage, so we needed a concept, a
model on how to do it...

LOOK AT US NOW. We have poked proteins; examined phthalates; uncovered

properties of skin elasticity; cared for the elderly; scrutinized kidney disease; held
heart to heart talks with immigrants; used history to explore our nursing identity;
examined symptom clusters in cancer; followed mothers and children with HIV;
wacked on a few mice; probed into psychiatric assessment; thought about sleep –
while we were losing it; investigated the impact of vitamin D in diabetes; examined
school performance in ex- preemies and studied the expenditure of energy in infants
with congenital heart disease… In essence, we have repacked our brains and in doing
so, we have added to the knowledge of nursing science, we are becoming
epistemologists…LOOK AT US NOW!

LOOK AT US – now we initiate and we lead the conversations on: “the literature tells
us”, “the research is lacking” and “recent data suggests”…that’s us talking and us
saying those words! LOOK AT US NOW!

LOOK AT US – while we repack of our brains, we also pack tools…tools to pioneer

new thought processes, tools to formulate new questions, tools to be a new wave of
nurse scientist...tools with which we will build new knowledge – epistemologically
speaking…

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LOOK AT US NOW… to everyone here, go-ahead look around - remember these
names and these faces for we are a generation of nurse scientists who are multi-
talented, and the world has just become our playground.

So, everyone, take a look…look at this class of PhD graduates of the University of
Pennsylvania, School of Nursing for 2011… But don’t blink or look away, because once
you do, you will miss the continuation of the repacking, you will miss epistemology in
the making… because along the way, we found out, the unpacking and repacking – it
doesn’t end, it just changes. We will forever unpack and repack – it is through that
process that tools for continued growth and advancement develop, it is through that
process that innovations and innovators – my graduating colleagues, are discovered…

LOOK AT US NOW…I am humbled, proud and so very honored to have been

nominated by you, my classmates to represent the 2011 PhD class…We walk out as
newly graduated nurse scientists who have the ability to teach, to practice, to question
and disseminate findings (please don’t forget to publish!)…and through the process we
will continue to add to the knowledge of the science of nursing

So, Dean Melesis, Ms Greco, Dr Savard, Dr Shalala, esteemed faculty, honored guests
and friends – keep your eyes on us, WE ARE A FORCE!

LOOK AT US NOW!!!

Thank you.

The Acquisition of Knowledge

"The acquisition of knowledge is always of use to the intellect, because it may thus
drive out useless things and retain the good. For nothing can be loved or hated unless
it is first known."
Leonardo da Vinci

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