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The Effectiveness of Modified Fat Breast Milk for the Treatment of Chylothorax in
Infants Following Cardiothoracic Surgery by
Sarah Linda Farmer
A thesis submitted in conformity with the requirements
Graduate Department of Nutritional Sciences
University of Toronto
© Copyright by Sarah Linda Farmer 2011
ii
The Effectiveness of Modified Fat Breast Milk for the Treatment of Chylothorax in Infants Following Cardiothoracic Surgery
Sarah Linda Farmer
Masters of Nutritional Sciences
Department of Nutritional Sciences University of Toronto
2011
Abstract Background: Chylothorax occurs in ~4 % of children undergoing cardiac surgery.
Treatment requires transition to a medium chain triglyceride (MCT) based formula.
Provision of breast milk (EBM) is discontinued due to the presence of long chain
triglycerides. Objective: To determine the effectiveness of a modified fat breast milk for
the treatment of chylothorax in comparison to an MCT formula. Methods: Infants with
chylothorax were eligible. Treatment infants (n=8) received EBM that had been modified
by removing the fat layer (centrifugation) from EBM and adding MCT and nutrients to
provide 67 kcal/ml and 11 g/100 ml protein. Control infants (n=8) received an MCT
formula. Results: Volume of chest tube drainage was not different (p<0.40). Treatment
infants experienced declines in mean weight (p<0.006), length (p<0.013) and head
circumference (p<0.008) z-scores. Conclusion: Modified fat breast milk allowed for
successful resolution of chylothorax. Strategies to address poor growth, however, need to
be tested before clinical adoption of this novel treatment.
iii
TABLE OF CONTENTS
Table of Contents............................................................................................................ .iii
i i
.viii List of Appendic CHAPTER 1 INTRODUCTION, RATIONALE AND
CHAPTER 2 REVIEW O 2.1 7 2.1.1 Definition of C 2.1.3.1 Congenital 2.1.3.2 Non-Traumatic or Obstructive C 2.1.3.3 Traumatic 2.1.4 Incidence of Ch 2.1.5 Composition o 2.1.6 Diagnosis of 2.1.7 Management of 2.1.8 Determinants of Successful Conservati 2.1.9 Complications of 2.1.10 Breast Milk and 2.2 MEDIUM CHAIN TRIGLYC .27 2.2.1 Chemical Structure and Properties of 2.2.2 Food Sources of Medium Ch 2.2.3 Metabolism of Medium Ch 2.2.4 Medium Chain Triglycerides and the Neo 2.2.5 Clinical Uses of Medium Ch 2.3 BREASTFEEDING AND THE PROVISION OF BREAST 2.3.1 Breast Milk and Di 2.3.2 Breast Milk and 2.3.3 Breast Milk and Diseas 2.3.3.1 Breast Milk and Dise
iv
2.3.3.2 Breast Milk and 2.3.3.3 Breast Milk and Gastrointe 2.3.3.4 Breast Milk and Cardi 2.3.3.5 Breast Feedin 2.3.3.6 Breast Milk an 2.4 NUTRITION ISSUES IN CONGENITAL HEART DISE 2.4.1 Congenital Heart Disease 2.4.2 Congenital Heart Disease an 2.4.3 Causes of Growth Failure in Cong CHAPTER 3 THE EFFECTIVENESS OF LOW FAT BREAST MILK FOR THE TREATMENT OF CHYLOTHORAX IN INFANTS FOLLOWING CARDIOVASCULAR SURGE 3.1 INTRODUCTION AND RA 3.1.1 Research Que 3.1.2 2 3.1.3 Hypoth 3.2 SUBJECTS AND 3.2.1 Subje 3.2.2 Study Inclusion C 3.2.2.1 Treatment Inclusi 3.2.2.2 Control Inclusion ..... 3.2.3 Study 3.2.4 Study D 3.2.4.1 Treatme 3.2.4.3 Fat Removal Following Discharge - 3.2.4.4 Fat Removal Following Discharge - 3.2.4.5 Nutrient 3.2.4.6 Contro 3.2.5 Fat Anal 3.2.6 Protein Anal 3.2.7 Electrolyte A 3.2.9 Data Coll 3.2.11 Statistical A
3.3.1 Subject Charact 3.3.2 Family Characteri 3.3.3 Fat Rem
v
3.3.4 Chest Tube 3.3.5 Modified Fat Br 3.3.5.1 Nutrient Enric 3.3.6 Nutrient An 3.3.6.1 Protein A 3.3.6.2 Fat A 3.3.6.3 Electrolyte 3.3.6.4 Intake 3.3.6.5 Feeding In 3.3.6.6 Nasogastric Tube 3.3.7 Gro 3.3.7.1 Weight-for- 3.3.7.2 Length-for- 3.3.7.3 Weight-for- 3.3.7.4 Head Circumference-for- 3.3.8 Microbiological 3.4 DISCUSSI 3.4.1 Chest Tube 3.4.2 Grow 3.4.3 Provision of Br
3.5.1 Conclus 3.5.2 Future Direct 15 4. REFERENCE 5. APPENDIC
vi
LIST OF TABLES Table 1. Features of chyl Table 2. Recipes for the Fortification of Mo Table 3. Approximate Energy and Select Nutrient Composition of Mature Human Milk, Portagen®, Modified Fat Human Milk and Nutrient Enriched Modified Fat Human Milk Subject characteris Table 4. Subject Characteristics Table 5. Family Characteristics Table 6. Percentage of feeds consumed by treatment subjects as modified fat milk vs. MCT formula Table 7. Measured protein content of breast milk sample after centrifugation Table 8. Measured sodium and potassium content of modified fat breast milk Table 9. Characteristics of infants requiring a feeding tube during the study period and timing of feeding tube removal in relation to study comp Table 10. Weight-for-age, Length-for-age, Weight-for-length and Head Circumference-for-age z-scores at study enrolment and study completion for treatment and control 1 Table 11. Microbiological analysis of milk sample pre-centrifugation and post- centrifuga Table 12. Average daily weight gain over the study period and expected daily weight gain for age for treatmen
vii
LIST OF FIGURES Figure 1. Care map flow sheet for the diagnosis and management Figure 2. Total volume of drainage for the treatment and control group 81 Figure 3. Variability of remaining fat content of samples of modified fat breast milk as measured using the creamatocrit method for all treatment subje Figure 4. Daily volume of milk intake (a), daily energy intake from milk feedings alone (b) and daily energy intake from milk feedings + solid foods (c) in the treatm Figure 5. Protein intake from milk and solids for the treatment group and contro Figure 6. Z-score for weight-for-age, length-for-age, weight-for-length and head circumference-for-age at study enrolment and study completion for subjects in the treatment and cont Figure 7. Microbiological De Figure 8. Trajectory of change in weight-for-age z-score for treatment and control subjects from study enrolment t
viii
ABBREVIATIONS BCPS Bidirectional cavopulmonary shunt CHD Congenital Heart Disease CoA Coenzyme A HMF Human Milk Fortifier ICPA Infant Care Practice Study IgA Immunoglobin A IGF-1 Insulin-like Growth Factor 1 IQ Intelligence Quotient LCFA Long Chain Fatty Acids LCT Long Chain Triglycerides LDL Low Density Lipoprotein MCFA Medium Chain Fatty Acids MCT Medium Chain Triglycerides MPR Milk Preparation Room PROBIT Promotion of Breastfeeding Intervention Trial SAS Statistical Analysis System SD Standard Deviation SGA Small for Gestational Age sIgA Secretory Immunoglobin A TEE Total Energy Expenditure TDEE Total Daily Energy Expenditure WASI Weschler Abbreviated Scales of Intelligence
ix
APPENDICES
Appendix A. Consent form Treatment Group Appendix B. Consent form Control Group Appendix C. Data Collection Forms Appendix D. Food Record Treatment Group Appendix E. Food Record Control Group Appendix F. Minimal Fat Diet Guidelines Appendix G: Chest Tube Drainage Data for all Subjects
1
1
1. INTRODUCTION, RATIONALE AND OBJECTIVES 1.1. INTRODUCTION AND RATIONALE Breast milk has long been recognized as the ideal food for the vast majority of
infants (1). Although rare, situations do exist in which the breastfeeding or the provision
of expressed breast milk is not possible (1). When an infant is diagnosed with
chylothorax, a post-operative complication following corrective surgery for a congenital
heart defect (CHD), breastfeeding or expressed breast milk must be temporarily replaced
with a therapeutic formula. In comparison to breast milk, which contains fat
predominantly as long chain triglycerides (LCT), the therapeutic formula contains fat
primarily as medium chain triglycerides (MCT). This raised the question of whether or
not it would be possible to modify breast milk to make it a safe and effective treatment
for infants with chylothorax. The idea of low fat breast milk was not novel. There have
been sporadic reports in scientific publications, as well as anecdotal reports accessible via
the internet, of the successful use of low fat breast milk to treat chylothorax. However, at
e effectiveness
of a modified low fat breast milk to treat chylothorax in infants following corrective
surgery for a congenital heart defect. Hamdan et al published a case study in which an
infant with chylothorax was successfully treated with a combination of medication and
low fat breast milk after a patient exhibited intolerance to the MCT based formula (2).
Chan et al published a report detailing experience with the use of fat free human milk for
the treatment of 7 infants with chylothorax that was either congenital or developed
following surgery to repair a cardiac defect (3). A more recent case study by Lessen
described successful treatment of chylothorax with skim breast milk in an infant
2
following repair of a coarctation of the aorta (4). However, none of these reports involved
a scientific comparison to one of the fat modified formulas that are the current treatment
standard for infants with chylothorax. Thus, the question was not; could we modify the
fat content of breast milk? The question was, if we remove as much fat as possible from
breast milk, will the resulting modified fat breast milk be an effective treatment for
chylothorax and if so, will it be as effective, more effective or less effective than the fat
modified formula that is currently used to treat chylothorax?
If a successful means of treatment is available, why seek out a new treatment?
Breast milk has long been recognized as the gold standard for infant feeding (5). The
World Health Organization recommends exclusive breastfeeding for the first six months
of life (6). The American Academy of Pediatrics, Health Canada and the Canadian
Paediatrics Society also promote exclusive breastfeeding through the first 6 months of
life (7-9). Properties inherent to human breast milk contribute to ease of digestibility,
improved tolerance of feeds and superior nutrient delivery (10). The list of health benefits
associated with breastfeeding is long and includes reduced risk of infections including
otitis media and gastrointestinal infections, suspected prevention of certain types of
childhood cancers and other diseas (11-16).
Breastfeeding may also prevent the development of certain allergies, reduce the risk of
obesity and aid in the prevention of cardiovascular disease (17-24). Importantly, many of
these studies supporting the role of breast milk in health also suggest that the duration of
breastfeeding is an important factor in these apparent health benefits (12-13, 18, 20).
3
recognized benefits are denied to infants with chylothorax for a period of approximately
6 weeks. Six weeks is a significant portion of time in the short duration of infancy.
Facilitating the continued use of breast milk throughout treatment of chylothorax may
increase the likelihood that mothers will pump to maintain their milk supply and thus
facilitate the resumption of breastfeeding and/or breast milk provision following
completion of treatment. In turn, this allows the infant to continue to receive breast milk
further into infancy and thus providing on-going exposure to its known benefits.
Cardiac infants are a delicate population in whom weight gain is a persistent
challenge and growth failure prominent (25). Any disruption in feeding pattern can
further complicate these issues (25). Anecdotal observations at our institution suggest that
the introduction of the fat modified formula that is the current standard of treatment is
frequently accompanied by feeding intolerance such as increased episodes of vomiting,
gassiness and discomfort with feeds, refusal to orally feed and the need for nasogastric
tube feeding for the duration of treatment. In addition, there is an important psychosocial
component to the provision of breast milk that cannot be ignored. Families are often very
distressed when they are told they cannot breastfeed or provide breast milk, in any form,
families have worked hard to establish a routine of providing breast milk for their cardiac
infant that effectively supports growth. Parents are often desperate to be able to do all
they can for their infant and to ensure their well being, especially when so much of their
medical care is dependent on others. Finally, the need to purchase an expensive
4
therapeutic formula can be an additional and often unexpected financial burden for
families.
This research examines the possibility of providing breast milk, in a modified
form, to infants with chylothorax, so that they may continue to receive some of its
recognized benefits, to allow parents to continue to provide an important component of
their infants care and to allow families to be consistent with the feeding and nutrition
goals that they have established for their infant. This thesis includes a comprehensive
review of the literature followed by the research data chapter providing an outline of the
methods, results and discussion of the completed research. A final chapter summarizes
the clinical significance of the research and examines the future clinical implications of
the results.
The literature review that precedes the description of the research discusses
chylothorax, the current treatment and the associated complications. Chylothorax is a
condition that occurs when there is leakage of chylous fluid into the chest cavity that, if
left untreated, can accumulate and lead to compromised respiration (26-28). Prolonged
leakage of chylous fluid, a fluid high in protein and fat, can also lead to associated
complications such as malnutrition and immunodeficiency, putting affected individuals at
increased risk of infection (29)
will be examined.
The second section of the literature review examines the properties of MCT and
how they differ from LCT thus setting the foundation for their use in the treatment of
5
chylothorax. Treatment of chylothorax in infants requires the use of a modified fat
formula. This formula is high MCT and low in LCT and forms the basis of conservative
management of this condition. Other clinical uses of MCT, particularly in the paediatric
population, will be briefly examined.
The third section of the literature review examines the benefits of breastfeeding
and the provision of breast milk. The World Health Organization as well as the American
Academy of Pediatrics and the Canadian Paediatric Society recommends the provision of
breast milk as the first and exclusive food for infants, continuing through infancy with
appropriate introduction of complimentary foods at 6 months (6-7, 9). There is growing
evidence to support the role of breastfeeding and the provision of breast milk in the
prevention of certain childhood diseases as well as playing an important a role in
establishing a foundation for good health later in life (21). This evidence will be
reviewed.
The final section of the literature review examines the nutritional issues and
challenges commonly faced by the cardiac infant. Recent literature suggests that infants
with CHD often start life at a disadvantage, more often being classified as small for
gestational age or were classified as being of low birth weight in comparison to healthy
infants (30-32). Postnatal life is complicated by increased energy demands and
difficulties achieving adequate caloric intake to support growth (25). The literature
review examines the nature of the growth difficulties experience by this population and
possible causes of growth failure.
6
1.2 OBJECTIVE
The objective of this research study was to compare the effectiveness of a modified
fat breast milk for the treatment of chylothorax in infants following cardiothoracic
surgery to the high MCT-containing therapeutic formula that is the current standard of
care.
7
2. REVIEW OF THE LITERATURE
2.1 CHYLOTHORAX
2.1.1 Definition of Chylothorax
Chylothorax is a condition in which there is an accumulation of chylous fluid in
the pleural cavity. Chylothorax occurs when there is injury to the thoracic duct or one of
its primary branches, causing chylous fluid to leak into the surrounding space (26-27, 33).
Chylothorax is initially asymptomatic. Associated symptoms only develop when a
significant amount of fluid has accumulated, causing the patient to experience an increase
in respiratory effort and ultimately respiratory distress (26). In previous years, mortality
rates were upwards of 50% in untreated cases (29, 33-35). Advancements in conservative
management through the use of MCT based diets or formulas or the use of parenteral
nutrition has significantly reduced associated morbidities and mortality by reducing the
amount of chylous fluid produced, facilitating resolution of the chylothorax and
subsequently improving outcomes for patients affected by chylothorax (29).
2.1.2 Anatomy of the Thoracic Duct
The thoracic duct is the largest vessel in the lymphatic system and functions as a
drainage route for the main lymphatic vessels of the body, with the exception of the right
side of the head and neck, right upper limb, right lung, right side of the heart and the
convex surface of the liver (28). It also functions as the primary transport pathway for
intestinal chyle into main circulation (28). Embryologically, the thoracic duct presents in
8
a two-pronged configuration and therefore may grow into a wide array of anatomical
arrangements (35-36)
become one common vessel, the thoracic duct (35-36).
The origin of the thoracic duct is a triangular dilatation known as the cisterna
chyli which is located in the abdomen at the level of the second lumbar vertebra (28).
From the abdomen, the thoracic duct begins its journey through the thorax. The thoracic
duct enters the thorax through the aortic hiatus (37). It then travels upward through the
thoracic cavity in the posterior mediastinum, directly in front of the vertebral column, to
the right of the aorta and behind the oesophagus. Initially, the thoracic duct ascends on
the right side of the oesophagus but then, at the level of the fifth or sixth vertebra, it
crosses to the left side (28, 35, 37). At this point, the thoracic duct follows a route behind
the aortic arch and leaves the thoracic cavity via the superior thoracic aperture. The
thoracic duct ends its journey at the base of the neck where it empties its contents into the
subclavian veins, below the shoulders, near the clavicle, at its juncture with the left
internal jugular (28, 36). During its ascent through the thorax, the thoracic duct comes in
close proximity with the aortic arch and other key structures of the heart, making it
particularly vulnerable to traumatic injury during cardiothoracic procedures.
In adults, the thoracic duct is variable in length and can range from 37 45 cm in
length. It can be structurally inconsistent and may segregate into two or more branches in
up to 40 per cent of individuals (28). These branches can form a complex arrangement as
the duct ascends through the thorax and may terminate as multiple branches or converge
9
into one duct before emptying its contents into the main circulation (28). The thoracic
duct may transport up to 4 L of chyle each day in the healthy adult and as much as 250 ml
in a neonate (28, 38). The magnitude of chyle flow may range from 10 ml to greater than
100 ml per kg bodyweight (28, 38). The volume of chyle is influenced by diet,
medications, intestinal function and physical activity levels (28, 36-37). The rate of flow
through the thoracic duct is largely dependent on the inflow from the lacteals, the
lymphatic capillaries found on the villi of the small intestine that are responsible for
absorption of fat. Consequently, chyle flow is especially amplified following a meal that
is high in fat (35-37)
of 13-14 seconds and are responsible for movement of chyle (28). Flow of chyle may also
be stimulated in situations of increased intrathoracic pressure. For example, during
inhalation, the diaphragm and liver descend in the abdomen creating an increase in
intrathoracic pressure, compressing the cisterna chyli, and subsequently increasing flow
of chyle. A similar effect may be seen if an individual coughs (28). The Bernoulli
suction effect, or the Bernoulli vacuum, is the force that drives the drainage of the chyle
from the thoracic duct into the subclavian vein and is produced by blood flow at the
opening of the thoracic duct (28, 36).
The anatomy of the thoracic duct can determine the nature of the chylothorax
(34). If the site of damage is the lower thoracic duct, the chylothorax is likely to occur on
the right side. Accordingly, damage to the upper thoracic duct results in a left-sided
chylothorax (34).
10
2.1.3 Classifications of Chylothorax
Chylothorax has a variety of causes and may be classified as congenital, traumatic
and obstructive (28, 35).
2.1.3.1 Congenital Chylothorax
Although congenital chylothorax is one of the most common causes of
chylothorax observed in the neonatal period, the actual occurrence of this disorder is
extremely rare occurring in 1:10,000-15,000 pregnancies (28, 36, 39). In the majority of
congenital chylothorax cases, no specific cause is ever identified. It may occur as the
result of birth trauma with hyperextension of the spinal column or increased venous
pressures during birth. However, in such cases there is often an underlying congenital
defect in the thoracic duct that can be identified and renders the lymphatic system
vulnerable to damage (28, 35, 38-41). Congenital chylothorax may be seen with the
occurrence of certain syndromes that are linked with malformations of the lymphatic
system such as Noonan Syndrome and Trisomy 21 as well as in cases of polyhydramnios,
tracheo-oesophageal fistulas, congenital lymphangiectasia as well as thoracic duct
hypoplasia and atresia (28, 36, 38, 41-42).
2.1.3.2 Non-Traumatic or Obstructive Chylothorax
Non-traumatic or obstructive chylothorax most frequently occurs in the adult
population and is often caused by an obstruction of the thoracic duct as a result of
intrathoracic tumours, inflammatory diseases or mediastinal lymphangiomatosis (38). An
obstruction causes an increase in pressure in the intrathoracic lymphatic system. This
11
increase in pressure forces collateral lymphatic vessels to dilate and renders the lymphatic
valves ineffective. This combination of increased pressure and ineffective lymphatic
valves creates redundant flow of chyle in the thoracic duct. The thoracic duct eventually
succumbs to the pressure and ruptures, creating a point of damage through which chyle
can escape into the thoracic cavity (26-27, 33, 36).
In the absence of an obstruction, chylothorax can also be caused by increased
pressure in the systemic venous system resulting from elevated right-sided cardiac
pressures. This is frequently seen following surgical procedures that are associated with
systemic venous hypertension such as the bidirectional Glenn and the Fontan procedure
(43). The elevated pressure is disseminated to the surrounding lymphatics which in turn
slows the flow of chyle through the thoracic duct. This triggers dilation and eventual
breach of the duct resulting in leakage of chyle into the thoracic cavity (43).
Chylothorax has also been reported as an infrequent consequence of an indwelling
central catheter that has resulted in a subclavian vein thrombosis (28, 38, 44). Wu et al.
described a case in which a 5-month-old boy developed chylothorax 2 months after a
cardiac surgery following the removal of a peripherally inserted central catheter (44).
Venography revealed occlusion of the innominate vein attributed to the peripherally
inserted central catheter (44). Factors that increase the risk for catheter-induced
thrombosis include small body size, catheter tip in the brachiocephalic vein, unstable
hemodynamics and use of parenteral nutrition (44). Beljaars et al reported on a case of
chylothorax that developed in a 4 year old boy with previous surgical correction for
12
Tetralogy of Fallot, following the insertion of a central venous double lumen catheter for
the administration of necessary medication (45). Unlike the case reported by Wu et al,
this case was not associated with a thrombus but was attributed to multiple factors
combination with elevated systemic venous and lymphatic pressures attributable to the
(45).
2.1.3.3 Traumatic Chylothorax
Traumatic chylothorax can be classified as surgical or non-surgical and results
from direct injury to either the thoracic duct, or one of its primary branches. (35-36, 41).
Traumatic injuries that pierce the chest, neck or abdomen may result in rupture of the
duct. Blunt trauma or sudden hyperextension of the cervical spine particularly after a
meal when the thoracic duct is distended may lead to a breach in the integrity of the
thoracic duct (41). In the infant population, traumatic chylothorax most frequently occurs
as an early post-operative complication, following a thoracic surgical procedure and more
specifically, following corrective surgery for an underlying cardiac defect (35, 41).
Although chylothorax can occur after any intrathoracic procedures, extrapericardial
interventions in the vicinity of the thoracic duct, such as ligation of a patent ductus
arteriosus or repair of a coarctation or double aortic arch, increase the risk of laceration
during surgery (29). From this point forward, infants who develop chylothorax after
corrective cardiac surgery will be the focus of this paper.
13
2.1.4 Incidence of Chylothorax
The occurrence of chylothorax can be an additional obstacle to the already
challenging recovery for paediatric patients with CHD following a surgical procedure.
Chylothorax is reported in the literature as affecting 2.5 to 4.7% of paediatric patients
undergoing cardiothoracic surgery (26-27). The recently observed increase in the
incidence of chylothorax is speculated to be the result of the escalating complexity of
corrective surgeries and earlier re-feeding in the post operative period (26-27).
2.1.5 Composition of Chyle
Chyle originates from the intestine and therefore much of its contents are enzymes
and products of digestion (28). Sixty to 70 percent of absorbed dietary fat passes through
the lymphatic system and therefore chyle is characteristically high in fat (29). The high
fat content of chyle imparts its characteristic, milky white appearance which can be used
to arouse suspicion regarding thoracic duct damage and the presence of chylothorax (28).
The fat in chyle is found primarily in the form of triglycerides that have been packaged
into chylomicrons (35-36, 46). In addition to a high triglyceride content, cholesterol and
fat soluble vitamins are also present. Chyle also contains a high concentration of
proteins, primarily albumin, as well as digestive enzymes and electrolytes. In addition to
its fat, protein and nutrient content, chyle contains a high concentration of lymphocytes
that play an important role in immunity (36). These unique characteristics of chyle form
the foundation of the most common consequences of on-going chyle losses that may
occur in chylothorax: nutritional depletion, most notably protein calorie malnutrition, and
immunodeficiency (26, 36).
14
Relative density 1.012-1.015
pH 7.4-7.8 Colour Milky (colourless in starvation) Sterile Yes Bacteriostatic Yes Fat (g/L) 5-30 Protein (g/l) 20-30 Albumin 12-42 Globulin 11-31 Albumin:globulin ratio 3:1 Fibrinogen (mg/l) 160-240 Glucose (mmol/l) 2.7-11.1 Urea (mmol/l) 1.4-3.0 Cell count (per dl) Lymphocytes 40000-680000 Erythrocytes 5000-60000 Enzyme concentration (units/ml) Pancreatic Lipase 0.5-2.4 Amylase 50-83 Aspartate aminostransferase 22-40 Alanine aminotransferase 5-21 Alkaline phosphatase 2-4.8 Acid phosphatase 0.3-0.8 Electrolyte concentration (mMol/l) Sodium 104-108 Potassium 3.8-5.0 Chloride 85-130 Calcium 3.4-6.0 Phosphate 0.8-4.2
Adapted from Valentine, V.G and Raffin, T.A. The management of chylothorax. Chest, 1992. 102(2): p586-91
2.1.6 Diagnosis of Chylothorax
Both biochemical and microscopic analysis of the chylous fluid form the
foundation for the diagnosis of chylothorax (47). Although one common diagnostic
proposed the following diagnostic criteria: > 1.1 mmol/L triglycerides (with oral fat
(46).
Similarly, Beghetti et al proposed: > 1,000 leukocytes/ml (>70% leukocytes);
Table 1. Features of Chylous Fluid
15
triglycerides > 100 mg/dL; protein > 20 g/L; sterile culture; milk appearance and positive
Sudan III (48).
Diagnosis of chylothorax at The Hospital for Sick Children is based on volume of
drainage as well as compositional analysis of the drainage fluid. If chest tube drainage
appears milky or exceeds 5 ml/kg/day on post operative day 4, a sample of pleural fluid is
sent for analysis to determine triglyceride content, cell count and the presence of
chylomicrons. A positive diagnosis of chylothorax is made and treatment initiated if the
sample is positive for chyle and/or the lymphocyte fraction of the cell count is > 80%
(49).
2.1.7 Management of Chylothorax
Current conservative management of chylothorax consists of pleural chyle
drainage and nutrition support (26, 28-29, 46). The goal of the nutrition support is to
manipulate the diet in such a way that chyle flow through the thoracic duct is minimized,
giving the damaged thoracic duct an opportunity to heal. For patients with chylothorax,
the fat composition of the diet is a fundamental component of treatment. The mechanism
of fat absorption depends on the fatty acid chain length (50). MCT contain saturated fatty
acids with chain lengths of 6 12 carbons (51). MCT are water soluble, making them
more easily absorbed than LCT. Digested MCT are primarily absorbed directly into the
portal vein circulation, bypassing the lymphatic pathway and thus reducing lymphatic
flow (40, 51-54). Conversely, digested LCT are absorbed via the lymphatic system and
transported via the thoracic duct into the blood stream, thus increasing thoracic flow (51,
16
54). Consequently, a diet rich in LCT increases chyle flow in the thoracic duct and
prevents healing of the damaged duct, further increasing the potential for complications
(46). Therefore, MCT plays a fundamental role in the enteral nutrition management of
chylothorax in the paediatric population. As an alternative therapy, parenteral nutrition
may be used to bypass the intestine completely.
Current management for chylothorax at our facility follows a defined algorithm
(Figure.1) that initially requires that affected infants be placed on a fat modified formula
such as Portagen® (49, 55). Portagen® is -protein based powder with 87%
MCT designed for use in children and adults (55). At standard concentration, Portagen®
provides 1.0 kcal/ml but is diluted for use in infants to provide a caloric content more
similar to that of breast milk or standard infant formulas e.g. 0.67 kcal/ml. Infants are
required to stay on this formula for a minimum of 6 weeks (49). Concerns regarding the
use of this product relate to the fact that it is not a specialized paediatric product and
therefore does not reflect the nutrient needs of young infants. Protein levels are
significantly higher than those found in human milk or standard infant formula. In
17
18
addition, some micronutrients, such as vitamin C, folic acid and vitamin D are found at
lower levels in comparison to those found in human milk or standard infant formula (55).
These nutrient deficits can be magnified when an infant is faced with a fluid restriction
and feed volumes are limited as is often the case with cardiac infants. At our institution,
digestive difficulties manifested as more frequent episodes of vomiting, increased
gassiness/discomfort and symptoms of reflux are frequently observed in infants with the
introduction of the MCT based formula. This in turn may result in increased use of
gastrointestinal medications and a prolonged hospital stay. Poor palatability in
comparison to breast milk or standard infant formula may contribute to decreased oral
feed consumption, particularly in older infants, resulting in reduced energy and nutrient
intake. Both tolerance issues and diminished feed volumes can make weight gain in the
post surgical period challenging, and increase the need for a nasogastric feeding tube to
ensure adequate intake of energy, nutrients and fluid. It is well documented that the
cardiac infant is at high risk for growth failure and any disruption to an already
established feeding pattern may exacerbate existing failure to thrive or put a previously
well nourished infant at risk for nutritional depletion (56-60). Final concerns are related
to the potential for bacterial contamination of powdered formula. The MCT formula
currently in use is available only in powdered form, thus is not a sterile product and like
other powdered formulas may harbour the dangerous bacteria enterobacter sakazakii (61).
The use of powdered formula increases the risk for infection and increases the possibility
of serious morbidities associated with this harmful bacteria in an already fragile
population (62).
19
2.1.8 Determinants of Successful Conservative Management of Chylothorax
The different causes of chylothorax in the paediatric cardiac population, either
direct trauma to the thoracic duct or increased venous pressures, are associated with
different clinical features of the pleural effusion and thus can determine success of
management. Le Coultre et al reported a shorter duration to diagnosis in cases of direct
trauma to the thoracic duct in comparison to those in whom chylothorax was associated
with an obstruction or elevated venous pressures, thus allowing earlier initiation of
treatment (63). It was also observed that volume of chylous drainage was higher in those
patients whose chylothoraces resulted from elevated venous pressures versus those who
suffered direct trauma to the thoracic duct (63). This result has also been reported in
other studies (33, 48). Subsequently, non-operative management (dietary manipulation)
was most successful in those with direct damage to the thoracic duct at the root of their
chylothoraces (48, 63). Pedra et al also reported a longer period to diagnosis and a longer
period of drainage in chylothoraces resulting from elevated pressures in the superior vena
cava (43). The authors suggest that in chylothoraces stemming from increased venous
pressures, the time required for accumulation of chyle, dilation and eventual rupture of
the thoracic duct accounts for the delay observed between surgery and diagnosis of
chylothorax. The resulting increased pressure in the lymphatic system is also responsible
for larger volumes and longer periods of drainage (26, 43). Chan et al observed a longer
duration of drainage with cavopulmonary anastomosis procedures, frequently associated
with increased venous pressures, in comparison to other surgeries, although the volume
of drainage was not significantly different (26). Ultimately, chylothorax resulting from
20
increased venous pressures appears to be associated with an increased risk of
conservative management failure (33, 48, 63-64).
Despite the advances made in the treatment of chylothorax, there continues to be
considerable debate surrounding the appropriate form and length of conservative
management (enteral feeding versus parenteral nutrition) of chylothorax in infants and
children (36, 46, 63). Success of conservative management relies on implementing
nutrition measures that reduce chyle flow to allow for healing of the damaged thoracic
duct (36). Literature exists to suggest that any oral intake, including water, increases
lymphatic flow, thus supporting the use of parenteral nutrition to bypass the gut
completely (40). However, there is a growing body of literature to support the use of
enteral nutrition as first line treatment in infants with chylothorax. Puntis et al reported
successful resolution of chylothorax in 80% (12/15) of their subjects using an enterally
based diet supplemented with MCT (65). A retrospective study conducted by Verunelli et
al also reported successful resolution of chylothorax in 91% (10/11) of the studied subject
group after receiving a low fat diet supplemented with MCT oil (34). According to a
study conducted by Allen et al, treatment with parenteral nutrition did not reduce duration
or quantity of pleural drainage compared to patients receiving MCT based enteral
formula. In addition, the probability of requiring surgical ligation of the damaged thoracic
duct was found to be similar in both forms of treatment (29). Nguyen et al reported a
similar duration and volume of drainage for those patients treated with low-fat, MCT
based enteral diets versus those initiated on parenteral nutrition. However, it should be
21
noted that 76% of subjects were started exclusively on parenteral nutrition and the
comparison between groups excluded 2 patients from the enterally fed group that were
switched to parenteral nutrition due to high drainage volumes attributed to high venous
pressure (33). Chan et al reported a 71% recovery with MCT based feedings alone,
which is similar to the results of other studies (26). Cormack et al also observed a similar
success rate using an MCT based formula, with 78% of patients having successful
resolution of their chylothoraces (66).
The length of treatment of chylothorax with conservative means continues to be a
topic of debate in the literature (63). Most authors appear to agree that initially attempting
to decrease chylous drainage using conservative management is warranted because of the
risk associated with an invasive surgery and the potential for spontaneous resolution
using conservative techniques (46). Use of an MCT based diet may be preferable in some
patients because of the minimal risk of infection and the ability to use the gut for
be administered as an outpatient in comparison to parenteral nutrition (33, 43, 53). If the
use of an MCT based diet is unsuccessful after a specified period of time, a trial of fasting
and parenteral nutrition is then indicated (46, 53). Le Coultre et al suggest treatment with
an MCT based diet for one week followed by the initiation of parenteral nutrition if there
is no improvement. Surgical management should be considered if conservative treatment
is unsuccessful within four weeks (63). Puntis et al suggest that three weeks of
conservative management not accompanied by a reduction in chylous drainage serves as
an indication for surgery (65). Prolonged conservative treatment may put the patient at
22
increased risk for nutritional depletion, immunosuppression and may impact the outcome
of surgical treatment (34, 65).
2.1.9 Complications of Chylothorax
Although the management of chylothorax has improved, complications of
chylothorax continue to significantly impact affected patients. The unique characteristics
of chylous fluid can make associated complications serious with the severity of adverse
effects being dependent on the volume and duration of chyle loss (28). Loss of chylous
fluid during prolonged periods of therapeutic drainage can lead to a vast array of
associated morbidities including protein-calorie malnutrition, fluid loss and electrolyte
imbalances as well as lymphocytopenia and immunodeficiency (26, 33, 51).
Resulting nutritional depletion with prolonged drainage or high volume drainage
make age appropriate weight gain extremely difficult with weight loss observed in some
cases (29, 43, 65). However, not all studies have yielded consistent results. Puntis et al
reported a weight loss of up to and greater than 8% in one third of patients, with the most
severe weight loss being observed in those with the largest volume of drainage (65).
Pedra et al reported a weight loss of up to 12% in 67% of patients (43). Le Coultre et al
reported a weight loss of < 5% with the exception of one patient who experienced a
weight loss of 10% (63). Allen et al observed weight loss of less than 10% in 14 of 18
children studied with no difference between those patients receiving MCT based enteral
diets and parenteral nutrition (29). In contrast, Nguyen et al observed weight maintenance
or age appropriate weight gain. This may be related to the routine use of intravenous lipid
solutions for provision of additional calories both in patients treated with parenteral
23
nutrition as well as in patients treated with MCT based enteral nutrition (33). Cormack et
al reported a weight gain from the time of surgery to the date of discharge in 14 of 17
patients (82%). The remaining 3 subjects (18%) were discharged at a lower weight than
was recorded prior to surgery but the overall weight loss was less than 3% (66).
Allen et al observed lymphopenia in 36% of subjects with available white blood
cell counts and 5 of 18 subjects developed infections (29). Of those patients who
developed infections, only 2 were patients with observed lymphopenia and therefore offer
no clarity regarding the effect of depleted T-cells and risk of infections (29).
2.1.10 Breast Milk and Chylothorax
The diagnosis of chylothorax can be challenging for any infant and extremely
disappointing for parents, especially for those who had hoped to provide breast milk as
the primary form of nutrition for their infant. Traditionally, infants with chylothorax have
represented a small group of infants for whom breast milk has been contraindicated.
Breast milk has long been recognized as the optimal food for infants (6). Breast milk
contains approximately 45% to 50% of its total energy as fat and of that fat content 80%
90% is LCT (67). Thus it is necessary to withhold breast milk from infants for the
duration of treatment of chylothorax (68-69). The inability to breast feed and/or provide
breast milk to an infant with chylothorax can lead to a multitude of feeding difficulties
such as those discussed above. For parents who wish to breast feed their infant, the
duration of treatment of chylothorax may make the ability to sustain adequate milk
production and to reinitiate exclusive breast feeding post treatment extremely
challenging. Ideally, treatment for chylothorax would involve minimal disruption to the
24
pt to avoid the development of potentially
detrimental feeding issues such as refusal to feed and dependence on nasogastric tube
feeding. Avoidance of further exacerbation of existing nutritional or growth concerns is
also an important goal. For these reasons, dietitians, doctors, nurse practitioners,
lactations consultants and other members of the multidisciplinary team at our facility
have demonstrated great interest in investigating the use of fat-modified, nutrient fortified
breast milk for patients with chylothorax.
At present, there are few published studies examining the use of a modified fat
breast milk in the treatment of infants with chylothorax. Hamdan et al published a case
study in which an infant with chylothorax was successfully treated with a combination of
drug therapy and modified fat breast milk after the patient exhibited intolerance to the
MCT based formula (2). The patient had a complex course of treatment that included the
initial use of parenteral nutrition followed by subsequent use of medication to reduce
drainage. Modified fat breast milk prepared using centrifugation and fortified with
medium chain fatty acids, complex sugars and protein was initiated only after a decrease
in drainage had already been observed (2). Therefore attributing successful resolution of
the chylothoraces to the use of the modified fat breast milk in this particular case is not
possible is. However, what is significant is that it did not increase the drainage and opens
up the possibility for its use in patients with chylothorax.
A study by Chan and Lectenberg published in 2007 described the use of modified
fat human milk for the treatment of chylothorax in infants with chylothorax of either
25
congenital or surgical aetiology (3). The milk was centrifuged at 3000 rpm for 15
minutes at 2ºC. The subsequent modified fat breast milk was then frozen for later use.
Analysis revealed that the mean fat removed was 5 ± 1 g/dl and that the total milk
recovery was 95 ± 2%. The authors noted that it took approximately 60 minutes to
process 1000 ml of milk (3). Supplementation of the modified fat milk was variable and
included the use of MCT based formulas, glucose polymers, medium chain triglycerides
and protein powder (3). Two patients did not receive nutrient enriched modified fat
breast milk and instead received additional nutrition support in the form of parenteral
nutrition and lipids (3). Analysis of the modified fat breast milk after centrifugation
revealed an electrolyte content similar to that of human milk and an expected deficiency
of calories, essential fatty acids and fat soluble vitamins (3). No information was
provided regarding the impact on the protein content of the modified fat breast milk. In
the seven infants treated, no reaccumulation of chylous fluid was observed. The mean
length of treatment with the modified fat breast milk was 16 days (range 7 34 days) (3).
Most recently, a case study was published describing the use of a modified fat
breast milk for a full term infant in whom chylothorax developed following repair of a
coarctation of the aorta (4). To prepare the modified fat breast milk, the breast milk was
allowed to sit in the refrigerator for 8 12 hours until the fat had separated to the top of
the container. The resulting modified fat breast milk in the bottom of the container was
removed using a nasogastric tube and a syringe. This procedure was repeated with the
resulting modified fat milk, allowing it to sit for several additional hours to remove any
remaining fat (4). Prior to being fed to the infant, the modified fat breast milk was
26
fortified with an MCT based formula to provide 20 kcal/oz (0.67 kcal/ml). The infant was
also provided with daily doses of walnut oil to ensure adequate provision of essential
fatty acids (4)
mother learned to perform the fat removal procedure in hospital, prior to the infants
discharge. The study did not comment on whether or not the fat content of the modified
fat breast milk was tested prior to fortification with the MCT formula (4). Unfortunately
the mother did not have adequate breast milk supply and the infant was ultimately
transitioned to exclusive formula feeding. However it was not clear from the study if this
Nevertheless, the chylothorax successfully resolved and no reaccumulation of chyle was
reported (4).
Anecdotal information is readily accessible on the internet and professional list
s -modified breast milk for the
treatment of chylothorax at other North American hospitals. Emerging case studies and
available information suggest that the use of modified fat breast milk for the treatment of
chylothorax is growing. However its effectiveness has not yet been systematically
evaluated.
27
2.2 MEDIUM CHAIN TRIGLYCERIDES
2.2.1 Chemical Structure and Properties of Medium Chain Triglycerides
Medium chain triglycerides (MCT) are a combination of medium chain fatty acids
(MCFA) ranging in length from C6:0 to C12:0 with the bulk of the fatty acids being C8:0
(65-75%) and C10:0 (25-35%) (70-73). These fatty acids are attached to a glycerol
backbone comprise a medium chain triglyceride. MCT were first introduced in the
clinical setting in the 19
pancreatic insufficiency, fat malabsorption, impaired lymphatic chylomicron transport
and severe chylomicronemia (72).
In comparison to oils containing primarily LCT, MCT oil has a lower melting
point, is liquid at room temperature and contains less calories (8.4 kcal/g versus 9.2
kcal/g) (70-72, 74-75). In addition, MCFA are relatively soluble in water. These
distinctive features can be attributed to their lower molecular weight. In addition, MCFA
act as weak electrolytes and are highly ionized at a neutral pH, further augmenting their
solubility in a biological environment (70-72, 74). This compilation of unique
characteristics ultimately affects the way MCFA are metabolized and absorbed (70).
2.2.2 Food Sources of Medium Chain Triglycerides
Although the vast majority of dietary fats are comprised of long chain fatty acids
(LCFA) with a 14 carbon chain or longer, there are some naturally occurring MCFA in
12% of total fatty acids as C6:0 to C10:0 and 2
5% as C12:0 (72). Coconut and palm kernel oil contain large amounts of MCFA. Pure
28
MCT oils are produced by the hydrolysis and fractionation of coconut oil or palm kernel
oil and subsequent re-esterification (71, 75). The resulting oil contains almost
exclusively C8:0 (67%) and C10:0 (23%) fatty acids (76).
2.2.3 Metabolism of Medium Chain Triglycerides
With a lower molecular weight and increased solubility in comparison to LCT,
MCT are digested more efficiently by the action of pancreatic lipase (71, 74-75). This in
part can be attributed to the rate and extent at which MCT emulsify in surrounding
solutions, quickly increasing the available surface area for action of pancreatic lipase
(74). MCT are preferentially hydrolyzed by preduodenal lipases and the resulting MCFA
can be partially absorbed through the stomach mucosa (74). In addition, MCT exert less
allosteric inhibition on pancreatic lipase, facilitating its action (74). If both LCT and
MCT are present, then the MCT are the preferred substrate of pancreatic lipase (71).
Long chain fatty acids and MCFA do not follow the same pathway for absorption.
In the case of LCFA, once they have reached the mucosa, they are converted into acyl-
coenzyme A (Acyl-CoA) by the enzyme acyl-CoA synthetase. These are then
incorporated into triacylglycerols which are subsequently packaged into chylomicrons for
transport into the main circulation via the lymphatic system (71). These LCT are then
subject to lipoprotein lipase hydrolysis and fatty acid utilization by extrahepatic tissues
prior to reaching the liver (70). The enzyme acyl-CoA synthetase is specific for fatty
acids with greater than 12 carbon atoms and therefore, the majority of MCFA are not
incorporated into chylomicrons, following an alternate pathway for absorption (71).
29
Instead, MCFA are solubilised in the aqueous phase of the intestinal contents, are
absorbed directly into the portal vein circulation and are transported as free fatty acids
attached to albumin (70). The resulting products of digestion of MCT are absorbed
quickly, as fast as glucose, and the resulting MCFA leave the intestine more quickly than
LCFA (71). The increased blood flow through the portal system, in comparison to slower
lymphatic flow, hastens the arrival of MCFA into the main circulation (74). The liver is
the first organ to receive MCFA in comparison to LCFA, which enter through the
lymphatic system and may perfuse other organs before arriving at the liver (74).
Once absorbed, MCT are highly favoured for oxidation and unlike LCFA, very few
are re-esterified (74). In addition, MCFA do not require carnitine palmitoyl transferase, a
transmembrane protein required to transport LCFA, to move into the mitochondria (70,
72, 76). Thus MCFA move without difficulty into the mitochondria and are readily
-oxidation (70, 72). This may have important implications for the neonate.
Newborns may have low carnitine levels and thus MCFA may be a more readily
metabolized (74).
2.2.4 Medium Chain Triglycerides and the Neonate
During the neonatal period, glucose production is just sufficient to meet the needs
of the newborn brain and therefore there is a need for an alternative energy source that
can spare glucose (77). Bougneres et al estimated that ketones may provide up to 25% of
a newborns energy requirements (77) -
hydroxybutyrate is necessary for survival of the newborn. Ketone bodies released by the
30
liver are utilized as a source of energy by peripheral tissues but perhaps more
importantly, ketone bodies serve as a major source of energy for the developing brain
(70). In an early study Adam et al studied the ability of the fetal brain between 12 to 21
weeks gestation, to take up -hydroxybutyrate and estimated that it could account for up
to 1/3 of the energy consumed by the fetus (78) -
hydroxybuturate was 1.47 times higher than that of glucose and lends support to the key
role of ketone bodies as a fuel for oxidative metabolism by the human fetal brain (78).
The inclusion of MCT in the diet of a newborn, particularly infants born
prematurely, is thought to confer some advantages (70). Pancreatic lipase and bile salts
necessary for LCT digestion may be limited and therefore an alternate form of fat may be
beneficial (70). Lingual and gastric lipases hydrolyze MCT quickly in comparison to
LCT and the resulting MCFA may be directly absorbed into the gastric mucosa (70).
MCT are hydrolyzed more rapidly and more completely than LCT by pancreatic lipase
and the resulting MCFA are absorbed quickly (70). Carnitine levels in the neonate may
be limited and this may be a limiting factor in the transport into and subsequent oxidation
of LCFA in the mitochondria. Given that mitochondrial uptake of MCFA and
subsequent oxidation takes place independently of carnitine, MCFA may be a readily
available source of energy for the neonate (70, 73). However, more recent research is
making a case for the role of carnitine in the metabolism of MCFA in term infants (76).
In neonates, urinary excretion of medium-chain dicarboxylic acids is associated
with increased consumption of MCT and is suggested to provide an indicator of the
31
efficiency of usage of MCFA as a source of energy (76). Dicarboxylic acids are formed
by cytochrome P- -oxidation of MCFA in the liver and kidney (76).
Research by Rebouche et al monitoring excretion of medium-chain dicarboxylic acids in
infants suggests a possible role for carnitine in the metabolism of MCFA during infancy
(76). The study consisted of 2 protocols. In protocol 1, 5 infants were fed a standard
infant formula for 1 week followed by 1 week of a specialty preterm formula that
contained 40% of the fat as MCT. Both formulas contained carnitine, with the carnitine
When infants were fed a higher MCT formula, urinary excretion of medium chain
dicarboxylic acids increased (76). Plasma carnitine levels were not affected by the
feeding routine (76). In protocol 2, 20 infants (10 infants per treatment group) were fed a
soy based formula that contained 40% of the fat at MCT and containing either carnitine
or no carnitine (76). Initially, excretion of medium chain dicarboxylic acids was similar
between groups. However, by day 56, infants receiving formula without carnitine were
excreting significantly more medium chain dicarboxylic acids than those who were
supplemented with carnitine (76). The authors hypothesize that a high intake of MCT
may lead to inefficient utilization of the resulting MCFA due to a limited availability of
free intra- and/or extra-mitochondrial coenzyme A (76). However, if carnitine is present,
it may act as a reservoir for transesterification of short-chain acyl groups thus liberating
coenzyme A and increasing efficiency of MCFA utilization (76). Therefore, in infants,
carnitine may play an important role in MCFA metabolism when intake of MCT is high.
32
A negative feature of MCT is their inability to provide essential fatty acids. If
MCT provide the only source of fat in the diet, supplemental essential fatty acids must be
provided to prevent deficiency. This is particularly important in the growing infant (70).
2.2.5 Clinical Uses of Medium Chain Triglycerides
As previously mentioned, MCT are used in the treatment of a number of clinical
diagnosis. In the paediatric setting, they have found a niche in specialty formulas for use
in the preterm infant in an attempt to improve fat absorption (79). The MCFA content of
these formulas can range from 40%-50% of total fatty acids, with the majority of the
MCFA component comprised of C6:0 and C8:0 fatty acids (73). In comparison, the
MCFA content of human milk ranges from 4% (if defined as C6:0 t0 C8:0) to 12% (if
defined as C6:0 to C12:0) of total fatty acids (73). The inclusion of high levels of C6:0
and C8:0 MCFA was based on the assumptions that MCT are absorbed more readily by
the neonatal intestine and that once absorbed, MCFA are completely metabolized in the
liver to CO2 or ketone bodies. It has also been suggested that high levels of MCFA in
formula will improve nitrogen retention and growth of preterm neonates (73). However
these suggested benefits of high levels of MCT remain speculative. Sulker et al, fed 28
healthy very low birth weight (VLBW) infants a formula containing 38% of fat as MCT
oil. A second group of babies received a formula with a fatty acid profile that more
closely resembled that of human milk and contained no added MCT (79). Although fat
absorption was higher and resulting fat accretion significantly higher in the MCT fed
group, there was no difference observed in weight gain (16.6 ± 2.42 g/kg/day vs. 16.1 ±
2.32 g/kg/day). Nitrogen absorption and excretion levels were not different between
33
groups and both groups experienced similar protein accretion levels. Overall, the MCT
formula did not appear to impact nitrogen retention or excretion nor do the results of this
study suggest related growth advantages (79). In a similar study by the same group, the
effects of an MCT based formula on mineral balance were examined (80). Fecal loses of
calcium in infants fed LCT formula were found to be significantly higher in comparison
to those infants fed an MCT formula and was correlated with excretion of fat. This led to
lower calcium absorption and retention. A similar pattern was observed for magnesium.
Therefore, although the previous study did not suggest growth advantages, this
subsequent study suggests that calcium and magnesium absorption is increased with the
use of MCT based formula (80).
Hamosh et al performed a similar study in which 12 preterm infants were fed both a
formula containing fat primarily as LCT (7% MCT) and a formula containing 42% of the
total fat as MCT (81). Each infant served as his/her own control and received both
formulas for a period of 1 week. Fat absorption and weight gain was not significantly
different when infants were fed either the MCT formula or LCT formula. However, as
mentioned in the discussion of preceding studies, detection of a difference in growth
would be difficult with such a small sample of infants (81). Both MCT and LCT were
hydrolyzed in the stomach of the infants with C8:0 and C10:0 being preferentially
released followed by the release of 18:1 and 18:2 fatty acids (81). The amount of C8:0
and C10:0 in the stomach was found to be low, suggesting that they had been absorbed
prior to sampling supporting the notion that MCFA are a readily available source of
energy for the newborn (81).
34
In a study by Wu et al, the effect of variable levels of MCT in infant formula on
gastrointestinal tolerance, fat absorption, plasma ketone and urinary dicarboxylic acid
levels was examined in 64 low birth weight infants (82). MCT content of the randomly
assigned formula was 0%, 17%, 34% or 50% of the total fat content. No difference in
gastrointestinal tolerance was observed as assessed by the presence of gastric aspirates,
abdominal distension and episodes of emesis (82). Fat absorption was not significantly
different between groups. Plasma levels of 3-hydroxybutyrate were significantly higher
in those infants who received 50% of their total fat intake as MCT in comparison to those
who received no MCT but was not significantly different from those infants receiving
17% and 34% of total fat as MCT. Urinary levels of dicarboyxlic acid increased with
increasing MCT content of the formula (82).
2.3 BREASTFEEDING AND THE PROVISION OF BREAST MILK
Breast milk is known to be the gold standard for infant feeding (5). The American
Academy of Pediatrics, the Canadian Paediatric Society and Health Canada strongly
suggest that breast milk be the favoured feeding for all infants for the first 12 months of
life, with appropriately timed introduction of complimentary solid foods (7-9). The
World Health Organization recommends exclusive breast feeding for the first six months
of life. Following this, infants should receive safe, nutritionally appropriate
complimentary foods with continued breast feeding for 2 years and beyond (6). Recent
breastfeeding data indicates that 90% of Canadian women express an intention to
35
breastfeed their infants with 90.3% actually initiating breastfeeding after birth (83). Thus,
breastfeeding is the initial feeding method of choice for most Canadian women.
2.3.1. Breast Milk and Digestibility
Properties inherent to human breast milk contribute to ease of digestibility,
improved tolerance of feeds and superior nutrient delivery (10). To illustrate, the protein
component of human milk is predominantly whey, making up approximately two-thirds
of the protein content (69). Once in the stomach of the infant, the whey protein forms a
soft curd which is more easily digested by the developing gastrointestinal tract of the
infant. In addition it promotes gastric emptying in comparison to casein, the predominant
protein found in bovine milk and, until the last decade, the predominant protein found in
most standard infant formulas (10). Human milk contains an inactive form of lipase that
is activated by bile salts in the duodenum and contributes to improved digestibility and
absorption of fat, the major source of energy in human milk (69).
2.3.2 Breast Milk and Immunity
In contrast to formula, breast milk is a complex living nutritional fluid that contains
antibodies, enzymes and hormones which impart important immunological and other
recognized health benefits to the infant e.g. disease prevention (84). One of the earliest
identified sources of immunity was through the transfer of immunoglobin A (IgA) from
mother to infant in breast milk and thus providing an acquired form of immunity. Early
human milk, known as colostrum, is especially high in IgA. If a nursing infant and
mother are exposed to a new enteric pathogen, a sample of the pathogen reaches the
36
maternal intestinal mucosa and initiates a cascade of events that results in the priming of
B cells for the production of antibodies. When these B cells are in close proximity to the
mammary epithelial cells, the IgA that is produced is equipped with a carbohydrate chain
and thus becomes secretory immunoglobin A (sIgA). When the sIgA is consumed in the
milk, it resists digestion, and attaches to the pathogen thus inhibiting the development of
disease. This serves as a primary form of defence for the newborn infant (85).
Human milk is not a sterile fluid but rather contains bacteria and other components
which may act as a prebiotic, promoting the development of beneficial bacteria that play
a role in disease prevention (86). Particular interest has been focused on species of
lactobacilli found in human milk, as they are thought to have prebiotic properties,
promoting the growth of bacteria which may offer immune protection to the infant (85-
86). It is known that breast milk fed infants have gastrointestinal microflora that is
distinctly different from that of the formula fed infant. The gut of the breast fed infant is
characterized by the predominance of bifidobacteria, a bacteria that produces acetic and
lactic acids, creating an acidic environment unfavourable to the growth of pathogenic
bacteria and thus assisting in disease prevention (86-87). The bifidobacteria compete for
colonization as well as nutrients and thus inhibits growth of the pathogenic bacteria (86).
Human milk contains oligosaccarides, a group of carbohydrates that can be found in
either their conjugated or unconjugated form which together are categorized as glycans
(88). Unconjugated oligosaccarides are the third most common solid component of
human milk behind lactose and lipids (88). These glycans are suggested to function as
37
prebiotics, promoting the growth of beneficial bacteria such as Lactobacillus bifidus. In
addition, they function as pathogen-binding agents, preventing harmful pathogens from
binding to receptors sites on the mucosal surface of the host gastrointestinal tract (85, 88).
Other immune factors include free fatty acids, especially monoglycerides that are
shown to be antiviral, antibacterial and antiprotozoal and may provide a source of
immunity against ingested pathogens (85). Lactoferrin, a protein found in the whey
portion of human breast milk, has been reported to have several immune functions
including the sequestering of iron from pathological bacteria and thus inhibiting their
growth in the infants gastrointestinal track (85). Further immune benefits can be derived
-lactalbumin to an alternate conformation that occurs in the
to be letha -lactoalbumin made lethal
(85).
2.3.3 Breast Milk and Disease Prevention
2.3.3.1 Breast Milk and Diseases of Childhood
The provision of breast milk has been suggested to play a role in the possible
prevention of certain childhood diseases as well as providing protection against the
development of chronic diseases later in life (21). Evidence exists to suggest that breast
feeding and/or provision of breast milk as well as duration of breast milk feeding may
provide a protective role against the development of Type I Diabetes Mellitus (89-90).
38
The provision of breast milk may contribute to risk reduction for certain childhood
(15-16). Breast feeding has also been shown to have a protective effect against the
development of celiac disease as well as ulcerative colitis and Chron s disease (21, 91-
92). The well recognized immune benefits of human milk may confer an advantage in the
prevention of allergy (93). As previously discussed, human milk does contain a multitude
of immune-modifying components such as IgA antibodies against bacteria, fungi, food
and inhalants (94). Breast milk also contains pro-inflammatory cytokines, such as tumour
necrosis factor- -inflammatory factors and chemokines. Depending on the
equilibrium of these substances, the immune response that plays a role in allergy
development may be enhanced or suppressed (94). Breast feeding has been associated
with a reduction in the risk of atopic dermatitis (93). Gut colonization through
environmental contact, especially with the mother, provides an important antigenic
which has a significant influence on the bacterial colonization of the gut as well as the
oral and nasal mucosal barriers by regurgitation (94).
2.3.3.2 Breast Milk and Otitis Media
Acute otitis media is among the most common of childhood illnesses and a
growing body of evidence supports a role for breastfeeding in the reduction of otitis
media infections (84). At meta-analysis conducted by Uhari et al examining the risk
factors for acute otitis media found that there was a reduction in risk with exclusive
breastfeeding for a minimum of 3 months (95). Duffy et al conducted a prospective study
39
to examine the effects of breast feeding, on the occurrence of acute otitis media and otitis
media with effusion (13). Results found that for the first 3 months of life, the cumulative
incidence of otitis media was the same in both breastfed and group formula fed infants.
However, from 6 to 12 months of age, the cumulative incidence of first episodes of otitis
media increased from 52% to 76% in formula fed infants versus 25% to 51% in
exclusively breast fed infants (13). Those infants who were exclusively formula fed were
also found to be at elevated risk for recurrent episodes of otitis media (13). Using data
derived from a cohort of patients who participated in the Infant Care Practice Study, a
prospective longitudinal cohort, Vernacchio et al reported an association between
breastfeeding and a reduction in maternal reports of otitis media infections with an odds
ratio of 0.69 (14). However, this study only looked at reported incidence of otitis media
within a one month time span and did not differentiate between exclusive and partial
breastfeeding.
Despite these described benefits, studies exist that have failed to observe such
benefits. Alho et al performed a retrospective cohort study with the goal of assessing the
relationship between modifiable risk factors, including breast feeding, and the occurrence
of otitis media (96). Little benefit was observed with breast feeding > 3 months with an
odds ratio of 0.9, in comparison to an odds ratio of 0.8 for those who were breast fed for
< 3 months (96). Therefore, the protective effect of breast feeding was small in
comparison to that seen in other studies. Issues with study design may have been a key
factor in the observed outcomes of the study. No distinction was made between exclusive
or partial breast feeding (96).
40
Stenström et al performed a retrospective case-control study to describe various
factors that differ between children who are prone to otitis media infections and those that
are not (97). Otitis prone children were defined as those children who experienced 5 or
more episodes before the age of 30 months (97). Similar to the study findings of Alho et
al, no difference in breast feeding duration was found between the otitis prone children
and the controls (97).
2.3.3.3 Breast Milk and Gastrointestinal Infections
The potential role of breast milk and an associated reduction in gastrointestinal
infections is important for all infants but particularly in developing countries where the
effects of diarrhoea can be devastating (6). Kramer et al conducted an observational
cohort study using a group of subjects from within the Promotion of Breastfeeding
Intervention Trial (PROBIT) study (12). Two groups of infants were examined: those
who were exclusively breastfed for 3 months (n=2862) and those who were exclusively
breastfed for 6 months (n=612). Exclusive breastfeeding was defined as no liquids or
solids other than breast milk. Infants exclusively breastfed for 6 months or longer were
found to have a significant reduction in the risk of gastrointestinal infections (12).
Quigley et al published the results of a case control study that examined the effects of
several factors, including breast feeding, on the occurrence of diarrhoeal illness in 1990s
England (11). Parents were asked to specify how their infant was currently receiving
milk: either exclusive breast feeding mixed breast feeding/bottle feeding or exclusive
bottle feeding. Provision of formula was associated with a fourfold increase in diarrhoeal
41
illness in infants under and over 6 months of age in comparison to those who were
exclusively receiving breast milk (11). Receiving no breast milk and not receiving
exclusive breast milk was also associated with an increase in diarrhoeal disease (11). The
odds ratio of diarrhoeal disease increased with increasing time since cessation of breast
feeding in those infants who had ever been breast fed (11).
2.3.3.4 Breast Feeding and Cardiovascular Health
The relationship between infant nutrition and long term cardiovascular health
continues to be an area of on-going research. In contrast to formula, human milk contains
cholesterol and infants receiving human milk have been found to have higher mean blood
levels of cholesterol in infancy (21, 98). However, when examined in adulthood, breast
feeding has been shown to be associated with lower levels of cholesterol in comparison to
those who were bottle fed (21). A recent systematic review by Owen et al examined 17
observational studies of either cross-sectional or longitudinal design (99). Results focused
on mean differences in total cholesterol values in adults who as infants had been either
breastfed or formula-fed. Adults who had been breastfed had a marginally lower total
cholesterol level than those who had been formula fed (99). However, the difference in
mean total cholesterol levels was more pronounced when those who had been exclusively
breast fed were compared to those who had been exclusively formula fed (99). Of note,
of the 7 studies included in the examination of the effects of exclusive breastfeeding, all
but one had feeding history recorded in infancy, increasing the likelihood of accurate
feeding data (99). These results lend further support to results of earlier work by Owen et
al where total cholesterol levels and low density lipoprotein levels were found to be
42
modestly lower in adults that had been previously breastfed versus those that had been
bottle fed (98). Interestingly, this relationship only appeared in adulthood as no
relationship between breast feeding and total cholesterol or low density lipoprotein levels
in adolescence was observed (98). The authors suggest that some form of nutritional
programming, possibly the results of the unique nutrient profile of human milk in
observed in adulthood (98).
Additional studies lend support to the protective role of breast milk against
cardiovascular disease. In a study by Singhal et al, preterm infants that received banked
human donor milk had lower blood lipid levels and lower blood pressures in adolescence
in comparison to those that were formula fed (100). Evidence from the Boyd Orr Cohort
suggests a reduction in the degree of atherosclerosis at age 65, as measured by intima-
media thickness and plaque prevalence, in adults that had been previously breast fed
versus those that were bottle fed. This effect was unchanged when factors such as blood
pressure, cholesterol and insulin resistance were controlled for (101). The Nurses Health
Study suggested an 8% reduction in risk of coronary heart disease in those that had been
previously breast fed (24). The problem that persists with these types of studies is that
accurate recall of breastfeeding history in an older cohort is plagued with the inaccuracies
of human memory, decreasing the likelihood of finding a protective effect.
43
2.3.3.5 Breast Feeding and Obesity
Of recent interest is the possible relationship between breast feeding and the
occurrence of obesity, a growing public health concern (102). Evidence continues to be
contradictory and studies are often confounded by the short comings of observational
studies. The means of protection associated with breast feeding are difficult to isolate
because many other aspects of development are related to the potential development of
obesity, such as maternal education, race/ethnicity, maternal size and birth weight, all of
which breast feeding is maintained (17). Suggested mechanisms may be related to
differences in protein content between breast milk and formula, variance in overall
energy intake, differences in hormonal responses to breast milk versus formula and effect
on adaptation to the introduction of solids (103).
A systematic review was conducted by Owen et al to examine the relationship
between feeding during infancy and obesity in later life (102). Sixty-one studies that
documented a relationship, either quantitative or observational, of the risk of obesity later
in life between those who were breastfed versus formula fed, were included. Of these 61
studies, 28 studies provided 29 quantified estimates of the effect of breastfeeding versus
formula feeding on the development of obesity later in life. Of these, 28 supported a
reduced risk of obesity with breastfeeding. A fixed-effects model revealed that breastfed
subjects were less likely to be classified as obese later in life when compared to formula-
fed subjects with an odds ratio of 0.87 (103). The positive relationship was stronger in
smaller studies but did exist in larger studies (103). The positive relationship was much
stronger in the 4 studies in which the feeding groups were defined as exclusive
44
breastfeeding with an odds ratio of 0.76 (103). Of the 14 studies that included
information on duration of breastfeeding, an increase in protection appeared to exist with
(103). When the important effects of
socioeconomic status, parental BMI and smoking status were controlled for in 6 studies,
the odds ratio was reduced to 0.93 (95% CI: 0.88 0.99) (103).
A meta-analysis was conducted by Harder et al to determine a possible association
between duration of breast feeding and occurrence of overweight (19). Seventeen studies
met the inclusion criteria of original data, a reported odds ratio and 95% confidence
interval and data on duration of breastfeeding for at least one exposure group (19). A
weighted meta-regression analysis showed an inverse relationship between duration of
breastfeeding and the risk of overweight (19). This was confirmed by categorical
analysis. Using a random effects model, each month of breastfeeding was associated with
a 4% decrease in risk of overweight with an odds ratio of 0.96/month (19). Only 2 studies
included in the analysis defined exclusive breastfeeding and yielded a similar odds ratio
of 0.94/month (19). The type and number of confounders differed largely between studies
included in this meta-analysis and as a result, no confounder-adjusted odds ratio was
calculated(19). Results from other studies suggest that the observed relationship may
weaken when confounders are considered (102).
The World Health Organization recently published a meta-analysis regarding the
long-term effects of breastfeeding that include the studies discussed above, all the papers
included in these meta-analysis and any newly identified in the literature search
conducted by The World Health Organization and at the University of Pelotas (102). This
new meta-analysis included 33 studies with 39 estimates of the relationship between
45
breast feeding and prevalence of overweight/obesity. Results of a random effects model
suggest a small protective effect of breastfeeding against the development of
overweight/obesity (102). Those who were breast feed were less likely to be classified as
overweight or obese with a pooled odds ratio of 0.78 (95% CI: 0.72 0.84) (102).
2.3.3.6 Breast Milk and Cognition
Long-chain polyunsaturated fats are present in breast milk (67). These fatty acids,
specifically decosahexanoic acid and aracadonic acid, accumulate rapidly in the brain in
the last trimester of pregnancy and in the first months of life and are believed to play an
important role in brain development of infants (102). Until recently, formula did not
contain these unique fatty acids and thus the provision of breast milk was thought to
promote improved cognitive development. For infants with chylothorax, the lack of
adequate long-chain polyunsaturated fats in the MCT based formula deprives them of
these important nutrients for the duration of their treatment (55, 104). Although existing
data continues to be conflicting, there is some evidence to support the role of breast milk
provision in improved cognitive development (105-107).
In a meta-analysis published in 1999, Anderson et al performed assessed the
differences in cognitive development between infants who were breast fed versus those
who were formula fed with and without adjustment for covariates known to be associated
with neurodevelopment (106). Twenty key covariates were identified and include
maternal intelligence, maternal age, maternal education, maternal training and training
and paternal education (106). Of the 20 studies meeting the initial inclusion criteria, 11
46
controlled for at least 5 of the 20 identified covariates (106). Before adjustment for
important covariates, a benefit of 5.32 points in cognitive function was observed in breast
fed infants in comparison to formula fed. After adjustment for key covariates, breast
feeding was associated with a 3.2 higher cognitive developmental score than was formula
feeding (106). Low birth weight infants exhibited the most pronounced benefit from
having received breast milk (106). The magnitude of benefit increased with duration of
breast feeding with the greatest benefit being seen in with > 8 weeks of breastfeeding
(106).
In 2000, Drane et al published the results of a systematic review to investigate the
impact of breastfeeding on cognitive development (105). To be included in this analysis
studies first had to clearly define the cognitive outcome and measure it using
standardized tests. Second, feeding had to be classified as a continuous variable or a
three-level categorical variable e.g. exclusively formula fed, exclusively breast fed or
partially breast fed. Finally, studies had to control for potential confounding variables
such as socioeconomic status and maternal intelligence (105). Twenty four studies were
identified and of these, only 6 met all three methodological criteria. Of the 6 studies, 4
found an advantage of breastfeeding on cognitive development of 2 to 5 IQ points for
term infants and 8 points for preterm infants (105).
Vohr et al examined the potential beneficial effects of breast milk provision on
intelligence scores in extremely low birth weight infants at 30 months of age (108). The
Bayley Scale of Infant Development II including the mental scale, motor scale and
47
behavioural scale was used to measure neurocognitive development. The group was
composed of 773 extremely low birth weight infants, 593 of whom received some breast
milk while in hospital. Mothers of those infants who received some breast milk were
more likely to be college educated, married, Caucasian and of higher socioeconomic
status than mothers who did not provide any breast milk (108). Breast milk provision was
divided into quintiles based on volumes of breast milk provided to the infant. Increasing
volumes of breast milk provided was associated with earlier achievement of full feeds
and shorter duration of hospitalization (108). Infants in the top 3 quintiles of breast milk
provision during initial hospitalization had higher mental and motor development than
those in the lowest quintile. Bayley scores were also significantly higher in the top 2
quintiles of breast milk provision for the behaviour rating scale (108). In addition, rates
of re-hospitalization were significantly lower for those infants who received larger
volumes of breast milk (108). Unfortunately, no information was collected about
maternal IQ, a factor that has highly predictive of IQ in offspring in other studies (108-
109).
Horwood et al examined the association between provision of breast milk and
cognitive abilities at 7-8 years of age in low birth weight babies (110). An association
was observed between increasing duration of breast feeding and cognitive abilities for
both verbal and performance intelligence quotient (IQ) (110). When potential
confounding factors frequently associated with duration of breast feeding such as
maternal education, two-parent families and smoking during pregnancy were taken into
48
consideration, the effect was diminished with only the effect between duration of breast
feeding and verbal IQ remaining (110).
In a recent study by Kramer et al, the cognitive development of infants enrolled in
the Promotion of Breastfeeding Intervention Trial (PROBIT) in Belarus was examined at
6.5 years of age (107). The PROBIT trial attempted to address methodological limitations
associated with observational breastfeeding studies by using cluster randomization.
number of characteristics e.g. number of births, rural vs. urban. Of each pair, one hospital
was randomized to receive the experimental breastfeeding intervention modelled on the
Baby-Friendly Hospital Initiative of the World Health Organization and United Nations
which promotes health care worker assistance with initiating and
maintaining breastfeeding and lactation and postnatal breastfeeding support (107). The
other hospital in the pair received standard care (107). Mothers who expressed an
intention to breastfeed their infants were eligible for enrolment. The experimental
breastfeeding intervention led to significantly longer duration of breast feeding and a
higher prevalence of exclusive breast feeding (107). The Weschler Abbreviated Scales of
Intelligence (WASI) was used to measure IQ at 6.5 years of age. Higher WASI scores
were observed with longer duration of any breastfeeding and with longer duration of
exclusive breastfeeding (107). IQ scores for both verbal and performance IQ were higher
in exclusive breast feeding for > 6 months in comparison to exclusive breast feeding for 3
6 months and < 3 months (107). One limitation of the study was that the
49
which may have favourable swayed the results for those infants who had been breast fed
(107).
In contrast to these supporting studies, Der et al used data from the US longitudinal
survey of youth to examine the relationship between breast feeding and intelligence and
to examine the role of potential confounders, most notably maternal intelligence (109). A
sibling comparison analysis was used as one method to control for confounders. The
Peabody individual achievement test was administered at 5 and 14 years of age. Results
revealed that children who were breastfed were more likely to have an older, non-
smoking mother with a higher IQ, education, in a supportive home environment (109).
Before adjustment for confounding factors, breast feeding was associated with improved
mental ability (109). However, once maternal intelligence was controlled for, this effect
was significantly reduced suggesting that maternal characteristics, such as maternal IQ,
were largely responsible for the observed effect of higher IQ in breastfed infants (109).
Although some conflicting evidence does exist, the suggested role of breast milk
feeding in the prevention of childhood illness such as otitis media and gastrointestinal
infections as well as the potential role in the prevention of chronic diseases of adulthood,
underscores the importance of supporting ongoing provision of breast milk throughout
infancy. Immune properties of breast milk alone are reason enough to ensure particularly
fragile infants, such as those with congenital heart disease, are afforded every opportunity
to continue to receive breast milk for as long as possible. When provision of breast milk
is interrupted for a period of time, such as it is when an infant requires treatment for
50
chylothorax, it opens the possibility for premature weaning of the infant and cessation of
exposure to the known benefits of breast milk. Not only will absolute exposure be
affected but also duration of breastfeeding will be affected. This is particularly
problematic as duration of breastfeeding has frequently been shown to enhance the
known health benefits (11, 102, 106-107). The use of a modified fat breast milk during an
lactation, promote an on-going sufficient milk supply and will resume breastfeeding or
breast milk feeding for their infant with the completion of treatment.
2.4 NUTRITION ISSUES IN CONGENITAL HEART DISEASE
Despite many significant improvements in the management of patients with
congenital heart disease (CHD), growth failure continues to be a significant problem in
this delicate population (25). Growth challenges frequently begin before birth and can
persist throughout infancy and into childhood, ultimately affecting long-term health (25,
32, 60).
2.4.1 Congenital Heart Disease and Birth Weight
The first evidence of growth difficulty is often evident at birth, with many infants
with CHD born at lower birth weights (25). The Baltimore-Washington Infant Study, a
population based, case-control trial examined the relationship between birth weight and
CHD, controlling for infant and maternal factors known to affect birth weight (30).
Results demonstrated that a greater percentage of infants within all categories of CHD
were classified as low birth weight (birth weight <2500g) in comparison to the control
51
population (30). Infants with tetralogy of fallot, endocardial cushion defect, severe
ventricular septal defects, atrial septal defect, coarctation of the aorta and hypoplastic left
heart syndrome all exhibited significant birth weight deficits (30). Infants with
transposition of the great arteries were found to have normal birth weights (25, 30, 32).
Likewise, Kramer et al examined the birth weights of 843 babies with CHD and
found these infants to have a significantly lower birth weight in comparison to a healthy
reference group (31). Although the difference was statistically significant, the authors
note, that the magnitude of the difference was only 57 g for healthy male controls and 56
g for healthy female controls (31). Those infants with tetralogy of fallot and secundum
atrial septal defects had the most pronounced deficit in birth weight (31). Infants with
CHD were also found to be more frequently classified as small for gestational age (birth
weight < 10th percentile) or low birth weight (birth weight < 2500g) in comparison to the
control population (31). In a more recent study, Jacobs et al examined the birth weight of
454 southern Chinese infants with symptomatic CHD. Infants were considered to be
small for gestational age (SGA) if their z-score for birth weight was < -2 Z reference
charts for Hong Kong (32). Results revealed that the mean birth weight of infants with
CHD was significantly lower than the reference group and 15% of infants with CHD
were classified a SGA (32). The birth weight of infants with transposition of the great
Arteries did not differ from reference values (32).
52
2.4.2 Congenital Heart Disease and Postnatal Growth
In the postnatal period, characteristic patterns of growth emerge. Historically,
research has suggested that infants with cyanotic lesions displayed more pronounced
growth failure than infants with acyanotic lesions (25). However, recent research
suggests a more pronounced growth failure in those with acyanotic lesions, particularly
those with increased pulmonary blood flow (in larger left-to-right shunts) and the
presence of congestive heart failure (111). Jacobs et al reported on postnatal growth in
363 Southern Chinese children less than 4 years of age with CHD (111). At the time of
surgery, mean weight-for-age, length/height-for-age and weight-for-height were all
significantly lower than the reference mean (111). Overall, ~ 40% of the subjects had
weight-for-age and height/length-for-age > 2 standard deviations (SD) below the mean of
the reference population (111). Girls were significantly more affected in weight-for-age
and weight-for-height at the time of surgery than boys (111). At the time of surgery, 57%
of patients with acyanotic defects had weights-for-age and heights-for-age > 2 SD below
the reference mean in comparison to 47% of those with cyanotic defects (111). More
children in the acyanotic group (28% versus 11%) were classified as having low weight-
for-height (111). Those with cyanotic defects were significantly more affected in height-
for-age than weight-for-age versus those with acyanotic defects who were equally
affected in both parameters (111). This shift in growth patterns maybe the result of earlier
surgical correction of severe cyanotic lesions which may help to attenuate and/or reverse
growth failure (25). It should be noted that this study did not exclude those with
chromosomal abnormalities, which likely impacted on the growth of some of the subjects
(111).
53
In a study by Schuurmans et al, growth data of 123 children with CHD were
retrospectively analyzed (112). The children studied had one of 5 diagnosis: ventricular
septal defect closed before 1 year of age, ventricular septal defect that closed
spontaneously, small ventricular septal defect but no surgical intervention, transposition
of the great arteries operated on within the first few weeks of life, tetralogy of fallot
undergoing repair within the first 2 years of life (112). Patients with a large ventricular
septal defect experienced preoperative weights and heights z-scores that were
significantly abnormal compared to the reference population (112). Following surgery,
height improved significantly in the first 12 18 months postoperatively. However,
weight continued to be abnormal in the 36-48 month period with a mean z-score of -1.15
(112). Weight z-score (mean -2.32) and height z-scores (mean -2.68) of patients with
tetralogy of fallot were also significantly abnormal compared to the reference population
prior to surgery (112). Following surgery, patients experienced an improvement in height
but values continued to be abnormal with a mean z-score of -1.22 at 36-48 months of age
(112). Weight in tetralogy of fallot patients normalized within 6 12 months (112).
Patients with transposition of the great arteries showed only minor growth disturbances
and growth of patients with a small ventricular septal defect was completely normal
(112).
Infants with single ventricle physiology are more likely to experience congestive
heart failure and hypoxemia and thus form a group of infants with CHD that are
particularly susceptible to growth difficulties (113). Vogt et al examined the somatic
54
growth of 123 infants with single ventricle physiology and who underwent staged
palliation including a bidirectional cavopulmonary shunt and Fontan. Suboptimal
nutrition was documented and was defined as the inability to tolerate feeds or to achieve
adequate caloric intake, requiring the placement of a nasogastric tube or gastrostomy tube
and calorie feeding (113). The infants with single ventricle physiology had a lower birth
weight than the reference group. Z-scores for weight declined significantly between birth
and the bidirectional cavopulmonary shunt procedure. Those who were classified as
experiencing nutritional difficulties in the pre-bidirectional cavopulmonary shunt
procedure period had lower weight z-scores than the remainder of the study group (113).
Following the bidirectional cavopulmonary shunt procedure, infants experienced catch up
weight gain which levelled off after the Fontan procedure. Z-scores for height
experienced a small improvement following the BCPS but no further improvement was
seen after the Fontan procedure. Z-scores also showed improvement following the
bidirectional cavopulmonary shunt procedure and drifted towards normal following the
Fontan (113).
Examining a more specific group of single ventricle subjects, Kelleher et al
performed a retrospective review of a group of 50 infants with a diagnosis of hypoplastic
left heart syndrome to determine prevalence and risk factors for malnutrition.
Malnutrition was defined as weight-for-age z-score < -2 (114). All infants studied
underwent a Norwood procedure with a Blalock-Taussig shunt followed by a
bidirectional Glenn (114). From the time of initial admission to discharge following the
Norwood procedure, median discharge weight remained unchanged from median
55
admission weight (114). At discharge, mean weight-for-age z-score was -1.4 (114).
Infants with longer hospital stay, longer stay in the intensive care unit, higher diuretic
dose at discharge and shorter duration of parenteral nutrition support had lower weight-
for-age at discharge (114). On readmission for the bidirectional Glenn, 58% of infants
were below the 5th weight-for-age percentile and mean weight-for-age z-score had
declined to -2.1. Thirty-eight percent were below the 5th length-for-age percentile (114).
Infants with lower caloric concentration of feedings at discharge post Norwood, more
frequent admissions prior to the bidirectional Glenn, worse right ventricular function and
higher oxygen saturations at discharge post Norwood tended to have lower weight-for-
age z-score at readmission for the bidirectional Glenn (114). The prevalence of
malnutrition was high among this group of patients and more aggressive nutritional
therapy in the form of parenteral nutrition and higher calorie feedings was associated
with improved nutritional status (114).
In a study by Varan et al, 65% of 89 infants studied were below the 5th percentile
for weight-for-age and 52% were below the 5th percentile for length-for-age (115). Forty
two percent of infants fell below the 5th percentile for both weight-for-age and length-for
-to- (115). Results suggested that infants with
cyanotic heart disease with pulmonary hypertension had a higher incidence of low length-
for- -to-
the study. Varan et al found that those infants with cyanotic heart disease accompanied
by pulmonary hypertension were reported to have lower caloric intake for their age in
comparison to cyanotic heart disease without pulmonary hypertension (115). Those with
56
pulmonary hypertension, regardless of cyanotic or acyanotic defects were more like to be
th percentile for both weight and height) (115).
2.4.3 Causes of Growth Failure in Congenital Heart Disease
There are many factors considered to be associated with growth failure in children
with CHD (115-116). Achieving adequate caloric intake in the infant with CHD can be
extremely challenging. Issues such as fatigue with feeding, oral aversion, early satiety,
poor feeding tolerance, decreased appetite and malabsorption of nutrients may all play a
role in preventing adequate intake of energy and nutrients (56, 114-116). In a study by
Schwarz et al investigating effective nutritional management of growth failure in infants
with CHD, only caloric intake that exceeded 150 kcal/kg/day by continuous nasogastric
infusion resulted in significantly improved nutrition status (117). Studies have shown that
although resting energy expenditure appears to be similar to age-matched reference
children, increased caloric requirements may be attributed to an increase in total daily
energy expenditure which would include energy required for physical activities that may
range from something as simple as feeding in infants to climbing a set of stairs in
children (118). Barton et al used the doubly labelled water technique to measure total
daily energy expenditure in 8 infants with CHD and significant growth failure (119).
Total daily energy expenditure was found to be significantly higher in infants with CHD
than in healthy infants and the authors estimated that a caloric intake of approximately
140 kcal/kg/day may be necessary to support normal growth in these infants (119). Using
both respiratory calorimetry and doubly labelled water, Leitch et al reported similar
results (120). No difference was found in resting energy expenditure or energy intake in
57
infants with uncorrected cyanotic CHD at 2 weeks of age and again at 3 months of age
(120). However, at 2 weeks of age, these infants did display slightly higher total energy
expenditure and by 3 months of age the TEE was significantly higher in comparison to
healthy controls (60, 120). Ackerman et al looked specifically at 4-month old infants and
found them to have total energy expenditure 2.5 times higher than their age-matched
controls (58).
In a study by van der Kuip et al, again using the doubly labelled water technique,
the energy requirements of 11 infants between the ages of 2 8 months with CHD were
studied in comparison to 46 healthy age-matched control infants (121). Of these 11
subjects, 6 met the criteria for classification of congestive heart failure. The infants with
CHD were found to have significantly elevated total daily energy expenditure when
compared to the health age matched controls. This result was confirmed in the meta-
analysis of 65 infants which suggested that total daily energy expenditure was 35%
higher in infants with CHD (121). The presence of congestive heart failure did not appear
to have a significant effect on total daily energy expenditure, an effect that was also
observed in the meta-analysis (121).
Although increased energy demands in infants with CHD appear to be related to
some degree of increased in total daily energy expenditure, other contributing factors
may include: 1) Over activity of the sympathetic nervous system in congestive heart
failure, releasing catecholamines and resulting in hypermetabolism 2) Increased brain
58
metabolism in undernourished children 3) Increased workload of the cardiac and
respiratory muscles translating into increased energy demands 4) Polycythemia as an
adaptation to chronic oxygen deprivation and compensatory acidosis 5) Incidence of
infection causing fever and subsequent increase in metabolic rate (56).
Complicating increased energy demands are the challenges associated with
provision of adequate calories (25, 115). Infants with CHD tend to tire easily with the
exertion of feeding and they may experience early satiety, resulting in the ingestion of
inadequate volume of feeds and thus inadequate energy and nutrients (56, 60, 117). The
presence of congestive heart failure may contribute to oedema and hypoxia of the gut
resulting in dysmotility and malabsorption (115, 117). Hepatomegaly decreases gastric
capacity and may increase the likelihood of emesis of stomach contents (60). The
occurrence of metabolic acidosis caused by hypoxia drives respiratory compensation and
results tachypnoea therefore increasing work of breathing and contributing to fatigue,
increased energy expenditure and difficulties with achieving adequate intake (115).
Infants with CHD may be at increased risk for gastroesophageal reflux disease resulting
from hepatomegaly causing gastric compression and thus a reduction in gastric capacity
(56, 122). Reflux causes discomfort with feeding and may contribute to the development
of an oral aversion if not properly managed (122). Diuretics and other medications may
contribute to decreased appetite and early satiety (56). The existence of malnutrition may
delay corrective surgery, slow recovery from surgery and make recuperation from any
resulting complications exceedingly challenging in infants/children with CHD (115).
Furthermore, long term malnutrition may put patients at risk for complications such as
59
impaired motor, cognitive development and may have an impact on surgical outcome and
morbidity (60, 115).
It has been suggested that the presence of congestive heart failure can significantly
affect the nutritional status of a child with CHD (60). Congestive heart failure is often
accompanied by insufficient energy and nutrient intake, poor absorption of energy and
nutrients and an increase in metabolic rate that makes meeting nutritional requirements
all the more challenging (60). In a study by Farrell et al, energy requirements of infants
with congestive heart failure and infants with a left-to-right shunt (no congestive heart
failure) were compared to a group of healthy controls. Open circuit indirect calorimetry
was used to measure resting energy expenditure and the doubly labelled water technique
was used to measure TDEE (118). No difference between groups was found in the resting
energy expenditure but those with congestive heart failure had significantly higher TDEE
(92 ± 20 kcal/kg/d) than the healthy control (61 ± 9 kcal/kg/d) (118).
More recently, attention has been focused on endocrine factors that may play a role
in growth issues. Insulin-like growth factor 1 (IGF-1) is a polypeptide that is secreted in
response to growth hormone and stimulates tissue growth (25). In a study by Dundar et
al, levels of IGF-1, among other factors, were compared between those with cyanotic
heart disease and age and gender matched controls (123). Those infants with cyanotic
heart disease who were malnourished were found to have the lowest levels of IGF-1.
Cyanotic infants that were not malnourished still had levels of IGF-1 that were lower than
the age-gender matched controls (123). Interestingly, there was a positive correlation
60
found between oxygen saturations and IGF-1 levels, supporting the role that hypoxemia
plays in the growth failure of these infants (123).
A vast body of research exists outlining the growth difficulties in infants with
congenital heart disease and the factors that contribute to these growth challenges.
Establishing a feeding regime that supports weight gain and growth is often complicated
by tolerance issues, frequent medical interventions, prolonged hospitalizations and
increased energy demands (25). Any changes in feeding routine could have an impact on
the success of a feeding regime and ultimately affect weight gain, growth and nutritional
status. When an infant develops chylothorax after surgery, a change in what the infant
feeds as well as a change in feeding method e.g. breast vs. bottle is imposed. This is
complicated by the fact that chylothorax itself is often associated with some degree of
weight loss due its corresponding nutritional losses (29, 43, 63, 65). The use of a
modified fat breast milk will help to minimize some of these changes, allowing those
infants who were receiving breast milk feeds prior to surgery to maintain some element
of their previously established feeding routine. The on-going use of breast milk will also
allow infants to benefit from the digestibility of breast milk in hopes of eliminating the
tolerance issues that are frequently observed at our institution with the introduction of the
MCT based formula (10). It is hoped that improved tolerance will result in improved
weight gain throughout treatment of chylothorax in infants.
61
3. THE EFFECTIVENESS OF LOW FAT BREAST MILK FOR THE TREATMENT OF CHYLOTHORAX IN INFANTS FOLLOWING CARDIOTHORACIC SURGERY. 3.1 INTRODUCTION AND RATIONALE Due to its ease of digestibility, immune properties and a suspected role in the
prevention of allergy and other childhood diseases breast milk is the ideal food for the
most infants (10, 21, 69, 84-85). Today, 90% of Canadian women initiate breastfeeding
after birth (83). When an infant is hospitalized immediately after birth, establishment of
breast feeding or the provision of breast milk can be challenging due to the frequent
separation of mother and baby, delays in initiation of breastfeeding and high levels of
stress affecting milk production. Therefore, successful establishment of breast feeding or
reliable provision of breast milk is no small feat for any mother/infant dyad, and in the
hospitalized cardiac infant, this is particularly true. Once a pattern of breast milk feeding
is established, the next hurdle to overcome is the achievement of a consistent pattern of
growth, again a significant challenge for the cardiac infant, well known to be faced with
growth difficulties.
A congenital heart defect is the most common anomaly present at birth and in
Canada, 1 in approximately 100 births will result in an infant affected by a congenital
heart defect (124). Of these infants, many will require surgery, some within the first year
length but inevitably longer for
those who experience complications. Chylothorax is a complication that can occur as a
result of damage to the thoracic duct during cardiothoracic surgery and results in the
accumulation of a fluid known as chyle in the chest cavity (26-28). Treatment is
primarily dietary in nature and requires that the infant be changed to a formula that is low
62
in LCT and provides the majority of fat as MCT (26-28, 46). Unlike LCT, which travel
through the lymphatic system after absorption and therefore contribute to increased chyle
flow through the thoracic duct, MCT are absorbed directly into the portal circulation,
bypassing the lymphatic system and decreasing chyle flow through the thoracic duct (72).
The fat component of breast milk is primarily LCT and therefore, at most institutions, the
provision of breast milk is precluded during the treatment period (69). Chylothorax can
be a devastating diagnosis and the mode of treatment difficult to accept for families who
have worked hard to establish a pattern of breast milk feeding to provide the inherent
benefits of breast milk and promote adequate growth in this challenging group of infants.
In addition, experience at our institution has been that the introduction of the MCT based
formula is often accompanied by exacerbation of feeding intolerance, the appearance of
new feeding tolerance issues, unwillingness to feed due to taste differences, decreased
intake and resulting growth difficulties. Finally, the MCT based formula is not an infant
formula and must be diluted for use in the paediatric population and as a result does not
provide a spectrum of nutrients that is ideal for young infants (55).
3.1.1 Research Question 1. Is nutrient enriched modified fat breast milk an effective treatment for chylothorax in
infants following cardiothoracic surgery?
3.1.2 Objective 1. To determine the effectiveness of a nutrient enriched modified fat breast milk for the
treatment of chylothorax in comparison to the MCT based enteral product that is the
current treatment standard.
63
2. To determine any existing differences in growth parameters between patients receiving
the nutrient enriched modified fat breast milk and the MCT based formula.
3.1.3 Hypothesis
Our working hypothesis is two-fold. Because of the inefficiencies associated with
manual removal of the fat layer, we hypothesize that the amount of LCT remaining in
breast milk after centrifuging will be, on average, higher than the known LCT content
(0.41g/100 ml at a concentration of 0.67 kcal/ml) of the MCT based formula (55, 125). A
higher LCT content may in turn contribute to increased drainage of chyle in infants
receiving the modified fat breast milk in comparison to the MCT based formula.
Therefore, we hypothesize that the amount of chest tube drainage will be significantly
higher in infants with chylothorax who receive the modified fat breast milk in
comparison to infants receiving the MCT based formula.
On the other hand, the inherent properties of breast milk may improve feeding
tolerance in comparison to the MCT based formula. As a result, the infant may receive a
more sufficient quantity of the nutrient enriched modified fat breast milk and thus have
improved energy and nutrient intake. The result would then be improved growth in the
infants receiving the nutrient enriched modified fat breast milk.
64
3.2. SUBJECTS AND METHODS 3.2.1 Subjects All infants less than 12 months of age diagnosed with chylothorax at the Hospital for
Sick Children following corrective surgery for CHD, were screened within 48 hours to
determine eligibility.
3.2.2 Study Inclusion Criteria
· < 12 months of age
· Confirmed diagnosis of chylothorax (Chylothorax Care Map page 16)
· Patient to have some portion of follow up care at the Hospital for Sick Children
· Informed consent obtained from one, but ideally both, parents
3.2.2.1 Treatment Inclusion Criteria
· Previously receiving a minimum of 80% of feeds from breast milk (breast milk may
be nutrient enriched)
· Parents/guardian would like to continue to provide breast milk during treatment for
chylothorax
· Mother willing to pump (with appropriate support) breast milk to supply her infant
with as much breast milk as possible throughout the study period
· Parents/guardian willing to be available for breast milk pickup and delivery
approximately twice each week for duration of study or are willing to perform the fat
removal at home using a small table-top centrifuge
65
3.2.2.2 Control Inclusion C riteria
· Infant receiving <80% of feeds as breast milk prior to surgery
· Infant exclusively formula fed prior to surgery
· Mother unable or unwilling to pump breast milk with the intent to provide as much
breast milk as possible throughout the study period
3.2.3 Study Exclusion Criteria
· Patient receiving full parenteral nutrition at the time of chylothorax diagnosis
· For medical reasons, patient unable to follow Chylothorax Care Map
· Primary caregiver unable to communicate effectively in English
3.2.4 Study Design
The study was a non-randomized clinical control trial. Randomization was not
possible for ethical reasons related to breastfeeding and therefore group assignment was
based on the infants feeding routine prior to surgery. Infants previously receiving a
minimum of 80% of feeds as breast milk prior to surgery and whose parents expressed a
desire to continue to provide breast milk were entered into the treatment group. Infants
who received feeds primarily as formula prior to surgery were entered into the control
group and received the standard MCT based formula for the duration of the study.
Lactation support and an electric pump for home use were offered to all mothers who
wished to maintain lactation during the study period. Mothers were provided with
guidelines around proper pumping technique and frequency to ensure maximum milk
production.
66
3.2.4.1 Treatment Group
Infants entered into the treatment group received all enteral feeds as nutrient
enriched modified fat breast milk as soon as it was available. While in hospital, mothers
were instructed to express their breast milk as per The Hospital for Sick Children
Protocol using a hospital grade electric breast pump. Following expression, milk was
placed in the freezer at -
Room (MPR) at The Hospital for Sick Children. If no breast milk was available for
immediate use or breast milk supply was insufficient, the infants received the MCT based
formula until breast milk was made available or to complement the existing breast milk
supply. Fat removal was carried out in the MPR according to the procedure outlined
below. The resulting modified fat breast milk was then nutrient enriched, according to
the method described below, to replace the calories and nutrients lost during fat removal.
The nutrient enriched modified fat breast milk was provided to infants via bottle
and direction of the responsible medical team. Volume of feeds and caloric content of
feeds was also determined by the medical team based on fluid allowance, tolerance and
energy requirements to support growth.
While infants remained in hospital, fat removal was be carried out by the study
coordinator as outlined below in Option 1. After discharge, two methods for fat removal
were offered to parents of participating infants. Both are described below.
67
3.2.4.2 Fat Removal in Hospital
Fat was removed from the breast milk using centrifugation performed by the
study coordinator in the MPR under aseptic conditions. A new refrigerated centrifuge
(Allegra X-22R, Beckman Coulter, Brea, California) was committed to the study and
used only for this purpose for the entire study period. Prior to centrifugation, frozen milk
was thawed overnight in the refrigerator at 4ºC or in tepid water bath. Milk was
centrifuged at 3000 RPM at 4ºC for 15 minutes. The fat layer was then manually
removed and discarded. The resulting modified fat breast milk was then frozen at -18ºC
for future use or was nutrient enriched for immediate consumption by the infant
according to the recipe found in Appendix C. While the subject was in hospital, the
modified fat breast milk was nutrient enriched in the MPR under a laminar flow hood on
a daily basis according to hospital policy. Once discharged, parents performed the
nutrient enrichment of the modified fat breast milk at home according to a recipe
provided to them. Each recipe was based on the recipes in Appendix C, but
and adjusted throughout the study period as required.
3.2.4.3 Fat Removal Following Discharge Option 1
Following discharge, breast milk was picked up from the families and transported
to The Hospital for Sick Children for centrifugation and fat removal using the procedure
described above. The resulting modified fat breast milk was then delivered back to
families for subsequent storage and nutrient enrichment prior to feeding. Breast milk was
picked up for fat removal twice weekly.
68
3.2.4.4 Fat Removal Following Discharge Option 2
If families so chose, they could take a small, non-refrigerated, tabletop centrifuge
(VWR® Clinical 200, VWR International, Mississauga, Ontario, Canada) home to
perform the fat removal themselves. If families lived outside of the greater Toronto area
(more than approximately 45 minutes by car), this was the only option available to them
as longer distances did not allow for biweekly pickup and delivery of breast milk. If this
option was chosen, parents were educated on how to use a small table top centrifuge to
remove the fat from their breast milk. Prior to discharge, parents were required to
demonstrate their competency of fat removal by achieving a remaining fat content of
resulting low fat breast milk was tested using the crematocrit method (126). The table top
centrifuge was provided to the parents at no cost for the duration of the study.
Throughout the study, all infants continued to follow the current protocol for
treatment of chylothorax as outlined in the Chylothorax Care Map. It should be noted that
all parents of infants in the treatment group were given a back up supply of the MCT
based formula and a recipe for preparation in the case of inadequate breast milk supply.
If the patient was of an age to receive solid foods, guidelines were given to the parents
regarding types of solid foods that were acceptable according to the Minimal Fat Diet
Guidelines (see Appendix F) during the treatment period.
Upon discharge, parents were instructed to continue with the same feeding
regimen established in hospital prior to discharge. Any change to the feeding regimen
69
was discussed and developed in conjunction with the study investigator during the
follow-up clinic visit or during weekly phone follow-up. If a fluid restriction was in
r
responsible nurse practitioner.
3.2.4.5 Nutrient Enrichment
Nutrient enrichment of the low fat breast milk was necessary to replace the
nutritional components lost with the removal of fat. In our previous pilot project, the
remaining fat (as measured by the creamtocrit method and a modified Folch technique),
protein (as measured using nitrogen analysis) and energy content of centrifuged breast
milk (as measured using bomb calorimetry) was measured (125). These results were then
used to determine the necessary fortification of the modified fat breast milk (125). Using
these, it was assumed that the average remaining fat, protein and energy content of the
breast milk after centrifugation was 0.95 g/100 ml, 0.9 g/100 and 47 kcal/100 ml
respectively(125). The modified fat breast milk was then fortified to provide fat, protein
and energy at levels identical to mature breast milk (4.0 g/100 ml; 1.1 g/100 ml; 67
kcal/100 ml) (104). To replace these nutrients, the modified fat breast milk was fortified
using either a combination of Similac Human Milk Fortifier (Abbott
Laboratories) and MCT oil or the MCT based formula Portagen® (Mead Johnson). The
method of nutrient enrichment was determined based on the age, size and nutrient
requirements of the baby. All recipes for nutrient enrichment were based on a standard
recipe (T
nutritional plan.
70
Table 2. Recipes for the Fortification of Modified Fat Breast Milk
RECIPE 1: 100 ml low fat breast milk + 2 packages human milk fortifier + 3.0 ml medium chain triglyceride oil
Ingredient Quantity Displacement (ml) Protein (g) Fat (g) CHO (g)Energy (kcal) Energy (kJ) Low Fat Breast Milk 100 ml 100 0.91 1 7.2 41.4 173.4 Human Milk Fortifier 1.8 g 1.3 0.5 0.18 0.9 7.0 29.3 MCT oil 3 ml 3 0 2.80 0 23.0 96.2 Total 104.3 1.41 3.98 8.1 71.4 298.9 % Total Calories 7.9% 46.7% 45.4%
Final Concentration (kcal/ml) 0.68
RECIPE 2: 100 ml low fat breast milk + 4 g of Portagen Powder + 1.5 ml medium chain triglyceride oil
Ingredient Quantity Displacement (ml) Protein (g) Fat (g) CHO (g)Energy (kcal) Energy (kJ) Low Fat Breast Milk 100 ml 100 0.91 1 7.2 41.4 173.4 Portagen 4 g 3 0.7 0.9 2.2 18.8 78.7 MCT Oil 1.5 ml 1.5 0 1.5 0 11.4 48.0 Total 105 1.61 3.4 9.4 71.6 300.1 % Total Calories 9.0% 38.9% 52.5%
Final Concentration (kcal/ml) 0.68
In addition to the standard nutrient enrichment, infants in the treatment group
-
linolenic (n-3) and linoleic (n-6) fatty acids were based on the joint recommendation of
the American Dietetic Association (ADA) and Dietitians of Canada (DC) with n-6
making up 4.0 % of total calories and n-3 making up 0.75% of total calories (127). Every
effort was made to provide as close to these recommendations as possible without
71
providing excessive amounts of LCT and compromising treatment. Soy oil, which
provides 2.089 g linoleic acid and 0.278 g -linolenic acid per teaspoon, was used to
Per 100 ml
Nutrients Portagen® Mature Human Milk
Modified Fat Human Milk
Nutrient Enriched Modified Fat Human Milk Recipe 1
Nutrient Enriched Modified Fat Human Milk Recipe 2
Energy, kcal (kJ) 67 68 41.4 69 69 Protein, g 2.4 1.2 0.9 1.3 1.5 Carbohydrate, g 7.7 7.2 7.2 7.8 9 Fat, g 3.2 3.9 1.0 3.8 3.3 Linoleic Acid, g 0.18 0.56 0.14 0.13 0.19 Linolenic Acid, g N/A 0.063 0.016 0.015 0.015 Minerals Calcium, mg 63 26 26 81 42 Phosphorus, mg 47 12 12 44 25 Magnesium, mg 14 3.4 3.4 5 7 Sodium, mg 33 16 16 23 25 Potassium, mg 84 50 50 79 71 Chloride, mg 57 42 42 59 56 Zinc, mg 0.62 0.25 0.25 0.72 0.41 Choline, mg 9 16 16 16 17 Iron, mg 1.3 0.04 0.04 0.23 0.37
N/A 1.8 1.8 2.0 N/A Vitamins
66 49 12 102 29 Vitamin C, mg 2.6 5 5 16 6
0.5 0.3 0.08 1.5 0.36 Vitamin E, mg 0.7 0.49 0.12 1.2 0.3
7 8.5 8.5 20 11 Milk nutrient composition values were obtained from the literature (68-69, 104). The composition of Portagen® was obtained from manufacturers information (55). The values for recipes 1 and recipe 2 do not include essential fatty acid supplementation as this was calculated on an individual basis for each subject. The powdered human milk fortifier used in this study was Similac Human Milk Fortifier (Abbot Nutrition, Montreal, Quebec, Canada)
Table 3. Approximate Energy and Select Nutrient Composition of Mature Human Milk, Portagen®, Modified Fat Human Milk and Nutrient Enriched Modified Fat Human Milk
72
meet these requirements. Individual requirements were calculated for each subject and
added to the modified fat breast milk.
3.2.4.6 Control Group
Upon enrolment into the control group, subjects received all enteral feeds as the
MCT based formula. The formula was prepared in the MPR according to current hospital
procedure. The MCT based formula was provided to infants via bottle and/or nasogastric
team. Volume of feeds and caloric content of feeds were determined by the medical team
based on fluid allowance, tolerance and energy requirements to support growth.
At the time of discharge, parents were provided with a recipe to prepare the MCT
based formula at home. A supply of the formula was provided for the infant free of
charge. Parents were instructed to continue to follow the same feeding regimen
established in hospital before discharge. Any changes to the feeding regimen were
developed in conjunction with the study investigator during the follow-up clinic visit or
during weekly phone follow-up. If a fluid restriction was in place, all changes in fluid
3.2.5 Fat Analysis
Remaining fat content of the centrifuged breast milk was measured using the
creamatocrit method. Samples of centrifuged breast milk were well agitated and then
extracted by suction into glass capillary tubes. Samples were then centrifuged in a
73
hematocrit centrifuge (Hettich Haematokrit, Fisher Scientific) at 3000 RPM for 3 minutes
(126). The resulting fat layer was then measured using a microhematcrit reader and
expressed as a percentage. All measurements were performed in duplicate.
3.2.6 Protein Analysis
Protein content of the centrifuged breast milk (prior to nutrient enrichment) was
determined using the Bicinchoninic Acid (BCA) protein assay. Bicinchoninic Acid is a
sodium salt that reacts with copper ions in an alkaline environment creating a purple
complex that gains in intensity with increasing protein concentrations (128). This purple
complex is then quantified spectrophotometrically at 562 nm (128-129). In a study by
Keller et al, using the Kjeldahl method used as the gold standard, the BCA protein assay
was found to provide the most consistent and reliable results when compared to other
colourimetric techniques (129).
3.2.7 Electrolyte Analysis
Analysis of the electrolyte content of the modified fat breast milk was conducted
using flame photometry, an atomic emission method used to detect and quantify metal
salts including sodium and potassium (130). All electrolyte analysis was conducted by
the Department of Laboratory Medicine at The Hospital for Sick Children.
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3.2.8 Microbiological Analysis
Quantitative cultures were used for the analysis of the microbiological content of
the breast milk prior to centrifuging and the resulting modified fat breast milk. This was
conducted by the Department of Laboratory Medicine at The Hospital for Sick Children.
3.2.9 Data Collection
The following variables were collected at the time of study enrollment by means of
parental interviews, conducted by the study coordinator, or from medical records: age of
the infant (months), date of surgery, diagnosis, type of surgical correction, birth weight,
birth length and head circumference if available, gestational age at birth, gender,
maternal/paternal age, maternal/paternal education as well as maternal and paternal
weight and height.
The data were used for one or more of the following purposes: assess subject
eligibility, compare baseline characteristics that may affect success of conservative
treatment of chylothorax, to compare post-discharge growth, and as a co-variate in the
statistical analysis.
Volume of chyle drainage, to the nearest millilitre, was monitored by nursing staff
diagnosis. Monitoring continued until the drainage subsided and the drainage tube was
removed. If the day of study enrolment was not the same day the diagnosis of
75
chylothorax was made, drainage data from the time of diagnosis was collected
Intake of the modified fat breast milk and/or MCT based formula, to the nearest
During the first week after discharge, parents were asked to complete a 3-day consecutive
weighted diet record. For accuracy, parents were asked to weigh volumes of all fluids
and solids consumed. A small scale accurate to 1 g (CS2000; Ohaus) was provided to the
parents for this purpose. Information from these diet records, in combination with the
information provided in Table 3, which describes the nutritional composition of the
nutrient enriched modified fat breast milk (treatment group) or according to the
nutritional profile of the MCT based formula (control group) was used to calculate
energy intake.
Growth measures were collected at regular intervals throughout the study period.
Weight was tracked on a daily basis, where medically possible, while the infant remained
in hospital. Weight was measured each day by the responsible nurse and recorded in the
ms to the nearest ± 10 grams.
Medela®) provided for home use. Parents were instructed to weight the infant on the
same day of the week, at approximately the same time of day, without clothes or diaper.
Weight gain was calculated on a weekly basis and was used to determine the need for
76
over the study period was done using the weight on Study Day 1 and weight on the final
day of the treatment.
Initial length and head circumference measures were taken on the day of study
enrolment, or as soon as possible thereafter. Length was measured by the study
coordinator using a length board and was recorded in centimetres to the nearest ± 0.1 cm.
Head circumference was measured using a non-stretchable measuring tape to the nearest
± 0.1 cm. Two measurements were performed and the average recorded. Length and
head circumference were performed at the first follow-up following discharge ± 3 days.
Final measures of length and head circumference were performed the last week of
treatment ± 1 week, either at the hospital or during a home visit. All measures of length
and head circumference throughout the study were taken by the study coordinator.
3.2.10 Sample Size
The primary outcome variable for this study was total chest tube drainage at
treatment day 5. For the purpose of calculating a sample size, existing chest tube drainage
data from the cardiac database at the Hospital for Sick Children of infant with
chylothorax who were treated with the MCT based formula was used. To detect no more
than a 1.0 standard deviation difference (6.9 ml/kg/d) in total volume of drainage on
treatment day 5 between the two feeding groups, a sample size of 14 per feeding group is
77
3.2.11 Statistical Analysis
Statistical analysis was conducted using SAS v9.1 (The SAS Institute, Cary, NC).
Baseline differences in demographic variables were assessed using t-tests for normally
2 statistics for all non-normally distributed variables
and categorical variables. Where differences were noted between treatment groups, as
appropriate, they were included in the statistical models used to assess differences in
outcome variables. Repeated measure analysis was use to further analyze growth data.
Statistical significant was set at a p-value < 0.05.
3.3 RESULTS
3.3.1 Subject characteristics
A total of 16 infants (56% males) were enrolled in the study. Infants included in
the study had a variety of cardiac diagnosis (Table 4). Infants in the treatment group
were more likely to be younger, with 5 of the 8 infants (63%) in this group being
newborn. As a result, infants in the treatment group tended to be smaller at study
enrolment. Neither of these differences was statistically significant. The most prevalent
diagnosis was Tetralogy of Fallot, which affected 6 of 16 (38%) subjects and was evenly
distributed between the treatment and control group. No statistically significant
difference was found in any baseline characteristics between the treatment and control
group.
78
Table 4. Subject Characteristics
Characteristics Treatment Control (n=8) (n=8) Age at enrolment, mo 2.8 ± 3.2 5.3 ± 1.9 a
Male sex, n (%) 5 (63) 4 (50) Gestational age at birth , weeks 38.6 ± 1.8 38.6 ± 2.2
Birth weight , g 3258 ± 596 2904 ± 873
Weight at study day 1, g 4588 ± 1853 5915 ± 1000 b
Length at study day 1, cm 56.3 ± 7.7 61.1 ± 3.8 c
Head circumference at study day 1, cm
37.7 ± 4.7
39.3 ± 2.5
Diagnosis Tetralogy of Fallot 3 3 Ventricular Septal Defect 0 1 Hypoplastic Left Heart Syndrome 2 0
Transposition of the Great Arteries 3 1
Atrial Septal Defect 0 1 Heart Transplantation 0 2 Differences between groups for categorical variables were assessed using one-sided t tests and X2 was used for all categorical variables. No statistically significant differences were noted between the two groups in any of the baseline characteristics. a P = 0.1125 b p = 0.1027 c p = 0.1027
3.3.2 Family Characteristics
Family characteristics are summarized in Table.5. There were no statistically
significant differences in the baseline characteristics of mothers between the treatment
and control group. However, a trend in the results suggested that mothers of infants in
the treatment group were more likely to be older, were more often Caucasian and were
more likely to have a university degree. This is consistent with recent breastfeeding
research which suggests that women who breastfeed tend to be older, and are more likely
79
to have a post-secondary education then mothers who formula feed their infants (83).
Older mothers as well as mothers with a university level education are more likely to
breastfeed longer (83). Fathers of infants in the treatment group were more likely to be
Caucasian (p=0.0336). No significant difference in the remaining family characteristics
was found between the treatment and control group.
Table 5. Family Characteristics
Characteristics Treatment Control (n=8) (n=8) Mother Age, mean ± SD (n), y 33 ± 3.2 29 ± 5.6 Ethnicity, n (%) White 5 (62) 2 (25) Other 3 (38) 6 (75) Education, n (%) University degree 5 (62) 3 (38) No university degree 3 (38) 5 (62) Father Age, mean ± SD (n), y 35 ± 3.3 33 ± 7.6 Ethnicity, n (%)a White 7 (87) 2 (29) Other 1 (13) 5 (71) Education, n (%) University degree 5 (62) 4 (57) No university degree 3 (38) 3 (43) Differences between groups for continuous variables were assessed using one-sided t tests and X2 was used for all non-categorical variables. Unless otherwise indicated, no statistically significant differences were noted between the two groups in any of the family characteristics. a Fathers of infants in the treatment group were more likely to be Caucasian p=0.0336
3.3.3 Fat Removal
As outlined in the methods sections, parents of infants in the treatment group were
offered the use of a small, easy to use, table top centrifuge, which would allow them to
80
perform the centrifuging of the breast milk and subsequent fat removal at home. This
option offered an advantage to those mothers who did not have sufficient breast milk
supply, allowing them to centrifuge milk as often as necessary to ensure that the infant
received as much modified breast milk as possible. Only 3 families chose this option.
Many infants have high care needs following cardiac surgery and thus families preferred
the ease of having this task performed for them. Some families expressed concern about
being able to perform the task properly and felt more comfortable having somebody with
more experience performing the centrifuging and fat removal. Of the 3 subjects whose
parents chose to learn to centrifuge the milk themselves, 1 infant was hospitalized for the
duration of treatment and thus the parents were not required to ever centrifuge breast
milk. The mother of a second subject had an excellent breast milk supply and thus
enough centrifuging could be done while in hospital to supply the infant with breast milk
for the bulk of the study period. As a result, the families of only 1 of these 3 subjects
actually performed a significant amount of centrifuging at home.
3.3.4 Chest Tube Drainage
No significant difference in total volume of chest tube drainage on treatment day 5
was found between the treatment (5.0 ± 5.1 ml/kg) and control group (5.7 ± 8.5 ml/kg)
(Figure 2). In addition, there was no significant difference in duration of drainage
between the treatment (7.3 ± 2.9 d) and the control group (12.5 ± 11.5 d). Detailed
drainage data for all subjects can be seen in Appendix G. Three of 8 (38%) infants in the
control group required progression to parenteral nutrition to treat their chylothorax while
none of the patients in the treatment group required parenteral nutrition, although again
this difference was not statistically significant.
81
Figure 2. Total volume of drainage for the treatment and control group on treatment day 5 (with standard deviations)
3.3.5 Modified Fat Breast Milk
Infants in the treatment group received an average of 79% of their feeds as
that not all infants were fed 100% of feeds as modified fat breast milk.
own milk supply was inadequate, the remainder of their feeds were provided as the MCT
formula. Of the 8 mothers in the treatment group, 4 were able to provide 100% of feeds
as modified fat breast milk. The remainder of the infants received a combination of
modified fat breast milk and the MCT formula. All efforts were made to support mothers
in the production of breast milk including the provision of an electric breast pump and
on-going access to a lactation consultant throughout the study for additional support.
0
1
2
3
4
5
6
7
8
9
10
Treatment Control
Volume of Drainage ml/kg
(treatment day 5)
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Table 6: Percentage of feeds consumed by treatment subjects as modified fat milk vs. MCT formula
Treatment Subject Modified Fat Milk (%) 3 45 5 56 6 100 7 100 8 72
10 60 11 100 12 100
Average 79 ± 23%
Time to centrifuge the breast milk and remove the resulting fat layer was
approximately 60 minutes per 1000 ml of breast milk. There were notable differences in
consistency of the resulting fat layer which affected ease of fat removal. Fat removal
from early milk (colostrum) was more challenging. If mothers had a good milk supply,
the colostrum was left in its unaltered form and provided to the parents to feed to the
infant after study completion. Milk volume was reduced on average by 10-15% following
fat removal. Therefore, for every 100 ml of breast milk, 85 - 90 ml of modified fat breast
milk remained after centrifugation.
3.3.5.1 Nutrient Enrichment
The supplementation of essential fatty acids did require the addition of long chain
fat to the modified fat breast milk. This is counterintuitive in the treatment of
chylothorax and did have the potential to increase chest tube drainage. However, the
supplementation of essential fatty acids was well tolerated in all the infants with the
83
exception of Subject 10. This subject returned to the outpatient cardiac clinic after
discharge and on examination was found to have some reaccumulation of chylous fluid.
When the fluid accumulation did not resolve on its own, the supplementation of essential
fatty acids was discontinued
incident.
Addition of MCT was not without associated difficulties. The MCT oil did not mix
easily and separated out quickly. For those infants feeding some or all of their feeds via
nasogastric tube (5 out of 8 treatment subjects at the time of discharge), a common
complaint of parents was that the MCT oil coated the tubing. Thus, some of the MCT oil
adhered to the tubing and as a result, infants likely did not receive all of the MCT oil
resulting in a lower than expected fat intake and overall calorie intake. This also made
cleaning the tubing challenging. Chyle is known to be high in fat and thus infants may
have had inadequate provision of fat during initial stages of treatment when chyle was
being lost through a chest tube (28). In comparison, the fat component of the MCT based
formula stays well emulsified, ensuring that the infant receives the fat portion of their
feeds and presumably contributing to a higher overall calorie intake.
3.3.6 Nutrient Analysis
3.3.6.1 Protein Analysis
The average remaining protein content for each sample of breast milk can be seen
in Table 7. The average remaining protein content was 14.3 ± 2.3 g/L. This is above the
accepted estimated protein content of mature human milk of 11.7 - 12.4 g/L (104).
84
Table 7. Measured protein content of breast milk sample after centrifugation
Treatment Subject Average Protein Content (g/L) 3 11.9 5 11.0 6 16.8 7 12.9 8 14.6 10 13.9 11 15.9 12 17.4
Overall Average 14.3 ± 2.3
Five of the 8 (63%) infants in the treatment group were newborn and it is known that the
protein content of milk tends to be higher in the earlier stages of lactation, declining as
lactation progresses (104, 131). Protein content of human milk may be as high as 14-16
g/L in early lactation, 8-10 g/L by 3-4 months of lactation and 7-8 g/L by 6 months of
lactation and onward (131). Milk samples taken from mothers of newborn infants would
have produced milk samples with higher protein content thus contributing to a higher
overall average protein content in the modified fat breast milk when compared to the
accepted protein content of mature breast milk.
85
Figure 3. Variability of remaining fat content of samples of modified fat breast milk as measured using the creamatocrit method for all treatment subjects
0
0.5
1
1.5
1 2 3 4 5 6 Remaining Fat Content
(%)
Milk Sample
Subject 3
0.83 ± 035
0.88 ± 0.23
0.69 ± 0.26
0.88 ± 0.48
0.75 ± 0.27 0.71 ± 0.26
0.86 ± 0.32
86
3.3.6.2 Fat Analysis
The remaining fat content of the breast milk after centrifugation was quite variable,
ranging from 0.5% to 1.5% of total volume, as measured using the crematocrit method
(Figure 3). The average remaining fat content after centrifugation for all samples taken
from all treatment subjects was 0.8 % of total volume, less than the previously measured
average value of 1.0 % of total volume (125).
3.3.6.3 Electrolyte Analysis
The average remaining sodium content of the breast milk after centrifugation was
6 ± 1.1 mmol/L (Table 8). This is only slightly less than the reported average level of
sodium in breast milk which is 7 mmol/L within the first 20 weeks of lactation and 5.6
mmol/L thereafter (132). The average potassium content of the breast milk after
centrifugation was 13.4 ± 1.5 mmol/L (Table 8). This is similar to the reported average
potassium content of 12.8 mmol/L mature human milk (132). These results suggest that
the electrolyte content of breast milk is not significantly altered by centrifugation.
Table 8. Measured sodium and potassium content of modified fat breast milk
Treatment Subject Na (mmol/L) K (mmol/L) 3 5 12.3 5 5 12.0 6 6 14.8 7 6 14.6 8 7 15.0 10 6 11.0 11 5 13.9 12 8 13.6
Overall Average 6 ± 1.1 13.4 ± 1.5
87
3.3.6.4 Intake Data
Data from the weighted 3-day food records regarding average energy and protein
intake from milk feedings (modified fat breast milk and/or MCT formula) as well as any
solid foods consumed by the subjects was analyzed using Food Processor SQL Ed v. 10.2
(ESHA Research, Salem, Oregon). Infants in the treatment group consumed significantly
larger volumes of milk feedings (145 ± 43 ml/kg) in comparison to infants in the control
group (105 ml/kg ± 23 ml/kg) (p=0.0435) (Figure 4). As a result, energy intake from milk
feedings was significantly higher in the treatment group (120 ± 32 kcal/kg) than in
control group (84 kcal/kg ± 29 kcal/kg) (p=0.0336) (Figure 3). When energy from solid
foods was included, the difference in energy intake was no longer statistically significant.
Figure 4. Daily volume of milk intake (a), daily energy intake from milk feedings alone (b) and daily energy intake from milk feedings + solid foods (c) in the treatment and control group *Milk = modified fat breast milk and/or MCT based formula (with standard deviations) There was no significant difference in the average protein intake from milk
feedings between the treatment group (3.1 ± 0.5 g/kg/day) and the control group (3.0 ±
0.8 g/kg/day) (Figure 5). When protein from solid foods was included, the protein
intakes were almost identical (3.2 ± 0.5 g/kg/day vs. 3.2 ± 0.7 g/kg/day). All infants in
p=0.0336 p=0.0435
a b c
88
the study had protein intakes well above the AI (1.52 g/kg/day) and RDA (1.2 g/kg/day)
for their respective age groups (104).
Figure 5. Protein intake from milk and solids for the treatment group (3.2 ± 0.5 g/kg/day) and control group (3.2 ± 0.7 g/kg/day)
3.3.6.5 Feeding Tolerance
There was no significant difference in the number of reported episodes of emesis
(0.6 ± 0.7 vs. 1.3 ± 2.4) or spit up (1.6 ± 2.3 vs. 1.1 ± 2.1) per day between the treatment
and control group.
3.3.6.6 Nasogastric Tube Requirement
It was hoped that fewer infants would require the use of a nasogastric tube for
feeding with the provision of the modified fat breast milk. Five of 8 (63%) infants in the
treatment group were discharged with a nasogastric tube for feeding versus 3 of 8 (38%)
infants in the control group. As a result, infants in the treatment group consumed an
average of 56% of their total milk feedings orally versus infants in the control group who
consumed 86% of their milk feeds orally. Neither of these differences was statistically
significant. Characteristics of infants requiring a feeding tube during the study are
89
presented in Table 9. One infant in the control group had a GJ tube in place prior to
cardiac surgery for feeding issues unrelated to chylothorax or the use of the MCT
formula. The remaining 2 infants in the control group who required a feeding tube during
the study had their nasogastric tubes removed within 1-2 weeks of discharge and fed
Table 9. Characteristics of infants requiring a feeding tube during the study period and timing of feeding tube removal in relation to study completion
Feeding Tube Removal
Subject
Group
Diagnosis
Type of feeding tube
Feeding tube in place prior to study
Before study completion
After study completion
3 Treatment Tetralogy of Fallot
NG No No Yes
5 Treatment Tetralogy of Fallot
NG No No Yes
6 Treatment Single Ventricle NG Yes No No
10 Treatment Tetralogy of Fallot
NG No Yes ----
11 Treatment Single Ventricle NG Yes No No
13 Control Atrial Septal Defect,
GJ Yes No No
14 Control Cardiomyopathy NG Yes Yes ----
16 Control Ventricular Septal Defect
NG Yes Yes ----
90
orally for the remainder of the study. Of the 5 infants in the treatment group who were
discharged with a feeding tube, 2 of these infants had a nasogastric tube in place prior to
their development of chylothorax. These same 2 infants continued to require their
nasogastric tubes for feeding after study completion, although 1 of these infants was able
to successfully transition to bottle feeding of expressed breast milk and finally
transitioned to exclusive breast feeding at approximately 4 months of age. The remaining
3 infants in the treatment group who required feeding tubes were older infants (e.g. not
newborns), 2 of who were exclusively breastfed prior to their cardiac surgery and refused
a bottle for the duration of the study.
Over the course of the study, it became increasingly clear that well established
breast feeding babies simply preferred the mechanism of breast feeding and refused a
ent group
discharged with a feeding tube had done a combination of breastfeeding and bottle
feeding prior to surgery and the nasogastric tube was removed within 1 week of
discharge. The infant fed orally for the remainder of the study.
3.3.7 Growth
3.3.7.1 Weight-for-Age
Mean weight-for-age z-scores between the treatment and control group were not
statistically different at study enrolment, although it appears to be approaching
significance (p=0.0954) (Table 10). There was no significant difference between groups
in mean weight-for-age z-scores at study completion. Infants in the treatment group
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experienced a significant decline in mean weight-for-age z-score from study enrolment to
study completion (p=0.0062). There was no significant change in mean weight-for-age z-
score in control infants over the study period.
3.3.7.2 Length-for-Age
Mean length-for-age z-score was significantly lower for infants in the control group
when compared to infants in the treatment group at study enrolment (p=0.0273). This
Table 10: Weight-for-age, Length-for-age, Weight-for-length and Head Circumference-for-age z-scores at study enrolment and study completion for treatment and control subjects
Anthropometric Study Enrolment Study Completion Treatment Control Treatment Control Weight-for-age, mean ± SD
-0.79 ± 0.75 -1.73 ± 1.26 -1.51 ± 0.85 -1.81 ± 0.94
Length-for-age, mean ± SD a,b
-0.48 ± 0.85 -1.84 ± 1.36 -0.93 ± 1.23 -1.82 ± 1.37
Weight-for-length, mean ± SD
-0.84 ± 1.09 -0.58 ± 0.78 -1.14 ± 1.18 -0.84 ± 0.85
Head circumference-for-age, mean ± SD c,d,e
-0.34 ± 0.95 -2.23 ± 1.83 -0.58 ± 1.16 -1.64 ± 1.45
Mean ± SD values are presented. Differences in z-scores at study enrolment and study completion were measured using t-tests. Unless otherwise noted, no statistical difference was detected between the treatment and control group. a Treatment > control group at study enrolment, p=0.0273 b Study completion < study enrolment in the treatment group, p=0.0131 c Treatment > control group at study enrolment, p=0.0257 d Study completion < study enrolment in the treatment group, group, p=0.0077 e Study completion > study enrolment in the control group, group, p=0.0256
statistically significant difference no longer existed by study completion. Again, infants
in the treatment group experienced a statistically significant decline in mean length-for-
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age z- score from study enrolment to study completion (p=0.0131). There was no
significant change in mean length-for-age z-score in control infants over the study period.
3.3.7.3 Weight-for-length
There was no statistically significant difference in mean weight-for-length z-score
between the treatment and control group at study enrolment or at study completion.
Neither group experienced a significant change in mean weight-for-length z-score over
the study period.
a Study completion < study enrolment in the treatment group, p=0.0062 b Study completion < study enrolment in the treatment group, p=0.0131 c Study completion > study enrolment in the control group, p=0.0256 d Study completion < study enrolment in the treatment group, p=0.0077
Figure 6. Mean z-score for weight-for-age, length-for-age, weight-for-length and head circumference-for-age at study enrolment and study completion for subjects in the treatment and control group
H ead ci rcumference -for-age W eight-for-length L ength-for-age W eight-for-age
a
b
c
d
93
3.3.7.4 Head Circumference-for-Age
Mean head circumference-for-age z-score was significantly lower for infants in the
control group when compared to infants in the treatment group at study enrolment
(p=0.0257). By study completion, this difference between the two groups was no longer
statistically significant. Again, infants in the treatment group experienced a significant
decline in mean head circumference-for-age z-score from study enrolment to study
completion (p=0.0077). In contrast, infants in the control group experienced an
improvement in mean head circumference-for-age z-score over the course of the study
(p=0.0256)
3.3.8 Microbiological Analysis
The results of the microbiological analysis of the breast milk samples for each
subject in the treatment group both before and after centrifugation are presented in Table
11. Breast milk is not a sterile fluid and all milk samples in the current study tested
positive for some form of bacteria (133). The most common organism isolated was
coagulase negative staphylococcus found in all 8 samples of milk. Coagulase negative
staphylococcus, gram positive bacteria, is commonly found on human skin and mucous
membranes in concentrations of 104 106 cfu/cm2 and has frequently been identified in
human breast milk samples (134-135). What was less predictable was the presence of
pathogenic bacteria such as Klebsiella Pneumoniae. The identification of potentially
harmful bacteria led to the formulation of a microbiological decision tree (Figure 7) to
determine the safest course of action when unacceptable levels of bacteria were found to
be -educated on hygiene when pumping breast
94
milk to minimize the risk of contamination. What was encouraging was that the level of
bacteria was almost always reduced following centrifuging suggesting that centrifuging
was not the point of contamination but more like occurred at the time the milk was
expressed. No mothers developed mastitis during the study period and no infant
developed a secondary infection.
Table 11. Microbiological analysis of milk sample pre-centrifugation and post-centrifugation Subject Microbiological Species Pre-centrifugation Post-centrifugation
Subject 3
Coagulase negative Staphylococcus 8 CFU/L 8 CFU/L
Subject 5
Coagulase negative Staphylococcus 70 colonies 40 colonies
Subject 6 Coagulase negative Staphylococcus
Subject 7 Coagulase negative Staphylococcus Klebsiella Pneumoniae* Diphtheroid organism
1 x 107 CFU/L 1.4 x 106 CFU/L 1 x 107 CFU/L
1 x 107 CFU/L 0.5 x 106 CFU/L -
Subject 8 Coagulase negative Staphylococcus Streptococcis Agalactiae Group B* Viridans Streptococcus Group*
> 108 CFU/L > 1 x 105/L <2 x 107/L
< 108 CFU/L - -
Subject 10 Coagulase negative Staphylococcus
< 108 CFU/L
< 108 CFU/L
Subject 11 Coagulase negative Staphylococcus < 108 CFU/L
< 108 CFU/L
Subject 12 Coagulase negative Staphylococcus Enterococcus Species* Staphylococcus aureus*
> 108 CFU/L > 1 x 105 CFU/L > 1 x 105 CFU/L
8 CFU/L 8 x 105 CFU/L 1 x 105 CFU/L
*Potentially pathogenic bacteria (135-136)
95
Figure 7. Algorithm of Steps to Take if Bacteria Cultured in Breast milk
3.4 DISCUSSION
3.4.1. Chest Tube Drainage
To our knowledge, this is the first systematic comparison between the effectiveness
of a modified fat breast milk and an MCT based formula for the treatment of chylothorax
in infants following cardiothoracic surgery. Examination of the primary outcome variable
revealed no statistically significant difference between those infants who received the
modified fat breast milk and those infants who received the MCT based formula in total
volume of chest tube drainage on treatment day 5 (5.0 ± 5.1 ml/kg vs. 5.7 ± 8.5 ml/kg) .
96
In addition, no statistically significant difference was observed in the duration of chest
tube drainage (7.3 ± 2.9 d vs. 12.5 ± 11.5 d) between the treatment and control group.
These results are contrary to our first hypothesis in which we speculated that volume of
chest tube drainage would be higher in infants who received the modified fat breast milk
compared to those who received the MCT based formula. This hypothesis was based on
our previous pilot study data which suggested that the amount of LCT remaining in the
modified fat breast milk after centrifugation was higher than the known LCT content of
the MCT based formula (55, 125). However, use of the crematocrit method to determine
remaining fat content after centrifugation suggested that in fact, the amount of LCT
remaining was often lower than expected. Thus, centrifugation of breast milk followed by
manual removal of the resulting fat layer resulted in a modified fat breast milk that
supported the resolution of chylothorax in affected infants. In addition, no subject who
received the modified fat breast milk experienced any reaccumulation of chylous fluid
after the treatment was complete. This result is similar to the experience described by
Chan and Lectenberg who described no reaccumulation in subjects treated with a low fat
breast milk for a mean of 16 days (range 7 34 days), a much shorter treatment period
than what is currently prescribed at our institution (3). Therefore, results from this study
suggest that use of a modified fat breast milk is neither better nor worse than the MCT
formula that is the current treatment standard and can support successful resolution of
chylothorax in infants following cardiothoracic surgery.
Although there was no statistically significant difference in duration of drainage
between groups, those infants who received the modified fat breast milk did appear to
97
have a shorter duration of drainage. This observed shorter duration of drainage may be
considered clinically relevant. If chest tube drainage as a result of chylothorax is the
primary factor keeping an infant in hospital following cardiac surgery, the results of this
study suggest that length of hospital stay would not be prolonged with the use of a
modified fat breast milk.
Not all infants in the treatment group received 100% of feeds as the modified fat
breast milk. Of the 8 treatment infants, 4 received exclusively modified fat breast milk.
The remaining 4 received a combination of modified fat breast milk and the MCT based
formula. The small number of subjects in this study precludes any meaningful statistical
comparison of those infants who received 100% of feeds as modified fat breast milk
versus those who received a combination of the modified fat breast milk and the MCT
formula. However, the average total volume of drainage on treatment day 5 in infants
who received 100% of their feeds as the modified fat breast milk was 6.9 ± 6.3 ml/kg/day
versus 3.1 ± 3.4 ml/kg/day for infants receiving a combination of the modified fat breast
milk and MCT formula. Duration of drainage in infants who received 100% of their feeds
as the modified fat breast milk was 7.0 ± 3.6 days versus 7.8 ± 2.6 days for infants
receiving a combination of the modified fat breast milk and MCT formula.
3.4.2. Growth
All infants in our study experienced growth challenges, particularly the infants who
received the modified fat breast milk, and thus measures must be taken to provide
adequate nutrient intake and to ensure optimal growth throughout the treatment period.
98
Nutritional loses are a well known side effect of chylothorax making weight gain and
growth challenging in affected infants (28). In the current study, no infants in the
treatment group experienced weight loss over the study period. Weight loss was observed
in only one subject in the control group (45 g total over the study period). Two subjects
(1 treatment, 1 control) experienced weight maintenance throughout the study. All other
subjects gained weight. However, only 3 subjects (2 treatment, 1 control) achieved
expected average daily weight gain for age. Average daily weight gain was 57% and
61% of expected age appropriate goals in the treatment and control group (Table 12)
(137). Low rate of weight gain or even weight maintenance in an infant over a 6 week
period, especially in a newborn infant in whom expected rates of weight gain are high,
would have a notable impact on z-score as was observed in infants in the treatment group
who experienced a significant decline in mean weight-for-age, length-for-age and head-
circumference-for-age z-scores over the study period.
The current study is not alone in reported issues with weight gain in infants and
children affected by chylothorax. Puntis et al reported a weight loss of up to and greater
than 8% in one third of patients, with the most severe weight loss being observed in those
with the largest volume of drainage (65). In a study of 9 children with a mean age of 26
months, Pedra et al reported a weight loss of up to 12% in 6 of the 9 subjects (43). Le
Coultre et al reported a weight loss of < 5% in a group of 24 children with chylothorax,
with the exception of one patient who experienced a weight loss of 10% (63). In a study
by Allen et al, weight loss was reported in 14 of 18 children studied. The magnitude of
this weight loss was reported to be < 10% (29). Nguyen et al reported weight
99
maintenance or even age appropriate weight gain in all surviving patients who left the
hospital (23 of 24 subjects ranging in age from 3 days to 11 years) (33). Therefore,
weight maintenance or even weight loss is frequently reported in infants and children
affected by chylothorax.
Table 12. Average daily weight gain over the study period and expected daily weight gain for age for treatment and control subjects
Subject Group Average Daily Weight Gain (g)
Expected Average Daily Weight Gain (g)135
1 Control 10 12 2 Control 10.2 11.5 3 Treatment 5.0 12 4 Control 0 16 5 Treatment 14.0 12 6 Treatment 8.7 32.5 7 Treatment 24.0 27.5 8 Treatment 33.0 32.5 9 Control 7.6 19
10 Treatment 0 13 11 Treatment 12.0 32.5 12 Treatment 15.4 32.5 13 Control 13.6 13 14 Control 14 16 15 Control 3.9 10 16 Control 7.5 17.5
There were likely several factors involved in the observed growth challenges. The
remaining fat content in the modified fat milk was likely overestimated. In the current
study, use of the crematocrit method revealed that the average remaining fat content of
100
the modified fat breast milk after centrifugation was 0.8 g/100 ml. This is less than the
previously measured average remaining fat content of 1.0 g/100 ml, the value upon which
nutrient enrichment of the modified fat breast milk was based. (125). As a result, nutrient
enrichment of the modified fat breast milk may have been inadequate, resulting in
suboptimal energy intake and contributing to the observed growth difficulties. Reported
difficulties with emulsification of the MCT into the modified fat milk may have also
contributed to less than expected fat intake, decreasing overall energy consumption by
infants in the treatment group.
The provision of inadequate protein could be a contributing factor in the poor
growth observed in treatment group. Using the BCA protein assay, the average
remaining protein content of the modified fat breast milk was determined to be 14.3 g/L
which is above the accepted average protein content of mature human milk at 11.7 12.3
g/L, suggesting that there was no change to the initial protein content of the breast milk
during centrifugation (104). Using the results of the BCA protein analysis in
combination with the intake data suggests that protein intake in both the treatment and
control group was well above the Adequate Intake for 0 6 month olds (1.52 g/kg/day)
and Recommended Dietary Allowance for 7 12 month olds (1.2 g/kg/day), the
recommended intakes established for healthy infants within their respective age groups
(104). In fact, protein intakes of the treatment and control groups were very similar.
However, the effects of chyle loss during early treatment of chylothorax may increase
protein requirements. Chyle is high in protein (20-30 g/L) and infants may have been in
an negative protein balance resulting from chyle loss through their chest tube and thus
101
required a period of repletion before deposition of new tissue was possible (28, 48). No
data exists regarding protein requirements in infants with chylothorax. However, given
the known protein content of chyle (20-30 g/L), it is reasonable to assume that protein
requirements in individuals affected by chylothorax are likely elevated to restore protein
losses and to support growth (28).
The frequent manipulation of the modified fat breast milk may have had an effect
on the macronutrient and ultimately on the energy content of the modified fat breast milk
the infants consumed. In the current study, the modified fat breast milk may have
required as many as 5-6 container changes from the point of pumping, through
centrifuging, fortification and subsequent feeding to the infant, potentially contributing to
a decrease in both fat and protein content of the modified fat breast milk. A similar effect
has been observed in the use of donor human milk. Donor milk has been found to have
lower protein content, as low as 0.9 g/L. Research suggests that this low protein content
is not related to pasteurization but may in fact be related to the frequent container
changes involved in the manipulation of the milk before it is consumed by the infant
(138). Evidence exists to suggest that preterm infants who receive donor milk do not
grow as well as those infants who receive preterm infant formula (139-141). Low protein
levels in donor milk is thought to play a pivitol role in this observed growth difficulties
(141). Even with fortification of this donor milk, protein levels may still be inadequate to
support high protein needs in these infants 3.5 -4.0 g/kg/day (141). A similar effect may
be a consideration in the current study, with multiple manipulations and container
102
changes having an impact on the resulting fat and protein content of the modified fat
milk.
From an analytical standpoint, the BCA method used to analyze protein content has
been suggested to overestimate protein content by as much as 20-40%, which may have
played a role in the high protein levels of the modified fat milk samples (129, 142). In
the current study, prior to analysis of the modified fat milk samples, the BCA method
was compared to the Kjeldhal technique using a certified standard infant formula. Results
of this comparison found no significant difference in the protein content of the standard
as measured by BCA method (n=13) (15.5 ± 1.15 g/L) in comparison to the Kjeldhal
technique (n=8) (16.1 ± 1.21 g/L) (143).
In order for protein to be adequately deposited as lean body mass, adequate non-
protein energy from carbohydrate or fat must be provided (104). If overall energy
provision was low, the protein content may have been used to provide energy rather than
to support tissue deposition and growth. Results of the 3-day weighted food record
suggest that all but 3 infants (1 treatment, 2 controls) met their estimated energy
requirements and in fact, similar to protein, most exceeded their estimated energy
requirements for age (104). However, these estimated energy requirements do not take
into consideration the protein and fat losses that occur with chylothorax and the resulting
impact on energy and protein requirements (29). These estimated energy requirements are
also not appropriate for those infants who have undergone a palliative procedure instead
of a full repair of their cardiac defect as these infants continue to have elevated energy
requirements related to their on-going struggles with complications of congenital heart
103
disease (25). Finally, the weighted 3-day food record only provided a look at energy
intake in a small window of time. Protein and energy intake may have been inadequate
in the period preceding or following the 3 days over which this data was captured.
impact on the growth of the infants. Two infants in the treatment group had single
ventricle physiology, a severe form of congenital heart disease that is frequently
associated with feeding and growth difficulties (114). Both of these subjects had
undergone an initial palliative surgery. The 2 subjects with single ventricle physiology,
both of whom were in the treatment group, had the slowest rate of weight gain in
comparison to the other infants in the treatment group, achieving only 27% and 37% of
expected average daily weight gain goals (137). As a result, these infants experienced a
large decline in weight-for-age z-score over the study period (Figure 8) from -0.26 at
study enrolment to -2.76 at study completion in Subject 6 and -0.95 at study enrolment to
-2.8 at study completion in Subject 11 and played a driving role in the overall effect on
growth observed in the treatment group. Therefore, it must be assumed that these infants
were not meeting overall energy requirements to support growth during this period of
their management. These results are in line with recent research that suggests the most
difficult time for growth in infants with single ventricle physiology is between the first
and second stage palliative surgeries (114). Kelleher et al found that median discharge
weight after Stage 1 Norwood procedure was unchanged from admission weight and
median discharge weight-for-age z-score was -1.4 (114). At the time of readmission for
the Stage 2 bidirectional cavopulmonary shunt, the median weight-for-age z-score was
104
-2.0 with 50% of the infants being significantly underweight, suggesting that achieving
adequate growth in the period between the Stage 1 Norwood and Stage 2 bidirectional
cavopulmonary shunt is a frequently observed challenge (114). A study by Vogt et al also
showed that growth between the Stage 1 Norwood and Stage 2 bidirectional
cavopulmonary shunt was impaired with a significant decline in weight-for-age z-score
between the 2 procedures (113).
The growth effects seen in the treatment group may be in part related to other basic
differences between the treatment and control group. The groups did tend to differ in age.
As illustrated in Figure 8, infants in the treatment group entered the study at younger age
with 5 of 8 (63%) infants being newborn. No infants in the control group were newborn.
Although this difference in age was not statistically significant, it may have had some
impact on the growth of the infants. In newborn infants, a higher proportion of energy
consumed is diverted to growth and tissue deposition (144). Over 1/3 of energy
requirements in the newborn is diverted to growth (144). Within the first year of life, the
cost of growth diminishes significantly. By 6 months of age, the cost of growth has
diminished to only a fraction of energy expenditure of the infant as the cost of physical
activity of the infant continues to increase (144). Thus, although energy intakes of the
infants in the treatment groups may have been significantly higher, it may still have not
provided sufficient energy to meet increased energy requirements and to support the
demands of rapid growth at this stage of life. Without a comparable number of newborn
infants in the control group, it is difficult to determine the impact of age on growth of
infants in the study. Given the known differences in growth requirements of newborn
105
infants in comparison to their older peers, it is impossible to discount this potential effect
of age on growth.
There are some well documented differences in growth of infants who are breastfed
versus formula fed that appear within the first year of life. Research by Dewey et al
revealed that infants who are breastfed and formula fed infants have similar weight gain
in the first 3 months of life (145). However, after this point, the weight gain of breastfed
infants slows. Rates of weight gain in breastfed infants continue to be slower than
-‐5
-‐4
-‐3
-‐2
-‐1
0
1
0 100 200 300
Weigh
t-‐for-‐age Z-‐score
Age (days)
Control Subjects
Treatment Subjects
Figure 8. Trajectory of change in weight-for-age z-score for treatment and control subjects from study enrolment to study completion
106
formula fed infants for the remainder of their first year (145). This difference in growth
was not seen in length or head circumference (145)
the 5 newborn infants in the treatment group. However it could explain part of the slower
rates of weight gain observed in the 3 older infants in the treatment group, who ranged in
age from 6 to 7.5 months of age at study enrolment. At this stage of life, expected rate of
weight gain would be slower in these infants receiving breast milk in comparison to their
formula fed peers (145).
Growth issues were not isolated to the treatment group. Mean length-for-age and
head circumference-for-age z-scores were well below that of the treatment group at study
enrolment and this difference was statistically significant. Although mean weight-for-age
z-scores were not significantly different between the two groups at study enrolment,
mean weight-for-age z-score of infants in the control was lower than that of the treatment
group and appeared to be approaching significance. Therefore, although infants in the
control group appeared to have better growth over the course of the study, these infants
entered the study in poorer nutritional status than infants in the treatment group. Given
the older age of infants and the known effects of unrepaired congenital heart defects on
growth, the growth deficits observed in the control infants at study enrolment are not
unexpected. Nydegger et al found that infants who underwent surgical correction later in
life (>10 days of age) had significant deficits in mean weight-for-age and length-for-age
z-scores at the time of admission for surgery (146). Resting energy expenditure was
increased before cardiac surgery in comparison to healthy control. One week following
surgery, resting energy expenditure had returned to normal levels (146).
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In contrast to the treatment group, all infants in the control group had full repair of
their cardiac defect and it is expected that following surgical correction, growth will start
to improve (112). In spite of this, infants in the control group did not show a significant
improvement in mean weight-for-age, length-for-age or weight-for-length z-scores over
the course of the study suggesting that these infants did not experience any catch-up
growth during the study and in fact many of the control infants struggled with similar
weight gain challenges to those observed in the treatment group. At study completion,
mean weight-for-age, length-for-age and weight-for-length z-scores remained well below
the standard for age. However, the length of the study may not have been sufficient time
to see expected improvements in growth parameters following corrective cardiac surgery.
Although improvements in growth are common following corrective surgery, growth
abnormalities can persist into childhood and deficits in weight and height continue to
exist in comparison to healthy controls (60, 112). Therefore, abnormalities in energy
metabolism may continue to have an impact on growth well into the post-surgical period
(60).
Unfortunately, the small number of patients in this study precludes stratification
based on diagnosis and/or surgical procedure. However, the cardiac condition of the
infant could have been a source of bias that we were unable to control for in this study. It
is well known that there are certain diagnosis and their associated surgical corrections
that occur in close proximity to the thoracic duct, such as Blalock shunts, repair of
coarctation and ligation of a patent ductus arteriosis that increase the risk of chylothorax
108
(48). Other procedures are known to be associated with prolonged chylous drainage such
as cavopulmonary procedures and the Fontan (26). In the current study, duration of
drainage was longest for 3 patients in the control group, all of whom required progression
to parenteral nutrition to treat their chylothorax. Of these 3 patients, 2 had undergone
heart transplantation. It could be suggested that perhaps the nature of the heart
transplantation procedure increased the risk of chylothorax and the likelihood of
prolonged drainage. In a study by Chan et al, heart transplantation was associated with a
higher incidence of chylothorax than other procedures with an incidence of 11.1% (4 of
36 heart transplantations performed over 28 months) (26). In theory, heart
transplantation is accompanied by extensive injury to the chest cavity increasing the
likelihood of damage to the delicate thoracic duct or associated vessels (26). It could be
suggested that had patients who developed chylothorax after heart transplantation been
excluded, the difference in duration of drainage results of this study may have been
different. Rather than excluding these patients at high risk for chylothorax, further study
with larger number of subjects would be of benefit to determine the impact of diagnosis
and/or surgical procedure on the effectiveness of modified fat breast milk.
3.4.3 Provision of Breast Milk
One of the primary goals of this study was to help ensure the on-going provision of
own benefits to these infants following their treatment for
chylothorax. All infants in the study were <12 months of age and many were <6 months
of age. The recommendation of the World Health Organization and other paediatric and
health organizations is that breast milk be the sole source of nutrition for 6 months, with
109
on-going provision of breast milk through the first year of life and beyond (6). It is
important to note that of the 8 infants in the treatment group, 5 infants went back to
partial or exclusive breast feeding and 1 patient continued to receive expressed breast
milk via nasogastric tube. Of the remaining 2 infants, 1 mother made the decision to stop
breastfeeding following study completion. The second infant, who had refused the
modified fat milk by bottle or cup and had been reliant on an nasogastric tube for the
duration of the study period, had great difficulty re-establishing breastfeeding. Mom did
not continue to pump after completion of the study and the patient transitioned to a sippy
cup and formula. However, 75% of the treatment subjects continued to receive the
benefits of breast milk following study completion.
3.4.4 Microbiological Analysis
The fact that breast milk is not a sterile fluid was well demonstrated in the current
study as all breast milk samples tested positive for the presence of at least 1 type of
bacteria, most commonly coagulase negative staphylococcus. The presence of bacteria in
human breast milk samples has been well documented. Law et al studied the bacterial
content in samples of raw (unpasteurized) human milk from all feedings provided to 98
premature infants within the first 2 weeks of life (135). Coagulase negative
staphylococcus was found in 77% of milk samples. All infants in the study were exposed
to Coagulase negative staphylococcus through human milk on at least one occasion, 41%
of infants were exposed to Staphylococcus aureus and 64% of infants were exposed to
gram-negative bacteria such as Acinetobacater species, pseudomonas fluorescens group
and Klebsiella pneumonia (135). Interestingly, in spite of frequent ingestion of
110
potentially harmful bacteria by the infants in this study, the authors could not attribute
any adverse event to the ingestion of the bacteria present in human milk (135). A study
conducted by Kvist et al examined the bacterial content of milk samples from healthy
mothers in comparison to mothers with symptoms of mastitis. Results revealed that 90%
of milk samples from healthy mothers contained coagulase negative staphylococcus
(147). In fact, in this study by Kvist et al, the 5 most common species found in milk
samples of both healthy mothers and those mothers with symptoms of mastitis were
coagulase negative staphylococcus, viridans streptococci, staphylococcus aureus, Group
B streptococci and enterococcus faecalis (147). Thus, it is not uncommon for healthy
women to produce milk samples that harbour potentially harmful bacteria. A similar
result was seen in a more recent study by Landers et al, who cultured 810 individual milk
samples prior to pasteurization for subsequent use by a donor milk bank (133). The most
commonly identified species was coagulase negative staphylococcus, found in 87% of
samples (133). Other species identified include enterococcus species in 16%,
staphylococcus aureus in 4% and dipthroids in 2% of samples (133). In the current study,
all 5 organisms reported in the above study by Kvist were isolated in at least one sample
of milk. However, one of the more surprising and concerning results was seen with a
milk sample from Subject 7, which was found to contain Klebsiella Pneumoniae. In a
study by Lindemann et al, 2% of milk samples tested contained Klebsiella species (148).
Again, Lindemann et al found the most common type of bacteria to be coagulase negative
staphylococcus 85% (148).
111
Reassuringly, the source of contamination did not appear to be the processes
associated with centrifugation of the breast milk. As previously mentioned, many of the
milk samples contained fewer bacteria after centrifugation than before, suggesting a
portion of the existing bacteria was eliminated with the removal of the fat layer. Method
of expression has been implicated as a potential source of bacterial contamination in
human milk (135). All mothers in the current study expressed milk using a hospital grade
electric pump. In a study by Liebhaber, milk expressed using a rubber bulb breast pump
contained significantly higher levels of bacteria than milk samples expressed using hand
expression (149). Tyson et al reported that milk samples expressed by manual expression
were less likely to be contaminated than milk collected by either manual or electric
pumps (150). The employment of more stringent cleaning procedures of the pump and its
associated parts reduced bacterial contamination but did not eliminate it (150). In a more
recent study by Boo et al, expressed breast milk obtained by electric breast pump had
significantly higher rates of bacterial contamination when compared to milk expressed
manually (151). In the current study, mothers were educated, and re-educated if
necessary, on proper hygiene and proper use of the breast pumps e.g. using a new pump
kit each time, ensuring the pump was marked as having been cleaned prior to use. The
effect of this hygiene education on the bacterial content of the resulting expressed breast
milk was not examined in the current study but the existing literature suggests that these
efforts may result in reduction of bacterial content but not elimination. However, no
mothers developed mastitis during the study period and no infant developed a secondary
infection.
112
3.5 CONCLUSIONS AND FUTURE DIRECTIONS
3.5.1 Conclusion
Breast milk is considered the optimal food for most infants (6). Infants with
chylothorax require dietary changes to limit intake of long chain triglycerides and as a
result are unable to have breast milk for the duration of treatment, a minimum of 6 weeks.
We conducted this study to determine the effectiveness of a modified fat breast milk for
infants with chylothorax in hopes of providing evidence to support the use of breast milk
in these patients and thus allowing affected infants to continue to receive its associated
benefits. Currently all infants diagnosed with chylothorax, whether previously breast fed
or formula fed, must transition to a medium chain triglycerides based formula. This can
be a difficult transition for all affected infants. The MCT based formula is not an infant
formula and is diluted for use in the infant population (55). Our experience with the MCT
formula suggests that there is often a decline in tolerance with the introduction of the
MCT based formula and volume of intake is frequently observed to be lower for the
duration of treatment. For previously breastfed infants, the change to the MCT based
formula also requires a change in mechanism of feeding. These can be difficult
transitions for all infants with CHD in whom feeding and growth is often challenging
(25).
To our knowledge, this is the first study to systematically evaluate the
effectiveness of a modified fat breast milk in comparison to the MCT based formula that
is the current treatment standard for the treatment of chylothorax in infants following
cardiothoracic surgery. Contrary to our first hypothesis, infants who received the
113
modified fat breast milk did not have significantly more volume of chest tube drainage on
treatment day 5 versus those infants who received the MCT formula. This result suggests
that use of a nutrient enriched modified fat breast milk can result in successful resolution
of chylothorax and may eventually offer an alternate treatment option for affected infants.
In addition, duration of drainage was not different between infants who received the
nutrient enriched modified fat breast milk and those infants who received the MCT
formula.
In spite of these positive results and contrary to our second hypothesis, growth in
infants who received the modified fat breast milk was not better when compared to those
infants who received the MCT based formula. In fact, growth in this group was
particularly challenging. The results of our study did not clearly identify the reason for
this poor growth. Although our second hypothesis speculated that tolerance of the
nutrient enriched modified fat breast milk may have been better than tolerance of the
MCT based formula, no significant difference in tolerance was observed between the two
groups.
Given the known elevated energy requirements of infants with CHD and especially
infants with single ventricle physiology, inadequate provision of calories may have been
a key element in the slow weight gain observed among the treatment subjects (25).
Although other nutrients appeared to be provided in adequate amounts, further
investigation would be of benefit to clarify if protein and fat were indeed provided in
adequate amounts for this vulnerable population of infants. Age of the infant, nutritional
114
losses associated with chylothorax, diagnosis and stage of cardiac treatment likely all
played a role in determining the observed growth patterns. Although infants in the
control group had improved growth in comparison to infants in the treatment group, the
majority of infants in this group also did not meet average daily weight gain goals for
age. In fact, the only infant who experienced weight loss over the course of the study
was in the control group. Although there is little literature that describes the growth of
infants with chylothorax, nutritional challenges are well recognized and weight loss as
well as weight maintenance, has been reported (29, 33). Although the growth results
were discouraging, difficulties with weight gain in infants with congenital heart disease
and in infants affected with chylothorax is not unexpected and highlights the need for
aggressive fortification of feeds and close monitoring of growth in all patients during
treatment.
This is the first study to suggest that the use of a modified fat breast milk for the
treatment of chylothorax in infants is successful reducing chest tube drainage for
resolution of chylothorax. This would allow on-going provision of breast milk and its
associated benefits not only during treatment for chylothorax but promote provision of
breast milk after treatment has ended. Most of the infants who received the modified fat
breast milk returned to breastfeeding or continued to receive expressed breast milk via
bottle or nasogastric feeding tube after study completion. However, the clear challenge
that emerged during the course of the study is that of achieving adequate weight gain in
the infant with chylothorax. A clearer picture of nutrient needs, taking into consideration
associated protein and fat losses, of the infant with chylothorax together with more
115
aggressive nutrient fortification, are key elements to consider when moving forward with
the possible use of a modified fat breast milk. However, based on the observed
suboptimal growth of the treatment infants in this study, further research is necessary to
ensure the safety of modified fat breast milk and to ensure optimal growth for all infants
with chylothorax and in particular, those infants receiving the modified fat breast milk.
3.5.2 Future Directions
The primary shortcoming of this study is the small sample size which limits the
value of the statistical analysis. Initially we had aimed to achieve a sample size of 14
subjects in each group however for practical reasons it was decided to end recruitment at
8 subjects in each group, resulting in limited statistical power. Because of the small
number of subjects, we were unable to control for diagnosis of the subjects enrolled in the
study, which as previously discussed, could have an impact on the nature of the
chylothorax e.g. duration of drainage, effectiveness of conservative treatment. For future
studies, stratification based on diagnosis it would be useful in establishing the impact of
diagnosis on the effectiveness of modified fat breast milk. However, the low overall
incidence of chylothorax (2.7-4.5% at The Hospital for Sick Children) in infants post
cardiac surgery would make achieving sufficient sample sizes within a diagnosis group to
support an adequately powered study very challenging (26). Although not statistically
significant, the impact of difference in age between infants in the treatment and control
cannot be discounted. For future studies, a larger sample size resulting in two groups
more similar in age may help to tease out the effects of age and stage of development on
growth in infants being treated for chylothorax. Although not analyzed statistically, there
116
were some observed differences in volume of drainage between infants who received
100% of their feeds as modified fat breast milk and those infants who received a
combination of the modified fat breast milk and MCT formula. Study of a larger number
of subjects and analysis of more defined feeding regimes e.g. exclusively modified fat
breast milk versus combination modified fat breast milk and MCT, would be required to
determine if these differences are statistically significant. Finally, on-going growth
monitoring of patients after study completion would provide a clearer picture regarding
the impact of chylothorax and its treatment on growth in all infants.
Ultimately, it is hoped that the outcomes of this study will pave the road for the
possibility of offering cardiac infants affected by chylothorax the opportunity to receive
breast milk, in a modified form, during treatment for chylothorax. It is hoped that this
will allow for less of a disruption in established feeding routines and allow parents the
opportunity to be consistent with the nutrition goal of providing breast milk and its
known benefits to their infant with congenital heart disease.
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102. Owen CG, Martin RM, Whincup PH, Smith GD, Cook DG. Effect of infant feeding on the risk of obesity across the life course: a quantitative review of published evidence. Pediatrics. 2005 May;115(5):1367-77. 103. Horta B, Bahl R, Martines J, Victoria C. Evidence on the Long-Term Effects of Breastfeeding: Systematic Reviews and Meta-Analysis. Geneva, Switzerland2007. 104. Institute of Medicine. Dietary Reference Intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein and amino acids. Washington, DC: The National Academies Press; 2005. 105. Drane DL, Logemann JA. A critical evaluation of the evidence on the association between type of infant feeding and cognitive development. Paediatr Perinat Epidemiol. 2000 Oct;14(4):349-56. 106. Anderson JW, Johnstone BM, Remley DT. Breast-feeding and cognitive development: a meta-analysis. Am J Clin Nutr. 1999 Oct;70(4):525-35. 107. Kramer MS, Aboud F, Mironova E, Vanilovich I, Platt RW, Matush L, et al. Breastfeeding and child cognitive development: new evidence from a large randomized trial. Arch Gen Psychiatry. 2008 May;65(5):578-84. 108. Vohr BR, Poindexter BB, Dusick AM, McKinley LT, Higgins RD, Langer JC, et al. Persistent beneficial effects of breast milk ingested in the neonatal intensive care unit on outcomes of extremely low birth weight infants at 30 months of age. Pediatrics. 2007 Oct;120(4):e953-9. 109. Der G, Batty GD, Deary IJ. Effect of breast feeding on intelligence in children: prospective study, sibling pairs analysis, and meta-analysis. Bmj. 2006 Nov 4;333(7575):945. 110. Horwood LJ, Darlow BA, Mogridge N. Breast milk feeding and cognitive ability at 7-8 years. Arch Dis Child Fetal Neonatal Ed. 2001 Jan;84(1):F23-7. 111. Jacobs EG, Leung MP, Karlberg JP. Postnatal growth in southern Chinese children with symptomatic congenital heart disease. J Pediatr Endocrinol Metab. 2000 Apr;13(4):387-401. 112. Schuurmans FM, Pulles-Heintzberger CF, Gerver WJ, Kester AD, Forget PP. Long-term growth of children with congenital heart disease: a retrospective study. Acta Paediatr. 1998 Dec;87(12):1250-5. 113. Vogt KN, Manlhiot C, Van Arsdell G, Russell JL, Mital S, McCrindle BW. Somatic growth in children with single ventricle physiology impact of physiologic state. J Am Coll Cardiol. 2007 Nov 6;50(19):1876-83. 114. Kelleher DK, Laussen P, Teixeira-Pinto A, Duggan C. Growth and correlates of nutritional status among infants with hypoplastic left heart syndrome (HLHS) after stage 1 Norwood procedure. Nutrition. 2006 Mar;22(3):237-44. 115. Varan B, Tokel K, Yilmaz G. Malnutrition and growth failure in cyanotic and acyanotic congenital heart disease with and without pulmonary hypertension. Arch Dis Child. 1999 Jul;81(1):49-52. 116. Weintraub RG, Menahem S. Growth and congenital heart disease. J Paediatr Child Health. 1993 Apr;29(2):95-8. 117. Schwarz SM, Gewitz MH, See CC, Berezin S, Glassman MS, Medow CM, et al. Enteral nutrition in infants with congenital heart disease and growth failure. Pediatrics. 1990 Sep;86(3):368-73.
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118. 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. Am J Cardiol. 2001 May 1;87(9):1128-31, A10. 119. Barton JS, Hindmarsh PC, Scrimgeour CM, Rennie MJ, Preece MA. Energy expenditure in congenital heart disease. Arch Dis Child. 1994 Jan;70(1):5-9. 120. Leitch CA, Karn CA, Peppard RJ, Granger D, Liechty EA, Ensing GJ, et al. Increased energy expenditure in infants with cyanotic congenital heart disease. J Pediatr. 1998 Dec;133(6):755-60. 121. van der Kuip M, Hoos MB, Forget PP, Westerterp KR, Gemke RJ, de Meer K. Energy expenditure in infants with congenital heart disease, including a meta-analysis. Acta Paediatr. 2003 Aug;92(8):921-7. 122. Weesner KM, Rosenthal A. Gastroesophageal reflux in association with congenital heart disease. Clin Pediatr (Phila). 1983 Jun;22(6):424-6. 123. Dundar B, Akcoral A, Saylam G, Unal N, Mese T, Hudaoglu S, et al. Chronic hypoemia leads to reduced serum IGF-1 levels in cyanotic congenital heart disease Journal of Pediatric Endocrinology & Metabolism. 2000;13:431-6. 124. The Heart and Stroke Foundation. Congenital Heart Disease. Available at: http://www.heartandstroke.com/site/c.ikIQLcMWJtE/b.3484063/k.E84C/Heart_disease__Congenital_heart_disease.htm. The Heart and Stroke Foundation; 2009. 125. Farmer S, Bannister L, Cornelius V, Rafii M, O'Connor D, Mager D. Development and analysis of low fat breast milk for use with in-hospital paediatric patients diagnosed with chylothorax - a pilot study. Unpublished. 2005. 126. Wang C, Chu P, Mellen B, Shenai J. Creamatocrit and nutrient composition of human milk. Journal of Perinatology. 1999;19(5):343-6. 127. Kris-Etherton PM, Innis S, Ammerican Dietetic A, Dietitians of C. Position of the American Dietetic Association and Dietitians of Canada: dietary fatty acids. J Am Diet Assoc. 2007 Sep;107(9):1599-611. 128. Smith P, Krohn R, Hermanson G, Mallia A, Gartner F, Provenzano M, et al. Measurement of protein using bicinchoninic acid. Analytical Biochemistry. 1985;150:76-85. 129. Keller R, Neville M. Determination of total protein in human milk: comparison of methods. Clinical Chemistry. 1986;32(1):120-3. 130. Hald PM. The flame photometer for the measurement of sodium and potassium in biological materials. J Biol Chem. 1947 Feb;167(2):499-510. 131. Lonnderdal B. Nutritional and physiological significance of human milk proteins. The American Journal of Clinical Nutrition. 2003 June;77(6):1537S-43S. 132. Institute of Medicine. Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate Washington, DC: The National Academies Press; 2004. 133. Landers S, Updegrove K. Baceteriological screening of donor human milk before and after Holder pasteurization. Breastfeeding Medicine. 2010;5(3):117-21. 134. Huebner J, Goldmann D. Coagulase-negative staphylococci: role as pathogens. Annual Review of Medicine. 1999;50:223-36. 135. Law BJ, Urias BA, Lertzman J, Robson D, Romance L. Is ingestion of milk-associated bacteria by premature infants fed raw human milk controlled by routine bacteriologic screening? J Clin Microbiol. 1989 Jul;27(7):1560-6.
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136. Gladwin MT, B. Clinical Microbiology made ridiculously simple. Edition 4 ed. Miami. Florida.: MedMaster, Inc. ; 2007. 137. Sickkids. Guidelines for the Administration of Enteral and Parenteral Nutrition in Paediatrics. Third Edition ed. Toronto, Ontario, Canada2007. 138. Valentine CJ, Morrow G, Fernandez S, Gulati P, Bartholomew D, Long D, et al. Docosahexaenoic Acid and Amino Acid Contents in Pasteurized Donor Milk are Low for Preterm Infants. J Pediatr. 2010 Dec;157(6):906-10. 139. Arslanoglu S, Moro GE, Ziegler EE, The Wapm Working Group On N. Optimization of human milk fortification for preterm infants: new concepts and recommendations. J Perinat Med. 2010 May;38(3):233-8. 140. Tyson JE, Lasky RE, Mize CE, Richards CJ, Blair-Smith N, Whyte R, et al. Growth, metabolic response, and development in very-low-birth-weight infants fed banked human milk or enriched formula. I. Neonatal findings. J Pediatr. 1983 Jul;103(1):95-104. 141. Schanler RJ, Lau C, Hurst NM, Smith EO. Randomized trial of donor human milk versus preterm formula as substitutes for mothers' own milk in the feeding of extremely premature infants. Pediatrics. 2005 Aug;116(2):400-6. 142. Bergqvist Y, Karlsson L, Fohlin L. Total protein determined in human breast milk by use of coomassie brilliant blue and centrifugal analysis. Clinical Chemistry. 1989;35(10):2127-9. 143. Sivagurunathan N. KS, Aufreiter S., O'Connor DL. Protein concentration in low-fat breast milk for infants during treatment of chylothorax. 2010. 144. Wells J, Davies P. Estimation of the energy cost of physical activity in infancy. Archives of Disease in Childhood. 1998;78:131-6. 145. Dewey K, Heinig M, Nommsen LP, JM, Lonnderdal B. Growth of Breast-Fed and Formula-Fed Infants From 0-18 Months: The DARLING Study. Pediatrics. 1992;89:1035-41. 146. Nydegger A, Walsh A, Penny D, Henning R, Bines J. Changes in resting energy expenditure in children with congenital heart disease. European Journal of Clinical Nutrition. 2009 Mar;63(3):392-7. 147. Kvist L, Larsson B, Hall-Lord M, Steen A, Schalen C. The role of bacteria in lactational mastitis and some considerations of the use of antibiotic treatment. International Breastfeeding Journal. 2008;3(6). 148. Lindemann P, Foshaugen I, Lindemann R. Characteristics of breast milk and serology of women donating breast milk to a milk bank. Archives of Disease in Childhood Fetal and Neonatal Edition. 2004;89:F440-F1. 149. Liebhaber M, Lewiston NJ, Asquith MT, Sunshine P. Comparison of bacterial contamination with two methods of human milk collection. J Pediatr. 1978 Feb;92(2):236-7. 150. Tyson JE, Edwards WH, Rosenfeld AM, Beer AE. Collection methods and contamination of bank milk. Arch Dis Child. 1982 May;57(5):396-8. 151. Boo NY, Nordiah AJ, Alfizah H, Nor-Rohaini AH, Lim VK. Contamination of breast milk obtained by manual expression and breast pumps in mothers of very low birthweight infants. J Hosp Infect. 2001 Dec;49(4):274-81.
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APPE NDI C ES APPENDIX A: CONSENT FORM TREATMENT GROUP
555 University Avenue Toronto, Ontario, Canada M5X Title of Research Project: The effectiveness of low-fat breast milk for the treatment of chylothorax in infants following cardiothoracic surgery. Investigators: Primary Investigator/Study Coordinator: Sarah Farmer, RD CNSD, The Hospital for Sick Children (416) 813-6747 Co-investigators:
Connor, PhD RD, The Hospital for Sick Children (416) 813-7844 Jennifer Russell, MD FRCPC, The Hospital for Sick Children (416) 813-7291 Purpose of Research: Chylothorax is a complication that affects some babies after heart surgery. When a baby develops chylothorax, they must be put on a formula that is made with a special type of fat, called medium chain triglycerides or MCT. This means that they cannot have regular formula or breast milk while they are being treated for chylothorax. Breast milk is the gold standard food for babies and it provides most nutrients in just the right amounts. Breast milk has unique properties that make it easier for babies to digest in comparison to standard infant formulas. Breast milk offers many immune benefits to babies. These immune benefits help a baby fight infection and help to decrease the occurrence of certain childhood illnesses such as diarrhoea or ear infections. These types of characteristics cannot be found in infant formulas. Babies with chylothorax, especially babies who were breast feeding or receiving breast milk by bottle before surgery, may have some trouble adjusting to the special formula. It tastes different than breast milk (or regular formula) and babies may not drink as much as they usually do. This can make weight gain difficult. It also has different ingredients than regular infant formula or breast milk and this can make it harder for the baby to digest. This means that babies may have more spit up or vomiting than they usually do and it may maalso be hard to keep a good milk supply while their baby is drinking the special formula.
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It would be ideal if infants who were receiving breast milk before surgery could continue to receive some breast milk while being treated for chylothorax. It is possible to remove most of the fat from breast milk. The purpose of this research study is to see if we remove most of the fat from breast milk, if the remaining low-fat milk is an effective treatment for chylothorax in comparison to the special formula that we are using now. This would mean that babies could continue to have some breast milk while they are being treated for chylothorax and might help avoid some of the issues described above. Description of the Research: Baby participating in this study will be placed into one of two groups. Which group your baby is placed in will depend on what your baby was eating before surgery. Babies that were breast feeding before their surgery, or drinking breast milk by bottle, have the option to be entered into the low-fat breast milk group. Babies in the low-fat breast milk group will get breast milk with most of the fat removed to treat their chylothorax. To be entered into this group, your baby must have been receiving approximately 80% of their feeds as breast milk (by breast or bottle) before surgery and you must be willing to pump breast milk for the entire time your baby is treated for chylothorax. Babies that were drinking formula before their surgery will be in the control group and will get the MCT formula that is normally used to treat chylothorax. If your baby was receiving breast milk before surgery, but you do not want to pump your breast milk throughout the study, you can be entered into the control group. Babies in the low-fat breast milk group will have some extra nutrients added to the breast milk. This is because taking the fat out of breast milk also takes out some of the calories (or energy) and vitamins that the babies need to grow. While you are in hospital, this mixture will be prepared for you in the milk preparation room. When you are ready to be discharged from hospital, you will be given detailed instructions on how to prepare this special mixture of low fat breast milk and additional nutrients at home. Babies will be fed the low-fat breast milk by bottle and/or by nasogastric tube, if necessary. If your baby was eating solids before surgery, you will also be given guidelines about what solid foods your baby can have while being treated for chylothorax.
chylothorax which is a minimum of 6 weeks. Before you leave the hospital, you will be told the date that it is safe for your baby to go back to their usual feeding routine. The study will last for approximately two years and will require a total of 28 babies. New information from this study or other studies may affect whether you want to continue to take part in the study. If this happens, we will tell you about this new information.
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What will you do in our study? If you live within the Greater Toronto Area, enrolling in the study will not require any additional visits to the hospital. All contact with the study coordinator (Sarah Kocel) will be arranged for the same day you will be visiting the cardiac clinic for your post-operative check- ologist. If your appointments do not fall within the treatment period, a home visit will be arranged at your convenience. For subjects who live outside of the Greater Toronto Area, one additional visit to the hospital at the end of the treatment period may be required. This appointment will be arranged with the study coordinator for a time that is convenient for you. If your baby does need extra appointments to closely monitor growth and feeding issues, this will be arranged at your convenience with Sarah Kocel, the study coordinator. Many babies need some extra monitoring of their growth after cardiac surgery. This is normal routine, even if you do not enrol in the study. If you agree to be in our study, we will ask some general questions about you (both Mom and Dad) such as your age, your background, how long you went to school. We will also
feeding history such as whether or not he or she was breast feeding or bottle feeding, how much he or she normally eats etc.
diagnosis and the type of cardiac surgery he or she had. We will also check to see if your baby has any other medical conditions, if they have had any other surgeries or medical
birth weight, length and head circumference are available. If this information is not in
We will weigh your baby everyday he or she is in hospital. This will happen even if you
erence at the beginning of the study and then once a week until you go home. While you are in hospital, we will monitor how much your baby drinks every day. If your baby is receiving any fluids/medications through an intravenous line, we will monitor this as well. We will also monitor how much fluid comes out of the drainage tube that is in
are not enrolled in the study.
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What happens at the beginning of the study while your baby is in hospital: Babies in the low-fat breast milk group will begin to receive the low-fat breast milk as soon as they are enrolled in the study. If no breast milk is available right away, they will receive the MCT formula until breast milk is available. Mothers of infants in the low-fat breast milk group can have the help of a lactation consultant if they would like. The lactation consultant can help with the proper way to pump and give guidelines about how often to pump to make sure you have enough milk to feed your baby. While you are in hospital, the low-fat breast milk will be prepared for you. Before you go
using the low-fat breast milk. You will also be given a recipe to prepare just the MCT formula in the event that you run out of breast milk. You will be given instructions on how much to feed your baby and how often. These types of instructions are normal routine for all infants who are being treated for chylothorax and require special feedings. While you are in hospital, very small samples of your breast milk that you pump, less than a half a teaspoon, will be taken on a regular basis. This will be done to be sure enough fat is being removed and to see if any other nutrients are being affected. What happens after you are discharged from the hospital? If your baby is in the low-fat breast milk group, you will need to continue to pump for the duration of the study. If you do not have an electric breast pump at home, one will be provided to you, at no cost, to use for the duration of the study. You will be asked to continue to follow the pumping instructions given to you by the lactation consultant. You will have access to a lactation consultant by phone if you feel you need extra instructions once you are home. You will have two options for the removal of fat from your breast milk. Option 1: Your breast milk will be picked up twice each week and brought to the hospital to have the fat removed. Once your breast milk has been centrifuged and the fat removed, the resulting low fat breast milk will then be returned to you for use. The date and time for pick-up and delivery will be arranged with the study investigator to best suit your schedule. A delivery service will be used to carry out the pickup and delivery of your breast milk. You will be given instructions on how to store the breast milk before and after pick up as well as how to pack up the breast milk for transport. Option 2: You will have the option to take home a small table top centrifuge so that you can remove the fat from your breast milk at home. This is the only option available to families who live outside of the greater Toronto area. If you choose this option, you will be taught how to use the centrifuge before you leave the hospital and given opportunities to practice so you are comfortable with the procedure. It will be important that you are
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able to remove as much fat as possible from the breast milk and you will work closely with the study coordinator to be sure you can do this each time you use the centrifuge. Once you are discharged, the study will be available to deliver the centrifuge to your home and set it up for you. If you choose this option and you live in the greater Toronto
Once you have left the hospital, your baby will need to be weighed once a week. This will be done at home on a scale that will be provided to you. This weight will need to be done on the same day of the week at about the same time of day e.g. in the morning, before a feeding. You will be required to record this weight on the weight and diet record. What happens at your first post-operative appointment? When you come to the cardiac clinic for your post-operative visit, you will also see the
th and head circumference. For this visit, you will need to write down everything that your baby eats and drinks in a booklet called a diet record. You must do this for each of the 3 days before you come to the hospital. To do this, you will need to measure the exact amount that your baby eats and drinks at each feeding. To do this we will ask you to weigh your
number. When your baby is done feeding, we will ask you to weigh the bottle (and/or dish of solids) again and record this number. A scale will be provided to you so that you can accurately measure the amount your baby has had to drink or has eaten by spoon. We will give you
· A booklet to write this information on · Simple instructions about how to record the feeding volumes (these instructions
will be reviewed with you before you go home) · A scale
You will need to bring these diet records with you when you come to your appointment. This will be the only time you need to do this for study purposes. If there are concerns about how much your baby is drinking, you may be asked to record intake as part of your
What happens for the remainder of the study period? If you have a scheduled appointment with your cardiologist during the remainder of the study period, you will also see the study coordinator at this time. For those in the low-fat breast milk group, the study coordinator will pick up your breast milk for fat removal and deliver the resulting de-fatted breast milk will be done twice a week for the remainder of the study period. The time of pickup and delivery will be arranged on a weekly basis to best suit your schedule.
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132
Throughout the remainder of the study period, all subjects will have a weekly phone call ll, you
drinking at each feeding and how often your baby is drinking. You will also be asked to report the weight of your baby. During this phone call, you can report any feeding or any other difficulties with the study protocol. If you have any questions or concerns, you will be able to contact the study coordinator at any time between your scheduled visits/phone calls using the contact information provided to you. Potential Harms: If the low-fat breast milk is not effective, the treatment of chylothorax may be longer than 6 weeks. Babies may require a period of intravenous nutrition, with no food taken by mouth, to help treat the chylothorax. This is also a risk for babies treated with the MCT formula. If the instructions for preparation of the low fat breast milk or MCT formula are not followed carefully babies may receive too many nutrients. In these cases, babies could become very sick. Also, if the instructions are not followed carefully, babies may not get enough nutrients and this may affect their ability to grow properly and recover from surgery. Potential Discomforts or Inconvenience: After leaving the hospital, you will be required to fill in a 3 day diet record that will require you to measure how much your baby drinks. You will also be required to weigh your baby once each week throughout the study period. For babies in the low-fat breast milk group, mothers are required to pump regularly and frequently to be sure you have enough breast milk to feed your baby. This breast milk will need to be packed for transport to the hospital. For those mothers who were previously breast feeding or providing breast milk by bottle but who choose enter the control group (to receive the MCT formula), regular pumping will be necessary if you wish to continue to breast feed or provide breast milk once chylothorax treatment is complete. Parents must be available for pickup and delivery of breast milk twice a week. For subjects who live outside of the Greater Toronto Area, one additional visit to the hospital at the end of the treatment period may be required. This appointment will be arranged with the study coordinator for a time that is convenient for you.
Subject Identifier:
133
Potential Benefits: Babies who can continue to have some breast milk while being treated for chylothorax may continue to get some of its benefits, such as its anti-infective properties, and may have less difficulties with digestion that are often seen with the switch to any formula, including the MCT formula. Mothers of those infants receiving breast milk will continue to pump on a regular schedule throughout the treatment for chylothorax, supporting the transition back to breastfeeding once treatment is complete by maintaining milk supply. Parents who have participated in other studies performed by our lab have found the additional contact with health care professionals during the study period extremely helpful and also found that this additional contact helped to make the transition home a little easier. This study will help us gain a better understanding of the effectiveness of using a low-fat breast milk to treat chylothorax and to offer this as a potential treatment option for parents who had hoped to provide breast milk as the main source of nutrition for their baby. Confidentiality: We will respect your privacy. No information about who you or your child is will be given to anyone or be published without your permission, unless the law requires us to do this. For example, the law requires us to give information about you or your child if a child has been abused, if you or your child has an illness that could spread to others, if you or someone else talks about suicide (killing themselves), or if the court orders us to give them the study papers.
Sick Kids Clinical Research Monitors health record to check on the study. For example, people from Health Canada Health Products and Food Branch, if necessary, may look at your records. By signing this consent form, you agree to let these pe
records. We will give you a copy for your files. The data produced from this study will be stored in a secure, locked location. Only members of the research team (and maybe those individuals described above) will have access to the data. This could include external research team members. Following completion of the research study, the data will be kept as long as required and then destroyed as required by Sick Kids policy. Published study results will not reveal your identity.
Subject Identifier:
134
Reimbursement: Any equipment required to complete this study will be provided to you at no cost e.g. breast pump and scale, MCT formula. If additional visits to the hospital are required solely for study purposes, we will reimburse you for all your reasonable out of pocket expenses associated with this visit e.g., meals, babysitters, parking and getting you to and from Sick Kids. Participation: It is your choice to let your baby take part in this study. If you choose to let your child take part in this study you can take your child out of the study at any time. The care your child gets at Sick Kids will not be affected in any way by whether your child takes part in this study. New information that we get while we are doing this study may affect your decision to take part in this study. If this happens, we will tell you about this new information. And we will ask you again if you still want to be in the study During this study we may create new tests, new medicines, or other things that may be worth some money. Although we may make money from these findings, we cannot give you (your child) any of this money now or in the future because you (your child) took part in this study. In some situations, the study doctor or the company paying for the study may decide to stop the study. This could happen even if the treatment given in the study is helping your child. If this happens, the study doctor will talk to you about what will happen next. If your child becomes ill or are harmed because of he or she took part in this study, we will treat he or she for free. Your signing this consent form does not interfere with your legal rights in any way. The staff of the study, any people who gave money for the study, or the hospital are still responsible, legally and professionally, for what they do. Alternatives to participation: If you choose not to participate in the study, your baby will receive the MCT formula to treat their chylothorax. This formula is that same treatment that babies in the control group will receive and is the current treatment that is used for all infants with chylothorax. Sponsorship: The sponsor of this study is the Labatt Heart Centre Innovation Fund. Conflict of interest: I, and the other research team members, have no conflict of interest to declare.
Subject Identifier:
135
Consent:
By signing this form, I agree that: 1) You have explained this study to me. You have answered all my questions. 2) You have explained the possible harms and benefits (if any) of this study. 3) I know what I could do instead of having my child take part in this study. I
understand that I have the right to refuse to let my child take part in the study. I also have the right to take my child out of the study at any time. My decision about my child takinSickKids.
4) I am free now, and in the future, to ask questions about the study. 5) medical records will be kept private. You will
give no one information about my child, unless the law requires you to. 6) I understand that no information about my child will be given to anyone or be
7) I have read and understood pages 1 to 9 of this consent form. I agree, or consent, that my child___________________ may take part in this study. _______________________ Printed Name of Parent/Legal Guardian Signature & Date
________________________________________ Printed Name of person who explained consent Signature & Date _______________________________________
does not read English) .
Who do I call if I have questions or problems? If you have any questions or concerns at anytime during the study, please contact the study coordinator, Sarah Farmer at (416) 813-6747 or pager (416)330-3036. A letter will be sent to your paediatrician to make them aware of your participation in this study. If you need to contact someone about medical issues related to the study, please contact Dr. Jennifer Russell at (416) 813-7291.
Subject Identifier:
136
For questions about your rights as a research subject or for information on who to contact in the event of injuries during a study, please call the Research Ethics Manager at (416) 813-5718.
Subject Identifier:
137
APPENDIX B: CONSENT FORM CONTROL GROUP
555 University Avenue Toronto, Ontario, Canada M5X Title of Research Project: The effectiveness of low-fat breast milk for the treatment of chylothorax in infants following cardiothoracic surgery. Investigators: Primary Investigator/Study Coordinator: Sarah Kocel, RD The Hospital for Sick Children (416) 813-6747 Co-investigators:
(416) 813-7844 Jennifer Russell, MD FRCPC, The Hospital for Sick Children (416) 813-7291 Purpose of Research: Chylothorax is a complication that affects some babies after heart surgery. When a baby develops chylothorax, they must be put on a formula that is made with a special type of fat, called medium chain triglycerides or MCT. This means that they cannot have regular formula or breast milk while they are being treated for chylothorax. Breast milk is the gold standard food for babies and it provides most nutrients in just the right amounts. Breast milk has unique properties that make it easier for babies to digest in comparison to standard infant formulas. Breast milk offers many immune benefits to babies. These immune benefits help a baby fight infection and help to decrease the occurrence of certain childhood illnesses such as diarrhoea or ear infections. These types of characteristics cannot be found in infant formulas. Babies with chylothorax, especially babies who were breast feeding or receiving breast milk by bottle before surgery, may have some trouble adjusting to the special formula. It tastes different than breast milk (or regular formula) and babies may not drink as much as they usually do. This can make weight gain difficult. It also has different ingredients than regular infant formula or breast milk and this can make it harder for the baby to digest. This means that babies may have more spit up or vomiting than they usually do and it may make their stomach also be hard to keep a good milk supply while their baby is drinking the special formula. It would be ideal if infants who were receiving breast milk before surgery could continue to receive some breast milk while being treated for chylothorax. It is possible to remove most of the fat from breast milk. The purpose of this research study is to see if we remove
Subject Identifier:
138
most of the fat from breast milk, if the remaining low-fat milk is an effective treatment for chylothorax in comparison to the special formula that we are using now. This would mean that babies could continue to have some breast milk while they are being treated for chylothorax and might help avoid some of the issues described above. Although your baby may not have been breast feeding or receiving breast milk by bottle before surgery, your participation in this study will make up the group of patients known as the control group. Infants in the control group will continue to receive the treatment that is currently provided to all infants with chylothorax. The control group will provide very important data that will be used for comparison against data taken from infants who receive the low fat breast milk and will help to determine its effectiveness. Description of the Research: Babies participating in this study will be placed into one of two groups. Which group your baby is placed in will depend on what your baby was eating before surgery. Babies that were breast feeding before their surgery, or drinking breast milk by bottle, have the option to be entered into the low-fat breast milk group. Babies in the low-fat breast milk group will get breast milk with most of the fat removed to treat their chylothorax. To be entered into this group, your baby must have been receiving approximately 80% of their feeds as breast milk (by breast or bottle) before surgery and you must be willing to pump breast milk for the entire time your baby is treated for chylothorax. If you agree to participate in this research study, your baby will be entered into the control group. Babies in the control group are babies that were drinking formula before their surgery and will get the MCT formula that is normally used to treat chylothorax. If your baby was receiving breast milk before surgery, but you do not want to pump your breast milk throughout the study, you will be entered into the control group as well. Babies in the control group will be fed the MCT formula that is normally used to feed all babies with chylothorax. This is the same formula your baby will receive if you decide not to enrol in the study. Babies will be fed the MCT formula by bottle and/or by nasogastric tube if necessary. While you are in hospital, the MCT formula will be prepared for you in the milk preparation room. One you are ready to be discharged from hospital, you will receive detailed instructions on how to prepare the MCT formula at home. If your baby was eating solids before surgery, you will also be given guidelines about what solid foods your baby can have while being treated for chylothorax.
chylothorax which is a minimum of 6 weeks. Before you leave the hospital, you will be told the date that it is safe for your baby to go back to their usual feeding routine. The study will last for approximately two years and will require a total of 28 babies. New information from this study or other studies may affect whether you want to continue to take part in the study. If this happens, we will tell you about this new information.
Subject Identifier:
139
What will you do in our study? If you live in the Greater Toronto Area, enrolling in the study will not require any additional visits to the hospital. All contact with the study coordinator (Sarah Kocel) will be arranged for the same day you will be visiting the cardiac clinic for your post-operative check-appointments do not fall within the treatment period, a home visit will be arranged at your convenience. For subjects who live outside of the Greater Toronto Area, one additional visit to the hospital at the end of the treatment period may be required. This appointment will be arranged with the study coordinator for a time that is convenient for you. If your baby does need extra appointments to closely monitor growth and feeding issues, this will be arranged at your convenience with Sarah Kocel, the study coordinator. Many babies need some extra monitoring of their growth after cardiac surgery. This is normal routine, even if you do not enrol in the study. If you agree to be in our study, we will ask some general questions about you (both Mom and Dad) such as your age, your background, how long you went to school. We will also
feeding history such as whether or not he or she was breast feeding or bottle feeding, how much he or she normally eats etc.
diagnosis and the type of cardiac surgery he or she had. We will also check to see if your baby has any other medical conditions, if they have had any other surgeries or medical
birth weight, length and head circumference are available. If this information is not in u to provide this information, if possible.
We will weigh your baby everyday he or she is in hospital. This will happen even if you
the beginning of the study and then once a week until you go home. While you are in hospital, we will monitor how much your baby drinks every day. If your baby is receiving any fluids/medications through an intravenous line, we will monitor this as well. We will also monitor how much fluid comes out of the drainage tube that is in
are not enrolled in the study. What happens at the beginning of the study while your baby is in hospital: Babies in the control group will begin to receive the MCT formula as soon as they are diagnosed with chylothorax. While you are in hospital, the MCT formula will be
Subject Identifier:
140
prepared for you. Before you go home, you will be given specific instructions on how to prepare the MCT formula for your baby. You will be given a recipe that will tell you how much formula and how much water is required. You will also be given instructions on how much to feed your baby and how often. This is the normal routine for all infants who are being treated for chylothorax and require special feedings, even if they are not enrolled in the study. Mothers of infants in the control group will be able to have the help of a lactation consultant to help them maintain their breast milk supply if they wish to return to breast feeding after chylothorax treatment is complete. What happens after you are discharged from the hospital? Babies in the control group will continue to feed your baby the MCT formula for the duration of the study. You will be provided with a supply of the MCT formula that will last for the rest of the study period. This formula will be provided to you for free whether or not you enrol in the study. Once you have left the hospital, your baby will need to be weighed once a week. This will be done at home on a scale that will be provided to you. This weight will need to be done on the same day of the week at about the same time of day e.g. in the morning, before a feeding. You will be required to record this weight on the weight and diet record. What happens at your first post-operative appointment? When you come to the cardiac clinic for your post-operative visit, you will also see the
t, length and head circumference. For this visit, you will need to write down everything that your baby eats and drinks in a booklet called a diet record. You must do this for each of the 3 days before you come to the hospital. To do this, you will need to measure the exact amount that your baby eats and drinks at each feeding. To do this we will ask you to weigh your
number. When your baby is done feeding, we will ask you to weigh the bottle (and/or dish of solids) again and record this number. A scale will be provided to you so that you can accurately measure the amount your baby has had to drink or has eaten by spoon. We will give you
· A booklet to write this information on · Simple instructions about how to record the feeding volumes (these instructions
will be reviewed with you before you go home) · A scale
You will need to bring these diet records with you when you come to your appointment. This will be the only time you need to do this for study purposes. If there are concerns about how much your baby is drinking, you may be asked to record intake as part of your
Subject Identifier:
141
What happens for the remainder of the study period? If you have a scheduled appointment with your cardiologist during the remainder of the study period, you will also see the study coordinator at this time. Throughout the remainder of the study period, all subjects will have a weekly phone call from
drinking at each feeding and how often your baby is drinking. You will also be asked to report the weight of your baby. During this phone call, you can report any feeding or any other difficulties with the study protocol. If you have any questions or concerns, you will be able to contact the study coordinator at any time between your scheduled visits/phone calls using the contact information provided to you. Potential Harms: If the MCT formula is not effective, the treatment of chylothorax may be longer than 6 weeks. Babies may require a period of intravenous nutrition, with no food taken by mouth, to help treat the chylothorax. This is a risk for all babies with chylothorax. If the instructions for preparation of the low fat breast milk or MCT formula are not followed carefully babies may receive too many nutrients. In these cases, babies could become very sick. Also, if the instructions are not followed carefully, babies may not get enough nutrients and this may affect their ability to grow properly and recover from surgery. Potential Discomforts or Inconvenience: After leaving the hospital, you will be required to fill in a 3 day diet record that will require you to measure how much your baby drinks. You will also be required to weigh your baby once each week throughout the study period. For babies in the low-fat breast milk group, mothers are required to pump regularly and frequently to be sure you have enough breast milk to feed your baby. This breast milk will need to be packed for transport to the hospital. For those mothers who were previously breast feeding or providing breast milk by bottle but who choose enter the control group (to receive the MCT formula), regular pumping will be necessary if you wish to continue to breast feed or provide breast milk once chylothorax treatment is complete. For subjects who live outside of the Greater Toronto Area, one additional visit to the hospital at the end of the treatment period may be required. This appointment will be arranged with the study coordinator for a time that is convenient for you.
Subject Identifier:
142
Potential Benefits: Babies who can continue to have some breast milk while being treated for chylothorax may continue to get some of its benefits, such as its anti-infective properties, and may have less of the digestive difficulties that are often seen with the switch to any formula, including the MCT formula. Mothers of those infants receiving breast milk will continue to pump on a regular schedule throughout the treatment for chylothorax, supporting the transition back to breastfeeding once treatment is complete by maintaining milk supply. Parents who have participated in other studies performed by our lab have found the additional contact with health care professionals during the study period extremely helpful and also found that this additional contact helped to make the transition home a little easier. This study will help us gain a better understanding of the effectiveness of using a low-fat breast milk to treat chylothorax and to offer this as a potential treatment option for parents who had hoped to provide breast milk as the main source of nutrition for their baby. Confidentiality: We will respect your privacy. No information about who you or your child is will be given to anyone or be published without your permission, unless the law requires us to do this. For example, the law requires us to give information about you or your child if a child has been abused, if you or your child has an illness that could spread to others, if you or someone else talks about suicide (killing themselves), or if the court orders us to give them the study papers.
health record to check on the study. For example, people from Health Canada Health Products and Food Branch, if necessary, may look at your records.
records. We will give you a copy for your files. The data produced from this study will be stored in a secure, locked location. Only members of the research team (and maybe those individuals described above) will have access to the data. This could include external research team members. Following completion of the research study, the data will be kept as long as required and then destroyed as required by Sick Kids policy. Published study results will not reveal your identity.
Subject Identifier:
143
Reimbursement: Any equipment required to complete this study will be provided to you at no cost e.g. breast pump and scale, MCT formula. If additional visits to the hospital are required solely for study purposes, we will reimburse you for all your reasonable out of pocket expenses associated with this visit e.g., meals, babysitters, parking and getting you to and from Sick Kids. Participation: It is your choice to let your baby take part in this study. If you choose to let your child take part in this study you can take your child out of the study at any time. The care your child gets at Sick Kids will not be affected in any way by whether your child takes part in this study. New information that we get while we are doing this study may affect your decision to take part in this study. If this happens, we will tell you about this new information. And we will ask you again if you still want to be in the study During this study we may create new tests, new medicines, or other things that may be worth some money. Although we may make money from these findings, we cannot give you (your child) any of this money now or in the future because you (your child) took part in this study. In some situations, the study doctor or the company paying for the study may decide to stop the study. This could happen even if the treatment given in the study is helping your child. If this happens, the study doctor will talk to you about what will happen next. If your child becomes ill or are harmed because of he or she took part in this study, we will treat he or she for free. Your signing this consent form does not interfere with your legal rights in any way. The staff of the study, any people who gave money for the study, or the hospital are still responsible, legally and professionally, for what they do. Alternatives to participation: If you choose not to participate in the study, your baby will receive the MCT formula to treat their chylothorax. This formula is that same treatment that babies in the control group will receive and is the current treatment that is used for all infants with chylothorax. Sponsorship: The sponsor of this study is the Labatt Heart Centre Innovation Fund. Conflict of interest: I, and the other research team members, have no conflict of interest to declare.
Subject Identifier:
144
Consent: By signing this form, I agree that: 1) You have explained this study to me. You have answered all my questions. 2) You have explained the possible harms and benefits (if any) of this study. 3) I know what I could do instead of having my child take part in this study. I
understand that I have the right to refuse to let my child take part in the study. I also have the right to take my child out of the study at any time. My decision about my child taking SickKids.
4) I am free now, and in the future, to ask questions about the study. 5)
give no one information about my child, unless the law requires you to. 6) I understand that no information about my child will be given to anyone or be
published without first asking my permission. 7) I have read and understood pages 1 to 8 of this consent form. I agree, or consent,
that my child___________________ may take part in this study. _______________________ Printed Name of Parent/Legal Guardian Signature & Date ________________________________________ Printed Name of person who explained consent Signature & Date
does not read English) .
Who do I call if I have questions or problems? If you have any questions or concerns at anytime during the study, please contact the study coordinator, Sarah Farmer at (416) 813-6747 or pager (416)330-3036. A letter will be sent to your paediatrician to make them aware of your participation in this study. If you need to contact someone about medical issues related to the study, please contact Dr. Jennifer Russell at (416) 813-7291.
Subject Identifier:
145
For questions about your rights as a research subject or for information on who to contact in the event of injuries during a study, please call the Research Ethics Manager at (416) 813-5718
Subject Identifier:
146
APPENDIX C: DATA COLLECTION FORMS
Confidential Subject Information*
Name of Subject
HSC#
Name of Mother Address City Province Postal Code Home Phone Work Phone Cell Phone Name of Father Address City Province Postal Code Home Phone Work Phone Cell Phone Other Caretaker Name Address City Province Postal Code Home Phone Work Phone Cell Phone
Subject Identifier:
147
Subject Eligibility Criteria
Date: (mm/dd/yy) Inclusion Criteria Yes No Infant < 12 months of age Positive diagnosis of chylothorax1
Infant to have follow-up care at The Hospital for Sick Children Patient lives within GTA At least one parent (ideally both) have voluntarily signed an informed consent
Treatment Group: Inclusion Criteria Yes No Parents/guardian would like to continue to provide breast milk
during treatment for chylothorax Mother agrees to express breast milk for duration of study Parents/guardian willing to be available for breast milk picks
up and delivery twice each week for duration of study Exclusion Criteria Yes No Infant receiving solely parenteral nutrition (no enteral feeds) Patient unable to follow the Chylothorax Care Map Neither parent able to effectively communicate in English If answers to a
then infant to be entered into the treatment group. Group Assignment:
Subject Identifier:
148
Enrolment Demographic Data (To be verified by medical record)
DOB (mm/dd/yy)
Gender Male Female
Gestational Age
Birth Weight
Birth Length Birth Head Circumference
Primary Diagnosis
Date of Surgery Procedure
Secondary Diagnosis
Other Medical Procedures (include dates)
Current Medications Mother Age (Complete Years)
Subject Identifier:
149
Ethnicity (descent) An Aboriginal person (e.g. North American Indian, Metis, Inuit, Eskimo) White Chinese South Asian (e.g. East Indian, Pakistani, Sri Lankan) Black Filipino Latin American Southeast Asian (e.g. Cambodian, Indonesian, Laotian, Vietnamese) Arab West Asian (e.g. Afghan, Iranian) Japanese Korean Other; specify Bi- or multiracial descent; specify
Last year of schooling completed (full-time equivalence) High School; specify number of years First year of college, university or trade school Second year of college, university or trade school Third year of college, university or trade school Fourth year of college, university or trade school Post-Graduate education; specify number of years Highest degree or diploma attained None High School Diploma Vocational Diploma College Diploma Post-graduate education; specify number of years Total years of education
(only if biological mother) measured reported (ft/inches) (cm)
measured reported (kg) (lbs)
150
Father or Partner Age (Complete Years) Ethnicity (descent) An Aboriginal person (e.g. North American Indian, Metis, Inuit, Eskimo) White Chinese South Asian (e.g. East Indian, Pakistani, Sri Lankan) Black Filipino Latin American Southeast Asian (e.g. Cambodian, Indonesian, Laotian, Vietnamese) Arab West Asian (e.g. Afghan, Iranian) Japanese Korean Other; specify Bi- or multiracial descent; specify
Last year of schooling completed (full-time equivalence) High School; specify number of years First year of college, university or trade school Second year of college, university or trade school Third year of college, university or trade school Fourth year of college, university or trade school Post-Graduate education; specify number of years Highest degree or diploma attained None High School Diploma Vocational Diploma College Diploma Post-graduate education; specify number of years Total years of education
(only if biological father) measured reported (ft/inches) (cm)
Subject Identifier:
151
measured reported (kg) (lbs)
152
Entrance Interview
1. Prior to surgery, how many times each day did you feed your baby either breast milk or formula? 2. How was your baby feeding in the time leading up to surgery? Breast feeding only Breast feeding + bottle feeding
Bottle feeding only
3. For infants doing any breast feeding: i) How many times each day does your baby feed at the breast? 4. For infants doing any bottle feeding: i) What does your baby drink by bottle? breast milk only breast milk fortified with formula Describe: formula only Describe: breast milk and formula Describe: ii) How many bottles do you usually give your baby each day? iii) Of the total number of bottles you give your baby each day, how many contain breast milk? 5. Does your baby eat any solids? i) If yes, how many times do you feed your baby solids each day? ii) If yes, what types of solids does your baby eat?
Subject Identifier:
153
6. Do you ever give your baby anything other than breast milk or formula to drink? Yes No i) If yes, please describe: If subject ject is eligible for the treatment group. If subject formula feeding or receiving < 80% of feeds as breast milk, subject is eligible for the control group. Group Assignment:
Subject Identifier:
154
Important Study Dates - Control
(mm/dd/yr) Study Enrolment
Study Day 1: initiation of feeding protocol
Discharge
Study Visit #1
Study Visit #2
Phone Follow-up #1
Phone Follow-up #2
Phone Follow-up #3
Phone Follow-up #4
Phone Follow-up #5
Phone Follow-up #6
Study Completion
Additional Phone Contact Dates (mm/dd/yy)
Subject Identifier:
155
Important Study Dates - Treatment (mm/dd/yy)
Study Enrolment
Study Day 1: Initiation of feeding protocol
Discharge
Study Visit #1
Study Visit #2
Phone Follow-up #1
Week 1 Delivery/Pick-up of LFBM*
#1 #2
Phone Follow-up #2
Week 2 Delivery/Pick-up of LFBM
#1 #2
Phone Follow-up #3
Week 3 Delivery/Pick-up of LFBM
#1 #2
Phone Follow-up #4
Week 4 Delivery/Pick-up of LFBM
#1 #2
Phone Follow-up #5
Week 5 Delivery/Pick-up of LFBM
#1 #2
Phone Follow-up #6
Week 6 Delivery/Pick-up of LFBM
#1 #2
Study Completion
Subject Identifier:
156
Additional Phone Contact Dates (mm/dd/yy)
Subject Identifier:
157
Intake Record In Hospital Date
(mm/dd/yy)
NPO
Part of day All day
Part of day All day
Part of day All day
Part of day All day
Part of day All day
Part of day All day
Part of day All day
Part of day All day
Feed
1. Formula 2. LFBM 3. PN/Lipids
1. Formula 2. LFBM 3. PN/Lipids
1. Formula 2. LFBM 3. PN/Lipids
1. Formula 2. LFBM 3. PN/Lipids
1. Formula 2. LFBM 3. PN/Lipids
1. Formula 2. LFBM 3. PN/Lipids
1. Formula 2. LFBM 3. PN/Lipids
1. Formula 2. LFBM 3. PN/Lipids
Strength
1. 2.
1. 2.
1. 2.
1. 2.
1. 2.
1. 2.
1. 2.
1. 2.
Intake
N/G tube 1. 2. PO 1. 2. IV Total:
N/G tube 1. 2. PO 1. 2. IV Total:
N/G tube 1. 2. PO 1. 2. IV Total:
N/G tube 1. 2. PO 1. 2. IV Total:
N/G tube 1. 2. PO 1. 2. IV Total:
N/G tube 1. 2. PO 1. 2. IV Total:
N/G tube 1. 2. PO 1. 2. IV Total:
N/G tube 1. 2. PO 1. 2. IV Total:
Drainage
Output
Vomiting
Total
LFEMB low fat breast milk N/G nasogastric tube PO by mouth
Subject Identifier:
158
Anthropometrics In hospital
Date
(mm/dd/yy)
Weight
(g)
Length (cm)
1. 2. Avg:
1. 2. Avg:
1. 2. Avg:
1. 2. Avg:
1. 2. Avg:
1. 2. Avg:
1. 2. Avg:
1. 2. Avg:
1. 2. Avg:
Head Circumferenc
e (cm)
1. 2. Avg:
1. 2. Avg:
1. 2. Avg:
1. 2. Avg:
1. 2. Avg:
1. 2. Avg:
1. 2. Avg:
1. 2. Avg:
1. 2. Avg:
Weight measured daily Length at enrolment and then weekly Head Circumference - at enrolment and then weekly Avg = average measurement
Subjects Identifier:
159
Study Visit #1 Treatment Group
* Questions regarding feeding pertain to feeding over the previous week Date of Visit: Date of Discharge: Discharge Weight: (mm/dd/yy) (mm/dd/yy) (mm/dd/yy) Weight (grams) [1] [2] [Average]
Weight gain (g/day): Percentile*: Length (cm) [1] [2] [Average]
Percentile*: Head Circumference (cm) [1] [2] [Average]
Percentile*: 1. Food Records Complete? Yes No 2. Food records reviewed: Name Date: (mm/dd/yy) 3. Are you still giving your baby part or all of their feeds as breast milk? Yes No a) If no, when did you stop giving breast milk? b) If no, what was the main reason you stopped giving breast milk? c) If no, what are you currently feeding your baby? How are you preparing this? d) If yes, since you left the hospital, has your baby received any feeds that did not contain any breast milk (formula only)? Yes No * WHO Growth Chart
Subject Identifier:
160
d) If yes, what was the reason? Ran out of breast milk/not enough breast milk
Formula was easier to prepare Other: 4. How many times per day are you pumping your breast milk? 5. Are you having any difficulty pumping? Yes No a) If yes, would you like to receive a call from the lactation consultant? Yes No 6. What is the recipe you are currently using to prepa 7. How is your baby feeding? po nasogastric tube po + nasogastric tube 8. How many feedings does your baby have each day? 9. If baby is feeding any po:
a) What is the minimum amount your baby will drink at a feeding (ml):
b) What is the maximum amount your baby will drink at a feeding (ml): 10. If baby is receiving any feed by NG:
a) What is the average amount that goes through the NG tube (ml): 11. Is your baby having any episodes of vomiting or spitting up? Yes No 12. If yes, how often does this happen? Daily Average number/day: Weekly Average number/week: Never 13. Is your baby taking any solid foods? Yes No a) If yes, how many times/day? 1 x/day 2 x/day 3 x/day b) cereals fruits/vegetables meats other
Subject Identifier:
161
14. Do you give your baby any juice? No Yes Describe (volume/frequency/diluted?): 15. Do you give your baby any water? No Yes Describe (volume/frequency): 16. In this past week, have you given your baby anything to drink that has not already been discussed? Yes No
a) If yes, please describe (what/how much)? 17. Do you give your baby any vitamins or other supplements? No Yes Describe (what/frequency):
1. Change to feeding routine? Yes No a) If yes, describe: 2. Date and time of scheduled pick-up/delivery of breast milk: Visit 1: Visit 2:
Plan
Subject Identifier:
162
Phone Documentation Treatment Group
Date of Call: * Questions regarding feeding pertain to feeding over the (mm/dd/yy) previous week Weight (grams) [Current Weight] [Weight Gain]
Percentile*: 1. Are you still giving your baby part or all of their feeds as breast milk? Yes No a) If no, when did you stop giving breast milk? (mm/dd/yy) b) If no, what was the main reason you stopped giving breast milk? c) If no, what are you currently feeding your baby? How are you preparing this? d) If yes, since you left the hospital, has your baby received any feeds that did not contain any breast milk (formula only)? Yes No
d) If yes, what was the reason? Ran out of breast milk/not enough breast milk
Formula was easier to prepare Other: 2. How many times per day are you pumping your breast milk? 3. Are you having any difficulty pumping? Yes No a) If yes, would you like to receive a call from the lactation consultant? Yes No * WHO Growth Charts
Subject Identifier:
163
5. How is your baby feeding? po nasogastric tube po + nasogastric tube 6. How many milk* feedings does your baby have each day? 7. If baby is feeding any po:
a) What is the minimum amount your baby will drink at a feeding (ml):
b) What is the maximum amount your baby will drink at a feeding (ml): 8. If baby is receiving any feed by NG:
a) What is the average amount that goes through the NG tube (ml): 9. Is your baby having any episodes of vomiting or spitting up? Yes No 10. If yes, how often does this happen? Daily Average number/day: Weekly Average number/week: Never 11. Is your baby taking any solid foods? Yes No a) If yes, how many times/day? 1 x/day 2 x/day 3 x/day b) cereals fruits/vegetables meats other 12. Do you give your baby any juice? No Yes Describe (volume/frequency/diluted?): 13. Do you give your baby any water? No Yes Describe (volume/frequency): 14. In this past week, have you given your baby anything to drink that has not already been discussed? Yes No
Subject Identifier:
164
a) If yes, please describe (what/how much)?
15. Do you give your baby any vitamins or other supplements? No Yes Describe (what/frequency):
1. Change to feeding routine? Yes No a) If yes, describe: 2. Date and time of scheduled pick-up/delivery of breast milk: Visit 1: Visit 2:
Plan
Subject Identifier:
165
Study Visit #1 Control Group
* Questions regarding feeding pertain to feeding over the previous week Date of Visit: Date of Discharge: Discharge Weight: (mm/dd/yy) (mm/dd/yy) (mm/dd/yy) Weight (grams) [1] [2] [Average]
Weight gain (g/day): Percentile*: Length (cm) [1] [2] [Average]
Percentile*: Head Circumference (cm) [1] [2] [Average]
Percentile*: 1. Food Records Complete? Yes No 2. Food records reviewed: Name: Date: (mm/dd/yy)
4. How is your baby feeding? po nasogastric tube po + nasogastric tube 5. How many feedings does your baby have each day? 6. If baby is feeding any po:
a) What is the minimum amount your baby will drink at a feeding (ml):
* WHO Growth Charts
Subject Identifier:
166
b) What is the maximum amount your baby will drink at a feeding (ml):
7. If baby is receiving any feed by NG:
a) What is the average amount that goes through the NG tube (ml): 8. Is your baby having any episodes of vomiting or spitting up? Yes No 9. If yes, how often does this happen? Daily Average number/day: Weekly Average number/week: Never 10. Is your baby taking any solid foods? Yes No a) If yes, how many times/day? 1 x/day 2 x/day 3 x/day b) cereals fruits/vegetables meats other 11. Do you give your baby any juice? No Yes Describe (volume/frequency/diluted?): 12. Do you give your baby any water? No Yes Describe (volume/frequency): 13. In this past week, have you given your baby anything to drink that has not already been discussed? Yes No
a) If yes, please describe (what/how much)? 17. Do you give your baby any vitamins or other supplements? No Yes Describe (what/frequency):
Subject Identifier:
167
1. Change to feeding routine? Yes No a) If yes, describe:
Subject Identifier:
Plan
168
Phone Documentation Control Group Date of Call: * Questions regarding feeding pertain to feeding over (mm/dd/yy) the previous week Weight (grams) [Previous Weight] [Current Weight] [Weight Gain]
Percentile*: 1. What is the recipe 2. How is your baby feeding? po nasogastric tube po + nasogastric tube 3. How many feedings does your baby have each day? 4. If baby is feeding any po:
a) What is the minimum amount your baby will drink at a feeding (ml):
b) What is the maximum amount your baby will drink at a feeding (ml):
5. If baby is receiving any feed by NG:
a) What is the average amount that goes through the NG tube (ml): 6. Is your baby having any episodes of vomiting or spitting up? Yes No 7. If yes, how often does this happen? Daily Average number/day: Weekly Average number/week: Never 8. Is your baby taking any solid foods? Yes No a) If yes, how many times/day? 1 x/day 2 x/day 3 x/day * WHO Growth Charts
Subject Identifier:
169
b) cereals fruits/vegetables meats other 9. Do you give your baby any juice? No Yes Describe (volume/frequency/diluted?): 10. Do you give your baby any water? No Yes Describe (volume/frequency): 11. In this past week, have you given your baby anything to drink that has not already been discussed? Yes No
a) If yes, please describe (what/how much)? 12. Do you give your baby any vitamins or other supplements? No Yes Describe (what/frequency):
1. Change to feeding routine? Yes No a) If yes, describe:
Plan
Subject Identifier:
170
APPENDIX D: FOOD RECORD TREATMENT GROUP
Three-Day Diet Record
The effectiveness of low-fat breast milk for the treatment of chylothorax in infants following cardiothoracic surgery.
You have been given this booklet to help in collecting information on your
the Cardiac Clinic.
171
Instructions - Treatment
· include the day you are coming for your appointment. Fill out a separate sheet for each of the 3 days
· You will be provided with a small scale to help you accurately measure the amount you feed your baby; do not use the measurements directly from the bottle
· Be sure to weigh the bottle on the scale before you start feeding your baby by mouth and then again immediately after your baby is finished
· Use this table to help you remember how to fill in each column
Column Heading Instructions Time · the time you start feeding your baby Feeding · what you fed your baby (either fortified low fat breast milk or
MCT formula) · check the correct box
Weight of Bottle (before feeding)
· the weight of the bottle before you start feeding your baby · use the scale provided to take this measurement
Weight of Bottle (after feeding)
· the weight of the bottle after you have finished feeding your baby by mouth
· use the scale provided to take this measurement NG Tube Volume · the volume of feeding that you put through the NG tube
· complete this column
Total · · this will be done by the study coordinator
Spit Up/Vomit · if your baby spits up a small amount of their feeding, check
· if your baby has a larger volume that is forcefully projected
· choose either spit-up or vomit but not both each time this happens
Subject Identifier:
172
Diet Record Treatment
Date: Feed/Concentration: (mm/dd/yy)
Feed
Time Started (a.m. or p.m.)
Feeding ( )
Weight of Bottle
(before feeding) (grams)
Weight of Bottle
(after feeding) (grams)
NG Tube Volume (ml)
Total (to be
completed by study
coordinator)
Spit Up/ Vomit
1
Fortified LFBM Formula Only
Spit Up Vomit
2
Fortified LFBM Formula Only
Spit Up Vomit
3
Fortified LFBM Formula Only
Spit Up Vomit
4
Fortified LFBM Formula Only
Spit Up Vomit
5
Fortified LFBM Formula Only
Spit Up Vomit
6
Fortified LFBM Formula Only
Spit Up Vomit
7
Fortified LFBM Formula Only
Spit Up Vomit
8
Fortified LFBM Formula Only
Spit Up Vomit
9
Fortified LFBM Formula Only
Spit Up Vomit
10
Fortified LFBM Formula Only
Spit Up Vomit
Total
Subject Identifier:
173
Introducing Solid Foods
· Transition to complementary foods at approximately 6 months of age · Continue to provide an adequate volume of fortified low fat breast milk/formula feeds as
instructed by the study coordinator · There will be some solid foods that your baby cannot have while being treated for
chylothorax; follow the guidelines provided
· If your baby is also eating solid foods, days before you come to the hospital
· Do not include the day you are coming for your appointment · Fill out a separate sheet for each of the 3 days · Also use this form to record anything your baby drinks that is not breast milk or formula · Use this table to help you Column Heading Instructions
Time · the time of day you fed your baby solids Type of Food · what you fed your baby e.g. strained peaches
· include anything you may have added during the preparation of the food e.g. rice cereal mixed with low fat breast milk
Brand · if you use commercially made foods, indicate which brand you
Amount · how much your baby ate/drank
If you have any questions about completing these forms, please call the study coordinator Sarah Farmer (416)-813-6747
Subject Identifier:
174
175
Other Foods
Date: (mm/dd/yy) Time Type of Food/Description Brand
(or homemade) Amount/Volume
8:00 AM
Infant rice cereal mixed with MCT Formula Peaches pureed
Nestle
Heinz
3 tablespoons
2 tablespoons
Subject Identifier:
176
APPENDIX E: FOOD RECORD CONTROL GROUP
Three-Day Diet Record
The effectiveness of low-fat breast milk for the treatment of chylothorax in infants following cardiothoracic surgery.
You have been given this booklet to help in collecting information on your
the Cardiac Clinic.
Subject Identifier:
177
Instructions - Control
·
include the day you are coming for your appointment. Fill out a separate sheet for each of the 3 days
· You will be provided with a small scale to help you accurately measure the amount you feed your baby; do not use the measurements directly from the bottle
· Be sure to weigh the bottle on the scale before you start feeding your baby by mouth and then again immediately after your baby is finished
· Use this table to help you remember how to fill in each column
Column Heading Instructions Time · the time you start feeding your baby Weight of Bottle (before feeding)
· the weight of the bottle before you start feeding your baby · use the scale provided to take this measurement
Weight of Bottle (after feeding)
· the weight of the bottle after you have finished feeding your baby by mouth
· use the scale provided to take this measurement NG Tube Volume · the volume of feeding that you put through the NG tube
· complete this column
Total · · this will be done by the study coordinator
Spit Up/Vomit · if your baby spits up a small amount of formula, check the
· if your baby has a larger volume that is forcefully projected
· choose either spit-up or vomit but not both each time this happens
Subject Identifier:
178
Diet Record - Control
Date: Feed/Concentration: (mm/dd/yy)
Feed
Time Started (a.m. or p.m.)
Weight of Bottle
(before feeding) (grams)
Weight of Bottle
(after feeding) (grams)
NG Tube Volume (ml)
Total (to be completed by study coordinator)
Spit Up/ Vomit
1
Spit Up Vomit
2
Spit Up Vomit
3
Spit Up Vomit
4
Spit Up Vomit
5
Spit Up Vomit
6
Spit Up Vomit
7
Spit Up Vomit
8
Spit Up Vomit
9
Spit Up Vomit
10
Spit Up Vomit
11
Spit Up Vomit
Total
Subject Identifier:
Subject Identifier:
Subject Identifier:
179
Introducing Solid Foods
· Transition to complementary foods at approximately 6 months of age · Continue to provide an adequate volume of formula feeds as instructed by the study
coordinator · There will be some solid foods that your baby cannot have while being treated for
chylothorax; follow the guidelines provided
· of the 3 days before you come to the hospital
· Do not include the day you are coming for your appointment · Fill out a separate sheet for each of the 3 days · Also use this form to record anything your baby drinks that is not formula (measure this
using the scale provided just like you would for the formula feedings) · Use this table to help you Column Heading Instructions
Time · the time of day you fed your baby solids Type of Food · what you fed your baby e.g. strained peaches
· include anything you may have added during the preparation of the food e.g. rice cereal mixed with MCT formula
Brand · if you use commercially made foods, indicate which brand you
Amount · how much your baby ate /drank
If you have any questions about completing these forms, please call the study coordinator Sarah Farmer (416)-813-6747
Subject Identifier:
180
Other Foods
Date: (mm/dd/yy) Time Type of Food/Description Brand
(or homemade) Amount/Volume
8:00 AM
Infant rice cereal mixed with MCT Formula Peaches pureed
Nestle
Heinz
3 tablespoons
2 tablespoons
Subject Identifier:
181
APPENDIX F: MINIMAL FAT DIET GUIDELINES
M I N I M A L F A T D I E T F O O D G R O UP F O O DS A L L O W E D F O O DS T O A V O ID
Milk & Alternatives
Dairy products (milk, yogurt) with less than 1% milk fat (M.F. or B.F. less than 1%)
Fat-free processed cheese slices Fat-free sour cream Fat-free cottage cheese Fat-free cream cheese Fat-free pudding Nestle Breakfast Anytime®
Powder (Strawberry & Vanilla only prepare with skim milk)
Dairy products (milk, yogurt) with greater than 1% milk fat (M.F. or B.F. greater than 1%)
Cheese (including low fat varieties) Regular or low fat cream cheese Regular or low fat cottage cheese Cheez whiz® Nestle Breakfast Anytime Powder
(chocolate flavour) or any ready to drink versions
Meat & Alternatives
Lean white fish, skinless chicken breast or turkey breast (1-2 oz/serving/day)
Beans & legumes Fat-free hot dogs Tuna in water (2-3 oz/serving/day) Fat-free deli meats Egg whites (if older than 1 year)
Peanut butter & other nut butters Fried & battered meats & poultry Egg yolks Beef, pork & fatty fish Seafood (shrimps, scallops, lobster)
& shellfish (clams, mussels, oysters)
Grain Products
Bread, buns, plain bagels & pitas Plain pasta Plain rice Melba toast, fat-free crackers Crumpets Cereals (except granola or those
containing nuts). Choose one with less than 1 g total fat/serving
Cheese &/or egg bread, buns, bagels & croissants
Meat or cheese stuffed pasta Egg noodles or fried rice Packaged noodle dishes (e.g. Side
Kicks , Mr. Noodle ) Crackers Granola
182
Vegetables & Fruit
All, E X C EPT avocado & olives Fruit & vegetable juices Apple & fruit sauces Dried fruit bars/fruit snacks (e.g.
Fruit-to-go & Fruit Roll-Ups ) Pasta sauce with less than 1 g total
fat/serving
Avocado Olives Pasta sauce with greater than1 g
total fat/serving (no meat, cheese or cream sauce)
Snacks & Treats
Rice cakes (no chocolate, cheese or butter read ingredients)
Fat-free granola bars Fat-free cookies Freezies & sorbet Air-popped popcorn (no butter) Baked plain pretzels Cereal (see above) Chocolate, strawberry & maple
syrup (fat-free) Ice cream & frozen yogurt (if less
than 0.1% fat) Gummy candy & gum Jell-O® & fruit gels
Chips & cheezies Chocolate Nuts & seeds Muffins & Cake Cookies Regular or flavoured popcorn Ice cream & frozen yogurt (if
greater than 0.1% fat) Toffee Caramel Fudge
Oils, Spreads & Other
Ketchup, mustard, relish Fat-free broth soups Salsa Fat free mayonnaise Jams & jellies Honey (if older than 1 year) Ultra low fat Cool Whip® (0.9%
fat) Pickles Fat-free salad dressing Fat-free croutons Soy sauce Teriyaki sauce Vegetarían sushi (no avocado, egg
or crab meat)
Butter Margarine Oil Regular mayonnaise Soup & cream soups Sushi with meat, fish, avocado, egg
or crab meat
183
Baby & Toddler
Portagen® (or Tolerex®) formula Plain infant cereal (with less than
0.5 g fat per serving) All fruits & vegetables (plain
homemade or jarred) Fruit & vegetable juices (limit to 4
oz/day or as per dietitian) Baby mum-mum rice rusks Homemade pureed or minced lean
white fish, skinless chicken breast or turkey breast (½-1 oz/serving/day)
All infant formula (except Portagen® or Tolerex®)
Minigo®, Danino® & Danimals® yogurt & cheese
Yogurt tubes & drinks with >1% M.F.
Infant cereal containing formula, milk &/or yoghurt (e.g. Milupa®)
Jarred baby
Cookies (including Arrowroot & Farleys®)
Baby jars of meat & meat containing foods
Please Note:
A lways read food labels: Fat-free = less than 0.5 g total fat per serving When cooking, do not add any oil, butter, margarine or other fats. Use a low fat cooking
method such as steaming, broiling, barbecuing or baking
If you have questions about a product, please phone your dietitian
184
APPENDIX G: CHEST TUBE DRAINAGE DATA FOR ALL SUBJECTS Subject
# Study G roup
(T reatment/Control) Study Day
Chest Tube 1
(ml)
Chest Tube 1 (ml/kg)
Chest Tube 2
(ml)
Chest Tube 2 (ml/kg)
Duration of
Drainage (days)
1 Control 1 23 3.5 5 1 Control 2 22.2 3.3 1 Control 3 22.8 3.4 1 Control 4 13.6 2.0 1 Control 5 0 0 2 Control 1 63 12.1 48.8 9.4 31 2 Control 2 37.5 7.4 44.2 8.7 2 Control 3 14 2.7 16.5 3.2 2 Control 4 16.9 3.3 34 6.7 2 Control 5 11 2.1 19.5 5.2 2 Control 6 15.1 2.9 34.8 4.5 2 Control 7 14 2.8 26.2 4.2 2 Control 8 10.7 2.1 22.8 3.7 2 Control 9 9.4 1.9 21.1 4.2 2 Control 10 3.1 0.6 18.8 3.7 2 Control 11 2.2 0.4 10.4 2.0 2 Control 12 0.5 0.1 13.4 2.6 2 Control 13 11.0 2.2 2 Control 14 9.0 1.8 2 Control 15 11.1 2.3 2 Control 16 4.7 1.0 2 Control 17 4.6 0.9 2 Control 18 2.0 0.4 2 Control 18 15 3.0 2 Control 20 5.5 1.1 2 Control 21 11.5 2.3 2 Control 22 9.5 1.9 2 Control 23 6.0 1.2 2 Control 24 13.4 2.6 2 Control 25 10 2.0 2 Control 26 1.2 0.2 2 Control 27 4.2 0.8 2 Control 28 2.2 0.4 2 Control 29 1.8 0.3 2 Control 30 0 0 2 Control 31 0.5 0.1 3 Treatment 1 45 6.2 5 3 Treatment 2 4 0.5
185
3 Treatment 3 6 0.8 3 Treatment 4 2 0.3 3 Treatment 5 2 0.3 4 Control 1 5 0.7 40 5.6 7 4 Control 2 110 15.5 30 4.2 4 Control 3 9.6 1.4 37 5.2 4 Control 4 71 10.1 10 1.4 4 Control 5 34 5.0 2 0.3 4 Control 6 11.6 1.7 0 0 4 Control 7 0 0 0 0 5 Treatment 1 31 5.1 17 2.8 12 5 Treatment 2 17 2.8 19 3.1 5 Treatment 3 16.5 2.6 22.8 3.6 5 Treatment 4 15.6 2.5 17 2.7 5 Treatment 5 21.1 3.3 26.3 4.2 5 Treatment 6 12.7 2.0 5.7 0.9 5 Treatment 7 12 2.0 2.2 0.4 5 Treatment 8 16.6 2.7 10.5 1.7 5 Treatment 9 7 1.1 40.5 6.4 5 Treatment 10 22 3.5 12 1.9 5 Treatment 11 7 1.1 8.9 1.4 5 Treatment 12 1 0.2 4 0.6 6 Treatment 1 60 17.1 9 6 Treatment 2 49 14.0 6 Treatment 3 116.5 33.3 6 Treatment 4 90.5 25.9 6 Treatment 5 53 15.1 6 Treatment 6 31 8.9 6 Treatment 7 19 5.4 6 Treatment 8 20 5.7 6 Treatment 9 12 3.5 7 Treatment 1 42 13.5 40 12.9 8 7 Treatment 2 50 16.1 24 7.7 7 Treatment 3 23 7.4 28 9.0 7 Treatment 4 17 5.6 15 4.9 7 Treatment 5 8 2.5 14 4.5 7 Treatment 6 3.9 1.2 10.4 3.3 7 Treatment 7 5.8 1.9 6.5 2.1 7 Treatment 8 3 1.0 0.6 0.2 8 Treatment 1 21.4 7.9 7 8 Treatment 2 18.1 6.7 8 Treatment 3 21.8 8.2 8 Treatment 4 12.9 4.8 8 Treatment 5 10.6 3.9 8 Treatment 6 12.5 4.5
186
8 Treatment 7 4.1 1.5 9 Control 1 10.5 1.9 6.5 1.2 4 9 Control 2 6.6 1.2 7.7 1.4 9 Control 3 12.2 2.1 8.4 1.4 9 Control 4 3 0.5 8.2 1.4 9 Control 5 0 0 0 0 10 Treatment 1 18.6 2.7 5 10 Treatment 2 23.5 3.5 10 Treatment 3 16.6 2.4 10 Treatment 4 3.8 0.6 10 Treatment 5 4 0.6 11 Treatment 1 47 14.7 3 0.9 4 11 Treatment 2 5 1.6 2 0.6 11 Treatment 3 13 4.1 2 0.6 11 Treatment 4 11 3.4 1 0.3 11 Treatment 5 0 0 0 0 12 Treatment 1 90 22.9 10 12 Treatment 2 53.2 13.9 12 Treatment 3 42.3 11.1 12 Treatment 4 44 11.4 12 Treatment 5 20.4 5.4 12 Treatment 6 22.9 6.0 12 Treatment 7 16 4.2 12 Treatment 8 9.8 2.6 12 Treatment 9 9 2.4 12 Treatment 10 0.2 0.05 13 Control 1 22 4.6 24 5 4 13 Control 2 27 6.1 15 3.4 13 Control 3 9.2 2.1 7 1.6 13 Control 4 3.2 0.7 2.5 0.6 13 Control 5 0 0 0 0 14 Control 1 36 6.1 29 14 Control 2 221 37 14 Control 3 155 26 14 Control 4 142 24 14 Control 5 146 25 14 Control 6 115 20 14 Control 7 58 10 14 Control 8 123 21 14 Control 9 144 25 14 Control 10 111 19 14 Control 11 54 10 14 Control 12 47.5 8.5 14 Control 13 41 7.3 14 Control 14 19.4 3.5
187
14 Control 15 5.8 1.0 14 Control 16 47.1 8.1 14 Control 17 24 4.1 14 Control 18 40 6.9 14 Control 19 21.4 4 14 Control 20 13 2.2 14 Control 21 8 1.3 14 Control 22 4.8 0.8 14 Control 23 1.7 0.3 14 Control 24 1.5 0.2 14 Control 25 0.2 0 14 Control 26 0 0 14 Control 27 0.1 0 14 Control 28 0 0 14 Control 29 0 0 15 Control 1 280 38.4 5 0.7 16 15 Control 2 101 13.8 0 0 15 Control 3 44 6.0 0 0 15 Control 4 76 11 0 0 15 Control 5 38 5.7 0 0 15 Control 6 39 5.8 0 0 15 Control 7 31 4.6 0 0 15 Control 8 16 2.3 0 0 15 Control 9 12 1.8 240 35.6 15 Control 10 68 10.2 100 15 15 Control 11 60.5 9 16 2.4 15 Control 12 31 4.7 40 6.1 15 Control 13 8.7 1.4 28 4.4 15 Control 14 9.2 1.5 7 1 15 Control 15 1.4 0.2 35 5.7 15 Control 16 0 0 0 0 16 Control 1 180 35.3 5 1.0 4 16 Control 2 89 18.7 10 2.1 16 Control 3 27 6.0 6 1.3 16 Control 4 8.8 2.0 0 0 16 Control 5 0 0 0 0