DETERMINATION OF PROTEIN NEEDS USING NITROGEN BALANCE … · DETERMINATION OF PROTEIN NEEDS USING NITROGEN BALANCE IN INFANTS IMMEDIATELY POST CARDIOPULMONARY BYPASS SURGERY Joann
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DETERMINATION OF PROTEIN NEEDS USING
NITROGEN BALANCE IN INFANTS IMMEDIATELY POST
CARDIOPULMONARY BYPASS SURGERY
by
Joann Elizabeth Herridge
A thesis submitted in conformity with the requirements
for the degree of Master of Science
Graduate Department of Nutritional Sciences University of Toronto
Table 1. Whole-body protein synthesis in humans at different life stages 13 Table 2. Oxygen consumption, carbon dioxide production, respiratory quotient, energy
expenditure and caloric intake in infants following the Norwood procedure 20 Table 3. Primene® and ProSol™ intravenous amino acid solutions composition 38 Table 4. Nitrogen balance equation 41 Table 5. Surgical characteristics and operative data 45
Table 6. Baseline characteristics 47
Table 7. Non-protein energy from parenteral and enteral nutrition 48
Table 8. Total parenteral and enteral protein intake 49
Table 9. Difference in nitrogen balance in protein intakes of 1.5, 2.2 & 3.0 g/kg/d for three study days 50
vii
LIST OF FIGURES
Figure 1. Nitrogen balance metabolic pathways 7
Figure 2. Anabolism and catabolism for energy and protein intakes in infants post cardiac surgery 16
Figure 3. Metabolic response to acute injury 30
Figure 4. Nitrogen balance study design 36
Figure 5. Participation flow chart 45
Figure 6. Effect of protein intake on nitrogen balance for 3 consecutive days 50
Figure 7. Protein intakes 1.5, 2.2, 3.0 g/kg/d versus nitrogen balance 51
Figure 8. Nitrogen balance results at each protein intake level 52
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ABBREVIATIONS
CHD Congenital Heart Disease CPB Cardiopulmonary bypass CRP C-reactive protein CCCU Cardiac Critical Care Unit EBM Expressed breast milk GH Growth hormone HLHS Hypoplastic left heart syndrome ICU Intensive Care Unit IGF Insulin like growth factor kg Kilogram LBM Lean body mass N Nitrogen PN Parenteral nutrition PRISM Pediatric risk of mortality REE Resting energy expenditure SD Standard deviation TUN Total urinary nitrogen UUN Urine urea nitrogen WAZ Weight-for-age z score
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LIST OF APPENDICES
Appendix A. Consent form Appendix B. Prosol™ and Primene® product monographs Appendix C. Parenteral nutrition volumes for nitrogen balance study Appendix D. Biochemistry monitoring and safety Appendix E. Data collection form Appendix F. Complete surgical characteristics Appendix G. Nitrogen balance: Complete data of intake and output for 3 consecutive day
1
CHAPTER 1: INTRODUCTION
1.1 Introduction
Nitrogen balance methods have been valuable clinically in assessing nutritional therapies to
determine the extent of catabolism in injury or illness in critically ill patients (2). The metabolic
response to injury is a complex series of hormonal and biochemical changes, characterized by
protein catabolism and alterations in energy needs, as determined by the degree of illness (3).
The breakdown of endogenous protein stores to provide amino acids for tissue repair, wound
healing and inflammatory markers is theorized to be an adaptive response (4). The intensity of
this response influences the extent of lean body mass (LBM) breakdown, which may have a
significant effect in infants with congenital heart disease (CHD) who present with limited
nutrient reserves. Optimal protein requirements for an infant recovering from cardiopulmonary
bypass (CPB) has not been adequately studied, consequently the amount of protein required to
limit the catabolism of LBM is unknown. Achievement of nutrition support that matches
infants’ needs following cardiothoracic surgery is essential in maintaining their metabolic
reserves throughout the initial recovery phase.
Congenital heart disease is the most common birth defect contributing to a large
percentage of mortality among infants (5). Its incidence is reported as varying between 4-50 per
1000 live births (6). During the fetal period of development, malformation in the structure of the
heart valves or associated vessels results in CHD (7). Congenital heart malformations are
divided into three classifications: simple defects that require a primary repair, moderate defects
that either undergo a primary repair or a palliative surgery and severe defects that necessitate
palliation (8). The more severe cardiac defects are referred to as cyanotic or as single ventricle
physiology. Children with these defects typically require multiple staged surgical procedures
2
that occur during the neonatal period throughout childhood, CPB is necessary in these reparative
surgeries (5, 9). Due to the invasive nature of surgeries that require CPB, the infant may
encounter significant physiological and hemodynamic changes in the immediate post-operative
period. There is a large body of literature describing the relationship between CHD and
malnutrition as characterized by poor growth and delays in achieving developmental milestones
(10-18). In one particular study malnutrition was evident in 70% of babies with cyanosis or
pulmonary over-circulation (11).
Surgical procedures place an infant at an increased risk for protein catabolism, which has
been reported as the hallmark of critical illness (19-22). There is an emerging body of literature
in the field of paediatric intensive care nutrition that attempts to evaluate body nitrogen losses as
a result of stress or trauma, including those recovering from surgery (23). It has been widely
noted that children recovering from surgery present with increased protein catabolism but are
not hypermetabolic as originally hypothesized from adult studies (4, 19, 24). Further,
complications that can arise from marked catabolism of body stores include, increased rate of
infections, delayed wound healing, multiple organ failure, prolonged mechanical ventilation,
increased length of hospital stay, increased mortality and greater health care costs (1, 25, 26).
In response to injury or stress an integrated series of events occurs during protein
metabolism, characterized by accelerated protein degradation, decreased synthesis of somatic
proteins and increased amino acid catabolism, resulting in increased body nitrogen losses (27,
28). The effects of this catabolic response to injury promotes a breakdown of somatic proteins
that support gluconeogenesis (27). It has been postulated that patients in an intensive care unit
(ICU) present with an increased rate of protein degradation which is greater than the proportion
of protein synthesis, resulting in a negative nitrogen balance (4). This breakdown of body
3
protein can enhance post-operative complications including decreased intravascular oncotic
pressure, increased severity of pleural effusions, intestinal wall oedema and ascites (10). These
complications may be intensified in infants with CHD who have not achieved adequate growth
between staged surgeries or interventions. Thus, with limited protein reserves their ability to
surmount an acute or prolonged stress response is compromised. Therefore, the evaluation of
this catabolic response is particularly important for infants with limited fat and LBM reserves
(4, 29, 30).
Quantifying the amount of protein needed to maintain body composition and to meet the
demands of surgical stress for the infant undergoing CPB is of clinical importance when
considering factors associated with increased morbidity and mortality. Protein metabolism is
affected by energy intake, amino acid intake and the underlying disease of the individual (31).
Preoperatively, infants with CHD are often characterized as having growth failure, in a
hypermetabolic state and possibly in a negative nitrogen balance (32). In consideration to this,
once hemodynamic stability has been restored post operatively, it is essential that adequate
nutrition be provided in a timely manner in an attempt to reduce nutritional deficits that could
impact recovery. Beyond the immediate recovery period nutritional insufficiency can cause
detrimental effects on body composition and growth occurring throughout various stages of the
disease process (33).
Complications that can arise from CPB surgery including, acute renal failure, liver
dysfunction, chylothorax, and necrotizing enterocolitis, present unique challenges in the
development of nutrition therapies (5). Additionally, the necessity of imposed fluid restrictions
limit the provision of optimal nutrition support. Fluid delivery is commonly restricted between
50-70% of maintenance needs (34). Furthermore, it has been extensively documented that
children who are critically ill, comprising a heterogeneous population of surgical and non-
4
surgical diagnoses, are nutritionally vulnerable, a process that if not addressed judiciously can
lead to increased physiological instability (4, 19, 33, 35). Other factors contributing to poor
nutritional delivery and growth failure are malabsorption, elevated energy expenditure, multiple
disruptions in feeding delivery, and varying clinician practices (36). These influences often
make it difficult to provide optimal, if not adequate nutrition to the acutely ill child. In due
course, poor nutrition in the ICU leads to an extended length of stay and ongoing nutritional
challenges during recovery (12).
The purpose of this intervention study was to measure nitrogen balance in post surgical
infants with congenital heart disease. The study was designed to provide graduated intakes of
parenteral amino acids to determine a sufficient amount that would indicate nitrogen retention in
this high risk group. Thus, our aim was to determine if increasing the level of parenteral protein
greater than the current clinical standard prescription of 1.5 g/kg/d would result in nitrogen
balance, in critically ill infants recovering from cardiopulmonary bypass surgery.
The literature review that follows examines topics that are integral to the interpretation
and assessment of nitrogen balance including, definitions of nitrogen balance states,
methodologies used to define balance and its interpretation. Furthermore, an understanding of
protein requirements in healthy infants and needs as studied in illness are relevant to
understanding the nitrogen input required in recovery from surgery or illness. Additionally, a
brief overview of energy expenditure in critically ill and surgical children will be described. An
interpretation of energy needs is essential when developing nutrition therapies in the
hospitalized child in order to reduce complications that are associated with energy deficits.
Adequate protein delivery in the presence of adequate energy that matches needs is necessary
for nitrogen to be utilized for tissue synthesis and not as a source of energy (37). The
5
relationship of energy to protein has an impact on nitrogen balance measurements. Nutrient
deficits are common in critically ill children and will be highlighted further in this review.
As inadequate growth is prevalent among children with CHD it deserves consideration in
the assessment of the post-surgical infant as malnutrition can impact recovery and clinical
outcomes. Several methods used in nutritional assessments and evaluations are of limited value
when attempting to understand nutrient needs of the acutely ill child. As an example, serum
protein markers are more likely better indicators of stress versus nutritional status (38).
Furthermore, measures of body composition are generally not useful assessment tools due to
technical drawbacks in an ICU setting. Due to the limitations of these methods nitrogen balance
plays an important role in the assessment of body protein catabolism.
For the purpose of determining appropriate nutrition therapy for infants susceptible to
protein catabolism, a brief description of the metabolic response to surgical stress or injury will
be reviewed. As CPB is a necessary component of surgery, the effects of its management
deserve consideration in the development of the child’s nutrition prescription. As in the
immediate post-operative critical phase of recovery infants are predisposed to LBM losses that
may be substantial (23)
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CHAPTER 2: LITERATURE REVIEW
2.1 Nitrogen Balance
2.1.1 Nitrogen Balance Definition
Nitrogen balance is the difference between nitrogen intake and the amount of nitrogen
that is excreted from the body (39). Through this analysis, nitrogen balance studies are
performed to evaluate protein turnover (40). By calculating the difference between intake and
output a determination of equilibrium, negative or positive balance can be made.
2.1.2 Nitrogen Balance States
2.1.2.1 Positive Nitrogen Balance
When nitrogen intake is greater than output individuals are in a positive balance. This
occurs in growing children, during pregnancy, athletic training or in recovery from illness (2,
41). Nutrient requirements during these conditions have been estimated through calculating the
retention of protein required to form new tissue in addition to an estimated amount of protein
required for the body’s maintenance functions (2). In the assessment of nitrogen balance in
illness, a positive nitrogen balance indicates anabolism which is characterized by weight gain as
indicated by the repletion of fat and skeletal muscle mass and consequently results in an
increase in strength (42, 43).
2.1.2.2 Negative Nitrogen Balance
Alternatively during catabolic states, as implied in critical illness or stress, a negative
nitrogen balance is typical, whereby nitrogen intake is less than output (20). A reliance on
muscle protein stores is necessary to support the metabolic demands of the body and may result
7
in a negative nitrogen balance (44). Importantly, nitrogen excretion in catabolic patients can be
highly variable as studied in adult trauma and surgical patients (45). If a negative nitrogen
balance persists the amount of protein catabolism can impact the patient’s organs (41).
In a state of negative nitrogen balance, the primary result is an increase breakdown of
body protein to support metabolic needs (19). During periods of acute metabolic stress protein
stores catabolize, resulting in an increase in urinary nitrogen losses. An increase in free amino
acids are utilized by the liver for glucose synthesis which results in increased nitrogen in the
form of urea in the urine (19). Coss-Bu et al concluded after studying critically ill children
receiving parenteral nutrition (PN), that those in a negative nitrogen balance had high protein
oxidation rates, implying increased protein utilization under catabolic conditions (46).
Additionally, in a study conducted by Marin et al, it was determined that following major
surgery total urinary nitrogen (TUN) was 3-4 times higher in fasting subjects as a result of lean
tissue catabolism (47). One of the main goals of nutritional therapy for the post-surgical cardiac
infant is to provide adequate energy and macronutrients that will facilitate nitrogen equilibrium
and attenuate whole body protein catabolism.
2.1.2.3 Nitrogen Equilibrium
Zero nitrogen balance occurs when nitrogen intake equals output, suggesting that the
body’s protein pool is in equilibrium (23). It is presumed that individuals are in a state of
nitrogen balance when nitrogen is not retained for growth or repair of muscle tissue and is not
lost as a result of injury or starvation (48). An assumption is made that protein turnover,
described as a dynamic process of protein synthesis and protein degradation, are in equal
balance (49). For a positive nitrogen balance to occur in newborns, a protein turnover of 12.8 to
8
18.7 g/kg/d has been reported (50). This was dependent on whether the infant received either a
commercial infant formula or human milk (50).
2.1.3 Nitrogen Balance: Intake and Output
Nitrogen intake in the form of dietary protein can be found in foods, human milk, enteral
formulas or parenteral amino acids. The actual amount of nitrogen delivery depends on its
primary source as proteins contain varying mixtures of essential and non essential amino acids
that contain different proportions of nitrogen depending on their chemical structure. Thus,
quantifying the actual amino acids contained in the diet is of importance in order to accurately
determine the amount of nitrogen intake.
Nitrogen output is primarily measured in urine, non-urinary losses from stool are
generally estimated in hospitalized patients (45). However, nitrogen excretion from the body
occurs in a variety forms including losses from integument (i.e. skin, hair and sweat), and body
(Fresenius Kabi, Sweden), providing 1.44 g/kg/d. The summation of these substrates provided
non-protein calories of 40 ± 5 kcals/kg/d. Parenteral volume required to support this study
design ranged from 26-42 ml/kg/d, depending on the infant’s weight and level of protein
investigated (Appendix C). Additional parenteral energy delivered from intravenous
medications suspended in 5% dextrose was recorded and calculated for inclusion into total
parenteral energy intake.
Minerals, trace elements and vitamins were provided according to The Hospital for Sick
Children’s standard parenteral additions for age (123).
3.2.3.3 Enteral Nutrition Energy and Protein Delivery
When it was deemed safe to feed by the attending physician, enteral nutrition was
initiated through a nasogastric feeding tube placed during surgery. Enteral nutrition was started
when the infant’s hemodynamic status was stable as indicated by the delivery of inotrope
medications (i.e. norepinephrine, epinephrine, vasopressin) at doses ≤ 0.05 µ/kg, and if there
were no concerns of gastrointestinal compromise. In the CCCU enteral feeding is not routinely
initiated with the infusion of high doses of inotrope medications (i.e. ≥ 0.05 µ/kg), as the
potential for reduced intestinal blood flow attributed to these medications increases the risk of
necrotizing enterocolitis (124). When these medications were infused at doses ≤ 0.05 µ/kg
46
minimal volume feeds were initiated as per postoperative feeding guidelines at 1ml/kg every
three hours. Advancement of enteral nutrition was dependent on the infant’s clinical status.
Enteral nutrition was in the form of expressed breast milk (EBM) or commercially
prepared infant formula. Intake volumes were recorded throughout the study period. The
calories delivered enterally were included with parenteral energy delivery for the determination
of total energy intake. The amount of nitrogen contained in the protein delivered from either
EBM or infant formula was accounted for in nitrogen input calculations.
3.2.4 Blood Biochemistry Monitoring & Safety
Blood samples were drawn from an arterial line or a central venous line into heparin-
coated tubes as per CCCU routine biochemistry post-operative protocol and for PN monitoring
(Appendix D). Biochemical values were recorded throughout the study period. To monitor
tolerance to the higher levels of protein delivery blood urea nitrogen, creatinine and acid base
blood gases were recorded.
3.2.5 Nitrogen Collection and Calculations
3.2.5.1 Urine Collection
Following an adaptation period on the PN prescription, the first timed 24 hour urine
collection for TUN was initiated. In hospitalized patients it has been recommended to use 3
consecutive complete 24 hour urine collections to account for intra-subject variation of urinary
nitrogen excretion (66). Urine was collected from a closed system urinary bag that was attached to
a urinary Foley catheter placed in the infant during surgery as part of routine care. Urine samples
were collected in a container with 30% hydrochloric acid, approximately 1ml per 50ml of urine.
Hydrochloric acid was used to prevent bacteria from breaking down urinary nitrogen. This acid
47
was added to the collection bottle in the lab using universal precautions for handling biological
and chemical substances.
Following the completion of each 24 hour collection, the amount of urine was measured in
a volumetric flask, recorded and two representative aliquot samples were stored at -200C until
analysis.
3.2.5.2 Additional Urine Losses
Urine leakage around the catheter site is common, this occurs due to the limitations of
catheter positioning and/or in combination with high doses of diuretic therapy that results in
increased urine output. Urine voided into the diaper was estimated as the difference between the
weight of the wet diaper to that of a dry diaper, for recording into the patient’s chart in millilitre
measurements. These losses were recorded for each subject and added to the daily urine output as
measured in the lab, under the assumption that the concentration of urinary nitrogen would be
standard throughout a 24 hour period.
3.2.5.3 Other Nitrogen Losses
In this population of infant’s nitrogen losses from stool, sweat and skin are considered
negligible (31). As these losses are considered inconsequential to nitrogen balance calculations
they were not measured in this study. Blood losses post-operatively vary depending on amount
of chest tube output and blood taken for biochemical analysis as dictated by the patient’s
medical status. Due to technical difficulties in quantifying this source of nitrogen loss it was not
considered in this study.
48
3.2.5.4 Nitrogen Balance Calculation
Nitrogen balance was calculated as nitrogen intake minus nitrogen excretion, expressed
as mg/kg/d. Refer to table 4, for intake and output parameters of the nitrogen balance equation.
Table 4. Nitrogen Balance Equation
Nitrogen Intake Nitrogen Calculation
Parenterala (PN) Primene® ProSol™
NI (mg/kg/d) = [(0.1415g N x amino acid intake g/d) x 1000]/weight (kg) NI (mg/kg/d) = [(0.1481g Nb x amino acid intake g/d) x 1000]/weight (kg)
Enteral (EN) Human Milk Standard Cow’s Milk Infant Formula
NI (mg/kg/d) = [0.16g Nc x protein intake g/d) x1000] /weight (kg)
Nitrogen Output NO (mg/kg/d) = (Total Urinary Nitrogen as quantified by Kjeldahl mg/ml x
urine output ml/d)/weight (kg)
Nitrogen Balance Equation
Dietary Nitrogen from PN & EN (NI) – Total Urinary Nitrogen (NO) = NB
N – Nitrogen, NB – nitrogen balance, NI – nitrogen intake, NO – nitrogen output a From Guelph Laboratory analysis, Primene® and Prosol™ b 20% ProSol™, contains 2.961g N per 100ml, therefore 10% ProSol™ (to balance 10% Primene®) provides1.481gN per100ml c A standard factor of 16% nitrogen (or 6.25g protein contains 1g of nitrogen) content in protein was applied to all forms of EN
3.2.6 Laboratory Analyses
3.2.6.1 Urine Analysis
Urine samples were analyzed for TUN at the Agriculture and Food Laboratory facility at
the University of Guelph using Kjeldahl method (125). All samples were packaged in dry ice for
shipment to the laboratory. Total nitrogen analysis was performed using Kjeldahl digestion and
automated spectrophotometric determination. This method was separated into three steps
digestion, distillation and titration. Each urine sample (1ml) was oxidized by heating and
refluxing sulphuric acid in the presence of an added catalyst (peroxide). The ammonium
49
sulphate was reacted with sodium hypochlorite to form chloramine, which then reacted with
phenol to form the final blue product, indophenol. The colour was proportional to the quantity
of ammonia present in the distillate as measured on a spectrophotometer against a known
standard curve (125).
3.2.6.2 Parenteral Amino Acid Analysis
For quality control purposes pure samples of Primene® and ProSol™ amino acid
solutions were sent to Guelph laboratory for nitrogen determination using the Kjeldahl method
as previously described. These results were compared to the composition of amino acids
published from the manufacture’s product monograph. For ProSol™ comparative results of
Guelph’s analysis and the manufacturers product monograph was within 7.7% (2.961 versus
3.209g N/100ml) and for Primene® there was a difference of 6.7% (1.415 versus 1.516g
N/100ml) (table 3). In this study, total nitrogen content of the parenteral samples as quantified at
Guelph laboratory were used in our study calculations, in accordance with applying the same
analysis used for the determination of nitrogen in the study urine samples.
3.2.7 Collection of Data
The following data were collected from review of the medical records including,
demographic data consisting of: gestational age, age at time of surgery, gender, chromosome
abnormalities and as available anthropometric measures of, birth weight, length and head
circumference, preoperative weight, length and head circumference and weight at CCCU
discharge. Additional data encompassing, date and time of surgery, sternal closure and urinary
catheter removal was recorded. Surgical data consisted of, surgical diagnosis, type of surgery,
CPB time and aortic cross clamp time. Other data recorded were stooling episodes, steroid
50
medications, antibiotics, and blood products given as packed red blood cells (PRBC) or frozen
free plasma (FFP). See Appendix E, for data collection forms.
Urine output volume to the nearest millilitre as measured in the laboratory was recorded
daily. Plus additional volume from voided urine in the infants diaper as measured by nursing
staff and entered into the patient’s chart was recorded.
Nutrition data collected daily during the study period were parenteral volume delivery,
dextrose delivery from medications and the type and amount of enteral nutrition as recorded in
the patient’s medical chart.
3.2.8 Statistical Analyses
The primary outcome variable was the change in nitrogen balance between protein
levels. In order to calculate the sample size, subject sample sizes from two nitrogen balance
studies in infants post gastrointestinal surgery were used for comparison to determine an
appropriate sample size for this study (66, 70). Group sample sizes were calculated to detect a
-0.075 standard deviation (SD) change in nitrogen balance between protein levels, with an 80%
power at an alpha level of 0.05. An estimated total sample size of 27 infants, 9 per group, was
required to show a difference.
Using the General Linear Model, age, preoperative weight and non-protein energy
delivery was analyzed to determine if differences existed in our study population. All statistical
analyses were performed with SAS software (version 9.1: SAS Institute Inc., Cary, NC, USA).
Results were considered significant at p < 0.05.
To determine distribution of the data, diagnostic plots of the residuals were performed.
An interaction test was done between protein levels and intake days. From Fit Test statistics
51
ANOVA was conducted using ProcMix (SAS code), controlling for subject, protein intake and
days of study. Testing for interaction between protein levels and days of study with subject and
time as a repeated measure. Data for all variables are expressed as mean ± SD.
3.3 RESULTS
3.3.1 Clinical Details
Infants were mechanically ventilated throughout the study period and received
analgesics and sedatives, with or without inotropes and/or neuromuscular blockade medications.
Parenteral nutrition was initiated within 29.6±11.5 hours post CPB. Parenteral nutrition infused
for a period of 14.9±1.0 hours until the first timed 24 urine collection was initiated. This time
period was defined as the PN adaptation period. Following the first 24 hour urine collection two
successive timed 24-hour urine collections were completed for nitrogen balance analyses.
3.3.2 Participation
As shown in figure 5, 32 families were approached to participate in the study. Informed
consent was obtained for 25 infants. Reasons for refusal to participate were, not interested in
research n=2, already consented to several studies n=3, unknown n=2. There were no
withdrawals from the study, 21 infants completed three study days. Reasons for incomplete
collections were central line removal (n=1), urinary catheter removal (n=2), one infant was
excluded due to early removal of the urinary catheter.
52
Figure 5. Participation Flow Chart
3.3.3 Participant Characteristics
The study sample consisted of 16 infants (< 1 month of age), 2 infants (1-3 months), 3
infants (4-6 months), and 3 infants (7-12 months). The average age of the infants was 2.2
months (range 2 to 281 days). There was no statistical difference in the ages between protein
groups (p=0.76). There were two infants with Di George syndrome (randomized to 3.0 g/kg/d
protein group). Cardiac malformations are common in infants with Trisomy 21 and 22q11.2
deletion (5). Without literature to suggest that protein needs of those diagnosed with Trisomy 21
or 22 would be altered after surgery, these infants were screened for inclusion into this study.
During the extended course of their CCCU admission two infants died (randomized to 1.5
g/kg/d protein group) however, not during the study period. The median post-operative length of
CCCU stay was 16 days (range 6-41 days). Refer to Table 6.0 for complete details of participant
characteristics.
Approached N = 32
Declined participation n = 7
• Unknown reason, n=2 • Did not want to participate in research, n=2 • Participating in several studies, n=3
Provided consent
n = 25
Completed
3 study days n = 21
Excluded n = 1
Urinary catheter removed
Completed
2 study days, n = 2 1 study day, n = 1
53
3.3.4 Surgical Characteristics and Operative Data
Surgical characteristics and operative data are summarized in table 5. In the 1.5 g/kg/d
group, 5 of the 8 infants were diagnosed with HLHS. There was only one infant with this defect
in each of the intervention groups. See Appendix F, for complete surgical details.
In the 2.2 g/kg/d protein group, the median operative CPB time was the highest at 166
minutes (IQR 117.5). Additionally, this group had the longest aortic cross clamp time at a
median of 129 minutes (IQR 135).
Table 5. Surgical Characteristics and Operative Data
Diagnosis Protein Groups g/kg/d n=24
1.5 2.2 3.0
Dextrocardia 1 Double outlet right ventricle 1 1 Double inlet right ventricle 1 1 Hypoplastic left heart syndrome 5 1 1 Interrupted aortic arch 1 1 L-atrial isomerism 1 Severe aortic stenosis 1 Shones complex 1 Tetralogy of Fallot 2 Total anomalous pulmonary venous defect 1 1 1 Transposition of the great arteries 1 Truncus arteriosis 1 Operative Procedure Times, minutes Median (IQR)
Surgery weight, kg 4.61 ± 2.0 3.66 ± 0.6 3.56 ± 0.5
Surgery weight-for-age z score -0.65 ± 1.67 -1.53 ± 2.26 -1.04 ± 3.27
Surgery length, cm 55.4 ± 8.12 50.4 ± 5.20 52.9 ± 3.79
Surgery length-for-age z score, n -1.02 ± 2.34 (7) -1.25 ± 1.49 (7) -0.70 ± 2.73 (8)
Surgery weight-for-length z score, n -0.13 ± 1.22 (6) 0.34 ± 1.99 (7) -1.35 ± 1.55 (8)
Differences between groups for categorical variables were assessed using General Linear Model, results were considered significant at p≤0.05. No statistically significant differences were found.
55
3.3.6 Nutrition Delivery
3.3.6.1 Non-protein Energy Delivery: Enteral and Parenteral
Parenteral non-protein energy delivery was similar across groups, closely matching the
protocol prescription of 40 ± 5 kcals/kg/d as shown in table 7. Additionally, intravenous
dextrose delivery from medications provided approximately 9% of total calories within each
protein level. There was no difference in total energy intake from both PN and EN, among the
three groups (p=0.46).
Throughout the study period EN accounted for 4.3% to 6.5% of total calories, depending
on the group. Of the 24 infants, 12 received EBM, 7 received standard infant formula, and 2
received a combination of EBM and infant formula. For infants receiving 1.5g/kg/d protein,
enteral volume intake over 3 days ranged from 4 to 68ml/d. Intake volumes ranged from 4 to
45ml/d and 3 to 35ml/d for those receiving 2.2 and 3.0 g/kg/d, respectively. Only one infant in
each group did not receive EN throughout the study period.
Table 7. Non-protein Energy from Parenteral and Enteral Nutrition, kcals/kg/d
Total Non-protein Energya 46.6 ± 5.1 44.3 ± 4.2 46.3 ± 4.0 a Differences between groups for total energy intake were not statistically significant as determined by GLM.
56
3.3.6.2 Protein Delivery: Enteral and Parenteral
Parenteral protein delivery approximately matched the prescription levels as designed in
the study protocol (Table 8). Due to minimal enteral volume delivery of EBM or standard infant
formula, protein from these sources did not significantly contribute to total nitrogen intake.
Table 8. Total Parenteral and Enteral Protein Intake, g/kg/d
On study day 1 nitrogen balance analyzed by ANOVA using ProcMixed, was significantly different from protein intakes 2.2 and 3.0 g/kg/d (p=0.03 and p=0.001)
At a protein intake of 1.5 g/kg/d, negative balances at 42% occurred throughout the
study period. Whereas, only 16% and 18% of nitrogen balances were negative in infants
receiving 2.2 and 3.0 g/kg/d protein throughout the study. In infants receiving 1.5 g/kg/d the
median of the balances appeared closer to nitrogen equilibrium for this study group (Figure 6).
Figure 6. Effect of Protein Intake on Nitrogen Balance on 3 Consecutive Days
In infants receiving 2.2 g/kg/d of protein, most negative balances occurred on the final
study day, whereas at 3.0g/kg/ negative balances primarily occurred on study day 2. As shown
in figure 8, data from all infants for each study day shows that as protein intake increased from
!
!
1.5 2.2 3.0
Protein Intake (g.kg-1.d-1)
Nitr
ogen
Bal
ance
(mg. kg
-1. d-1
)
58
1.5 g/kg/d there was a corresponding increase in nitrogen balance measurements at higher
protein intakes.
Figure 7. Protein Intakes 1.5, 2.2, 3.0 g/kg/d, versus Nitrogen Balance (NB)
The spread of the data for each level of protein intake illustrates wide variability (Figure
8). The most noticeable variation in nitrogen balance occurred at a protein intake of 1.5 g/kg/d,
with 5 infants in a negative balance on different study days. Additionally, the magnitude of
negative balance was most prominent at this level with a measurement of -155 mg/kg/d.
Whereas negative balances at protein levels 2.2 and 3.0 g/kg/d, were -79 and -84 mg/kg/d,
respectively.
At the intervention protein intakes (2.2 and 3.0 g/kg/d), only two infants were in a
negative balance at each level throughout the study period. The positive nitrogen balance ranges
for these groups were 12-222 and 6-247 mg/kg/d, respectively. Whereas the balance range for
infants receiving 1.5 g/kg/d was, 6-133 mg/kg/d. Refer to Appendix G, for complete nitrogen
balance data.
59
Figure 8. Nitrogen Balance Results for Each Protein Intake Level
A) Nitrogen Balance on Days 1, 2 and 3 for Protein Intake 1.5 g.kg-1.d-1
B) Nitrogen Balance on Days 1, 2 and 3 for Protein Intake 2.2 g.kg-1.d-1
C) Nitrogen Balance on Days 1, 2 and 3 for Protein Intake 3.0 g.kg-1.d-1
60
3.4 DISCUSSION
3.4.1 Nitrogen Balance
The present study was performed to assess an amount of protein delivery that would
result in nitrogen balance in a group of surgical infants with severe cardiac defects following
CPB. To our knowledge this is the first study to investigate three different parenteral protein
intakes using TUN analysis to determine nitrogen balance in this unique paediatric population.
As the effects of surgical injury are dynamic processes with considerable inter-patient
unpredictability, the examination of three protein intake levels provided valuable information on
balance measurements at each level, which has clinically relevant implications on the design of
future nutrition prescriptions.
In this study, a statistical difference in the mean nitrogen balances between infants
receiving 1.5 g/kg/d and both 2.2 (p<0.03) and 3.0 g/kg/d (p < 0.001), occurred on the first day
after surgery. However, no statistical significance occurred between 2.2 g/kg/d and 3.0 g/kg/d
on this study day. Also, no differences in nitrogen balances were found between protein levels
on study days 2 or 3. For the purpose of designing nutrition prescriptions aimed at providing a
sufficient amount of protein in the least amount of fluid, a finding of 2.2 g/kg/d is more
achievable in this clinical setting. The subject sample size in this study could have limited the
ability to determine a difference on study days 2 and 3.
An observed trend of increasing positive balances was noted between the lowest level of
protein intake and the intervention levels, 58% of balances were positive at an intake of 1.5
g/kg/d, whereas, at higher intakes of 2.2 and 3.0 g/kg/d the percentages of positive balances
increased to 83% and 81%, respectively. These findings support previous research that
demonstrated nitrogen balance improves with increasing protein provision (110). Coss-Bu et al
61
examined this trend in a group of critically ill children, at an average protein intake of 2.8 g/kg/d
versus 1.7 g/kg/d, there was an association with positive balances at the higher intake (46).
Additionally, in a similar group it was demonstrated that children with a protein intake of 2.2 ±
0.2 g/kg/d were in a positive balance, which was significantly higher than those receiving 0.9 ±
0.2 g/kg/d, who were in a negative balance (62). Of note, energy delivery in these studies was
approximately 60-78 kcals/kg/d. In a study of post-surgical cardiac infants, an association of a
positive balance occurred with increasing amounts of protein, from a median of -0.7 g/kg/d to
1.1 g/kg/d (1). Yet, in this study energy intake was substantially lower at 55 kcals/kg/d (1). In
summary, these studies infer that positive nitrogen balances occur at several different protein
intakes within a range of energy intakes.
The objective of this study was to determine nitrogen balance in order to assess a level of
protein that would indicate reduced catabolism for infants following CPB surgery. Infants
receiving the standard protein prescription of 1.5g/kg/d appeared to be in a more exaggerated
negative balance throughout the study period. This may be considered clinically relevant, if
approximately half of the infants receiving 1.5 g/kg/d were catabolic, it would seem judicious to
design a prescription containing a higher level of protein of 2.2 g/kg/d, to ensure equilibrium or
positive balance. This level of protein may be necessary to maintain nutrient reserves during
periods of acute stress.
Limitations inherent in nitrogen balance methods pertain to the accuracy of the
measurements, false positive balances are made due to the overestimation of intake and the
underestimation of losses (39). Further, incomplete measurement of losses could erroneously
result in a positive nitrogen balance. Although losses from skin and stool after surgery are
reported as negligible and may not contribute greatly to nitrogen output, other losses consisting
62
of blood, pleural or peritoneal drainage may contain a quantifiable source of nitrogen that could
alter overall nitrogen balance. It is conceivable that accounting for these collective losses may
have had a significant effect on balance measurements resulting in a greater number of infants
presenting in negative balance. Therefore, the apparent balances observed in this study could
have potentially been artificially positive.
At each level of protein intake positive balances occurred throughout study days 1 to 3,
with an energy delivery of approximately 44 to 47 kcals/kg/d. Positive balance measurements
occurred at the standard protein level of 1.5 g/kg/d, implying that energy provision was adequate
to promote anabolism for some infants. The amount of energy delivery in this study is
reasonably consistent with the results of the study conducted by Teixeira-Cintra et al, who
demonstrated that children recovering from cardiovascular surgery were anabolic receiving a
median of 1.1g/kg/d protein and 55 kcals/kg/d (1). Although the amount of protein required to
achieve nitrogen balance was slightly lower than our standard prescription, the investigators in
the previous study employed UUN analysis to determine nitrogen balance, which has been
shown to underestimate nitrogen excretion, resulting in false-positive balances (44).
3.4.2 Protein Adaptation
A possible explanation for not finding statistical significance between each of the study
days could be due to the period of acclimation to the parenteral protein intake. The significant
differences between the intervention protein intake levels on day 1 was no longer evident on
days 2 or 3, which may have been due to a continuing adaptation process occurring on study day
1. In this study, the adaptation time on PN was 14.9 ± 1.0 hour prior to starting the first 24 hour
urine collection. From PN initiation to study day 2 the average time of PN delivery was 53.6 ±
11.5 hours. If considering the dynamic changes in protein flux occurring in the body, a more
accurate nitrogen balance may have been detected by study day 3, as protein adaptation may
63
have occurred by this final study day. In a study of critically ill children, nitrogen balance was
studied once their diets had equilibrated for 48 hours (27). In some very early adult studies
nitrogen balance was used to determine protein requirements after a 5-7 day period of
stabilization on a tested level of protein (126). However, these studies were performed in
healthy individuals consuming solid food diets.
Ideally, it would be rigorous to study TUN in critically ill children for a longer period, of
5 to 7 days, to ensure protein adaptation has occurred. However, in an intensive care setting this
is generally not feasible as clinical care dictates early urinary catheter removal to minimize the
incidence of infection, which would make urine collections more difficult to obtain.
Additionally, during recovery there would be several changes in a patient’s metabolic status due
to alternations in medical management, nutrition practices and activity levels. These factors
could possibly add greater variability to balance results making it difficult to interpret the
results.
3.4.3 Nitrogen Balance and the Stress Response
Negative balances occurring at the higher protein intake levels of 2.2 and 3.0 g/kg/d may
be explained by an ongoing stress response or a change in clinical status causing more stress on
one day versus another. It is probable that continuing hormonal and metabolic alterations post
operatively persisted. As discovered by Briassoulis et al, studying a group of critically ill
children, despite a protein intake of 2.8 ± 0.17 g/kg/d, negative nitrogen balance occurred by
study day 5, it was suggested that contributors to these findings were the presence of sepsis or
multi-organ failure (28). Although the infants in the current study were excluded in the presence
of these inciting stresses an underlying mild degree of infection could have resulted in
64
catabolism however, this was not fully examined. In this study, three infants were investigated
for sepsis, though cultures were unrevealing. Of note, each of these infants was in a positive
nitrogen balance throughout the study period.
Further, as previously mentioned, the amount of protein required to maintain nitrogen
balance in critically ill patients depends on their level of stress, severity of the inflammatory
response and organ function (46). Nitrogen excretion is related to the degree of injury and
metabolic status of the patient. Studies evaluating UUN in acutely ill children have reported a
range of nitrogen losses between 170 - 254 mg.kg-1.d-1 (46). Correspondingly, in a study
measuring TUN, the average amount of nitrogen excretion in a similar paediatric population was
higher at 347 mg.kg-1.d-1 (46). In this study, the average TUN across the study days and within
each protein intake level was 269 mg.kg-1.d-1 (range 88-542 mg.kg-1.d-1), these results are
consistent with studies in critically ill children that report a variable range of balances.
Nevertheless, it is problematic to compare our results to those of other studies due to a
compilation of factors consisting of: varying methods of nitrogen analysis, distinctly different
diagnoses, variances in stress levels and differences in subject ages, and weights.
Another factor that may have contributed to increased stress in the infants presenting in
negative balance, is the procedure of sternal closures performed at the patient’s bedside. For
patients who return to the ICU with an open sternum, closure can be delayed for several days
after CPB, depending on their hemodynamic and pulmonary stability. As reported in the
literature, blood glucose levels, an indicator of stress, increase following sternotomy (127).
Thus, it is likely that a similar response occurs during sternal closure. Of the 24 infants studied 6
had an open sternum throughout the study period. During this time 56% of the balances were
negative. The inability to perform sternal closures on these select infants may imply a greater
degree of illness, which could be indicative of increased stress. Interestingly, none of the infants
65
who had chest closures either prior to the study or on days 1 or 2 were in a negative nitrogen
balance. Perhaps suggesting that they were less acutely ill, with the study prescription meeting
their energy and protein needs on those days.
3.4.3.1 Evaluation of the Stress Response
In this study PRISM scores were measured for 84% of the study days. These scores were
within a similar range regardless as to whether the infants were in a positive or negative balance,
7-32 (median 15) and 9-28 (median 18), respectively. Those in a negative balance did not
present with higher PRISM scores as might be expected. A study in critically ill children
reported scores ranging from 6-18, with lower scores found in those receiving EN implying that
they were less acutely ill (46). By comparison, the median PRISM scores in the infants in this
study were relatively high, inferring that infant’s post CPB exhibit a greater stress response than
those studied in a heterogeneous population of critically ill children.
3.4.4 Nitrogen Balance and Clinical Factors Indicated in Post-operative Status
The relationship between nitrogen balance and clinical variables was not examined in
this study. However, other investigators have considered the effects of medications, severity of
illness, creatinine height index and stress mediators (1, 20). Consideration to these factors can
be valuable in enhancing an understanding of the stress response occurring in infants post CPB.
Thus, these factors may guide clinicians in developing improved nutrition therapies aimed at
reducing catabolism of body mass stores.
In one particular study, investigators collected data on vasoactive agents and
neuromuscular blockade medications. They found that patients supported on these drugs were in
a more negative nitrogen balance, which was statistically significant on study day 5 (28). It was
66
proposed that the study patients were enduring a prolonged stress state, hence were more acutely
ill given that these medications were still required by day 5 of their ICU admission (28). The
infants in this investigation received a combination of vasoactive and neuromuscular blockade
medications during the study period however, these were not accounted for in our final analysis.
As suggested in the literature, for an accurate determination of nitrogen balance all body
losses of nitrogen should be accounted for in calculations (45). In this study infants sweat losses
were considered minimal and stool losses were minor. Stooling episodes were recorded for 13
inants. There were no stools recorded on 69% of the total study days. Only one infant in the 2.2
g/kg/d group presented with excessive stooling on days 1 and 2 of the study (8 and 6 episodes
per day), nitrogen balance results were positive on both days. Despite the infant being in a
positive nitrogen balance it is likely that stooling output contributed to a degree of nitrogen loss.
Additionally, other non-routinely measured losses from chest tubes, peritoneal drains and blood
may have added to increased nitrogen losses that were not captured in this study. Collectively,
these introduce a level of error, through an underestimation of nitrogen losses more infants
could have been in a negative balance had these losses been considered.
Another potential miscalculation could have occurred from measurements of urine
voided into an infant’s diaper. As this volume could not be accurately collected, it may have
influenced the content of urinary nitrogen output. In a study by Helms et al, for a collection to
be complete at least 80% of actual urine output was required for measurement (56). In the
infants in this study, 89% of voided volumes into the diaper were less than 20% of a total urine
collection on a given day. Possible factors to account for an increase in voided volumes could
have been due to increase doses of furosemide (diuretic) to promote diuresis for chest closure, in
combination with technical aspects of urinary catheter positioning that would result in leakage
around the tube.
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Also, at the onset of this study we set out to examine nitrogen balance in a narrow age
group of infants from 0-3 months. Due to difficulties with recruitment our sample population of
infants was expanded to 12 months of age. At the time of operation our study sample had WAZ
scores ranging from approximately -0.70 to -1.2, indicating a degree of growth impairment
(table 6), which is in agreement with the current literature (12, 32, 128). In consideration to an
infant’s age there is generally a corresponding higher weight and thus better nutritional status
prior to surgery may occur for older infants than with younger ones. Although at surgical
admission mean WAZ scores were low across all groups there were some infants in this study
who had adequate weight measures for age and perhaps better stores to rely on during periods of
stress.
Clinical factors that challenge approaches to nutrition therapy in the immediate period
are fluid restrictions and gastrointestinal intolerance (86). Post operatively fluid intake is strictly
controlled, given the nature of severe fluid restrictions in the management of this surgical group
designing nutrition prescriptions that provide adequate protein in the least amount of fluid is
paramount to an infant’s recovery. As suggested by Skillman et al, haemodynamic instability
can limit nutrition delivery, thus the time to return to a stable state may require the institution of
PN therapy (88). Additionally, it has been shown that children receiving PN had improved WAZ
scores at discharge (12). Although a shorter time receiving parenteral nutrition was associated
with a decrease in WAZ scores (12). Parenteral nutrition is a viable form of therapy to offset
some of the challenges associated with nutrient deficits in this vulnerable group. Concentrated
amino acid solutions can deliver sufficient amounts of protein to promote nitrogen balance as
was demonstrated in this study.
Moreover, certain aspects of nutrition provision in an ICU require thoughtful
consideration. As reported in the literature, cardiac patients were fasted for longer and
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experienced greater feeding interruptions, which were identified as main barriers to providing
estimated energy requirements (86). Also, as widely stated, protein energy malnutrition exists
among children with cardiac disease resulting in a greater prevalence of acute and chronic
wasting (11, 12, 86). In view of this, it seems rather primary that nitrogen balance is achieved
post-operatively to potentially lessen further nutritional deficits. Therefore, a combination of
providing PN with EN, or PN when enteral feeding is contraindicated is ideal and has been
justifiably supported in the literature (12, 90). In this study we were able to achieve adequate
delivery of protein and energy to promote a positive nitrogen balance through the use of
concentrated amino acid and lipid solution.
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CHAPTER 4: CONCLUSION AND FUTURE DIRECTIONS
4.1 Conclusion
Nutrition delivery is largely inadequate in paediatric intensive care units resulting in an
increase prevalence of malnutrition in critically ill children (4). Deficits in protein and energy in
children with CHD have been elucidated in several studies (1, 81, 82, 87). It is increasingly
being appreciated that nutrition is necessary in the maintenance of body composition, metabolic
and physiological functioning in critically ill infants, including those with CHD (86). Due to a
scarcity of studies investigating protein needs in infants immediately post CPB this study was
designed to determine a level of protein that would produce nitrogen balance after surgery in a
nutritionally vulnerable population.
This distinct group of infants with CHD are reported as being nutritionally compromised
prior to surgery, which can be exacerbated by operative stress that results in biological and
physiological alterations, that accelerates body mass breakdown (129). Consequently,
inadequate nutritional therapy can result in unfavourable outcomes if not provided timely after
surgery. An understanding of protein balance is clinically useful especially for a population that
is at risk for marked catabolism during an acute or prolonged stressed state. Of clinical
importance, one of the findings emerging from this study was that infants receiving 1.5 g/kg/d
of protein were in a more negative balance than those receiving the higher protein intakes of 2.2
and 3.0 g/kg/d. In view of our study findings and considering that other protein containing fluid
losses were not measured, a protein intake of 2.2 or 3.0 g/kg/d, appears to be more clinically
appropriate to ensure nitrogen balance occurs. Additionally, these higher amounts may be
required in the development of nutrition therapies that are designed to assist with reducing
cumulative energy and protein deficits.
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As positive nitrogen balances occurred equally at both 2.2 and 3.0g/kg/d of protein, it
would be reasonable to suggest that providing 2.2 g/kg/d of protein, in light of current fluid
restrictions, is clinically feasible and appropriate for this post operative population. The
findings of this study have important implications for future clinical practice as aiming for a
provision of 2.2 g/kg/d of parenteral protein can potentially minimize the breakdown of body
stores in infants post CPB surgery. This is significant in the development of nutrition
prescriptions that are intended to reduce negative effects associated with suboptimal nutrition
and to facilitate metabolic processes during periods of stress.
Rogers et al studied a group of critically ill children with cardiac disease compared to
those without CHD. They reported that the cardiac group younger than 1 month of age had
significantly lower intakes meeting only 31.3% of REE versus 64.8% in the non cardiac group
(86). They were also less likely to receive full estimated energy requirements during their ICU
stay, they were fasted longer (1-4 days), and experienced significantly more feeding
interruptions (86). Not surprisingly, they had a longer duration of stay in the ICU at a median of
7.5 days. Additionally, WAZ scores from ICU discharge were significantly less than on
admission and did not improve prior to hospital discharge (86). It is evident from this study, and
including other studies that investigated WAZ scores postoperatively, that inadequate nutrition
in the post-operative period negatively impacts growth (10, 12, 93, 99, 130).
Anderson et al performed a retrospective study examining nutrition and growth data
from 44 surgical centers in the United States. Results revealed that following the Norwood
procedure for infants diagnosed with HLHS, the median time to full enteral feeds was 13 days
(4-77 days) (99). The authors noted considerable variation in growth between surgeries from
different cardiac centers as evidence from varying nutritional practices from one site to another
71
(99). Given the significant duration of time to reach full enteral feeding, the institution of PN in
the early period following surgery may be essential to compensate for potential nutritional
deficits.
As indicated previously, to our knowledge there is no reliable evidence to suggest
protein requirements for infants post cardiovascular surgery. Recommendations for protein
intake in critically ill children have been proposed by the American Society of Parenteral and
Enteral Nutrition (ASPEN), suggesting that children 0-2 years of age, should receive 2-3 g/kg/d
of protein (131). However, these guidelines were based on non-randomized cohort with
historical controls or case series, uncontrolled studies and expert opinion (131). Furthermore,
the critically ill population that these recommendations are intended encompass a heterogeneous
group of diagnosis and are not specific to surgical infants with CHD. In consideration to the
results of this study, providing a protein delivery of 2.2 g/kg/d after CPB surgery could be
essential to reduce the effects of adverse developmental outcomes that may be associated with
nutritional deficits during a critical recovery period.
4.2 Future Directions
In regard to the results of this study, a number of suggestions can be made for future
research endeavours. The definition of nitrogen balance is simplified to nitrogen intake minus
output, however protein metabolism is more complex. The processes of protein degradation and
synthesis results in a dynamic series of protein turnover (29). Nitrogen balance techniques do
not define intermediary metabolism (132). Contemporary techniques used to determine protein
requirements can assist with contributing to an improved understanding of protein turnover. The
use of stable isotopes or indicator amino acid oxidation methods have been employed in the
evaluation of amino acid utilization in both health and disease (126). These methods have been
72
used sporadically in studies in critically ill children and could hold further benefit in
investigations of protein metabolism in infants post CPB (66).
As protein metabolism is dependent on energy metabolism the role of achieving nitrogen
balance requires examining protein and energy intake concurrently. Future research could
therefore investigate protein-energy nutrition therapy to include defined nutrition prescriptions
based on REE and RQ measurements as determined through indirect calorimetry. Presumably
goal directed energy and protein nutrition support could possibly result in improved clinical
outcome measures such as growth and length of hospital stay.
Likewise, an examination of clinical factors would assist with providing a further
understanding of the acute stress response during the immediate post-operative period.
Incorporating serial monitoring of clinical indicators such as, severity index scores (i.e. PRISM)
may contribute to describing the degree of stress. Also, the evaluation of stress mediators,
including acute phase proteins (i.e. CRP, fibrinogen), pro-inflammatory and anti-inflammatory
markers (i.e. interleukin–1, 6, 10, and tumour necrosis factor alpha) may hold further benefit. In
sum, a severity of illness index score and biological markers could provide valuable data
contributing to an enhanced understanding of the cardiac infant’s stress response in the
immediate post surgical period.
The goal of nutrition support in critically ill infants is to promote tissue synthesis and to
reduce catabolism of body stores for the maintenance of body composition and to support organ
function. Providing an appropriate level of protein is crucial to supporting optimal recovery in
the immediate period after surgery (34, 61). It is anticipated that the results from this study have
contributed to an emerging body of literature that aims to understand protein needs in this
nutritionally fragile group of infants. Ultimately, it is hoped that this study will add to an
73
exciting area of research and stimulate further studies in nutritional support therapies designed
to aid in improved outcomes for this high-risk population of infants with CHD.
83
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Appendix A
Research Consent Form
555 University Avenue Toronto, Ontario, Canada M5X 1G8 Research Consent Form for Parents or Guardian Consenting for Child Title of Research Project: Determination of protein needs using nitrogen balance in infant’s immediately post cardiothoracic surgery. Investigator(s): Principal Investigator: Dr. Paul Pencharz, MB ChB PhD MD FRCPC Division of Gastroenterology (416) 813 - 7733 Co-investigators: Joann Herridge, RD Heart Centre/Cardiac Critical Care (416) 813 - 6193 Dr. Steven Schwartz, MD FRCPC Heart Centre/Cardiac Critical Care (416) 813 - 6186 Purpose of the Research: This study is being performed to improve the nutrition care of infants with congenital heart disease who will be fed through a vein following surgery. A solution given into a vein is called parenteral nutrition; it contains protein, fat, carbohydrate, vitamins and minerals. This solution is necessary when an infant cannot be given any or enough of their mother’s breast milk or infant formula. Parenteral nutrition is provided to make sure a child will receive the nutrients they need after surgery. There is limited information about how much protein babies require in parenteral solutions after their heart has been surgically repaired. We are studying different amounts of protein that can be added to these solutions. To measure how much protein a child may need we calculate the amount of protein going into the body and subtract the amount coming out of the body in the urine. The goal of this study is to determine the best amount of protein that will help an infant recover and grow after surgery. Description of the Research: Infants participating in this study will be placed into one of three groups. We will determine the group that your child will be in through rolling a dice. Each group will be given a different amount of protein. Your child will receive one level of protein and this level will be studied for an expected time of three days. The type of protein solution that your baby will be given is routinely provided to infants in the Cardiac Critical Care Unit. When the medical team decides it is safe for your baby to feed through a tube in their nose, he or she will be started on either mother’s breast milk or a standard infant formula, as you prefer. Standard feeding guidelines will be followed to ensure the feeds are delivered safely while your baby is recovering. We will be calculating the amount of protein in these feeds in addition to the protein in the parenteral solution that your baby is receiving. Your child’s urine will be collected for an expected three days or more while he or she is receiving the protein solution during the study. A tube for withdrawing urine will be put into your child during surgery; this is a routine procedure. Urine will be collected in a container that is attached to this tube. After we have measured the amount of protein in your child’s urine we will discard it by following the hospital’s safe procedures.
Subjects
84 We will be reviewing your child’s chart and will be observing the results of the blood samples that are taken as part of his/her routine post-operative care. We do not require additional blood samples and the results will help us to understand if your child is tolerating his/her nutrition solution. Along with this we will monitor any fluids/medications that your baby is receiving through an intravenous line. Also, as part of our study which is normal practice of care for all babies after cardiac surgery we will check your baby’s medical record to find out information about your baby’s diagnosis and the type of cardiac surgery he or she had, his or her weight history, length and head circumference. If this information is not in your baby’s medical chart, we will ask you to provide this information, if possible. Throughout the study the individual conducting the research (Joann Herridge, study coordinator) will be helping with the extra attention your child will be receiving. After the study is completed the research data will be destroyed. Potential Harms: We know of no harm that taking part in this study could cause your child. Potential Benefits To individual subjects: Your child will not benefit directly from participating in this study. However, it will provide information that should result in the design of better solutions for future children in need of parenteral nutrition. 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. At your request we will provide study results in a format that you prefer. To society: The study results may provide information about the amount of protein required to reduce body protein breakdown following surgery in a group of infants with congenital heart disease. This can help with designing better nutrition plans for infants that need intravenous nutrition solutions. Confidentiality: We will respect your privacy. No information about who you are (your child is) will be given to anyone or be published without your permission, unless required by law. For example, the law could make us give information about you if a child has been abused, if you have 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, employees of the funder or sponsor, or the regulator of the study may see your health record to check on the study. By signing this consent form, you agree to let these people look at your records. We will put a copy of this research consent form in your patient health record and give you a copy as well. 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 then destroyed as required by Sick Kids policy. Published study results will not reveal your identity. Participation: If you choose to let your child take part in this study you can take your child out of the study at anytime. The care your child gets at Sick Kids will not be affected in any way by whether you take 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.
85 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 your child took part in this study. If your child becomes ill or are harmed because of study participation, we will treat your child 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 standard amount of protein in their parenteral nutrition solution. This standard solution is provided to infants as part of routine clinical treatment. Sponsorship: The funder of this research is provided by Dr. Pencharz CIHR amino acid and metabolism grant. Conflict of interest: I, and the other research team members have no conflict of interest to declare. 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 part in the study will not affect my child’s health care at Sick Kids.
4) I am free now, and in the future, to ask questions about the study. 5) I have been told that my child’s medical records will be kept private except as described to me. 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 understand pages 1-5 of this consent form, I agree, or consent, that my child___________________ may take part in this study.” _________________________________ Printed Name of Parent/Legal Guardian Parent/Legal Guardian’s signature & date _________________________________ Printed Name of person who explained consent Signature of Person who explained consent & date Printed Witness’ name (if the parent/legal guardian Witness’ signature & date 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, Joann Herridge at (416) 813-6193 or pager (416) 235-9515. If you need to contact someone about medical issues related to the study, please contact Dr. Steven Schwartz at (416) 813–6186. If you have questions about your rights as a research subject in a study or who to contact in the event of injuries during a study, please call the Research Ethics Manager at 416-813-5718.
The biochemistry investigation schedule can be performed every 2-4 hours on days 0-2, and every 4-6 hours on days 2-4; the timing of blood analysis and the biochemical values monitored is dictated by the patient’s hemodynamic status and biochemical results Monitoring Schedule for Stable Patients on Parenteral Nutrition Parameter
At start of therapy Monday Thursday
Glucose Yes Yes Yes
Electrolytes Yes Yes Yes
Intralipid Level No Yes Yes
Complete blood count No Yes No
BUN, phosphate, calcium, magnesium, conjugated bilirubin, albumin
Yes
Yes
No
AST, ALT, alkaline phosphatase, creatinine, acid base
Yes
If indicated
If indicated
Study Biochemistry Data Recorded Arterial blood gases Glucose ALT WBC Arterial mixed venous saturation INR AST Blood urea nitrogen (BUN) Intralipid level GGT Creatinine Complete Blood Count CRP* * as available Additional data collected: PRISM score (as available)
Determination of protein needs using nitrogen balance in infants immediately post cardiopulmonary bypass surgery Inclusion Criteria: All inclusion criteria must be answered yes to be eligible
Yes No 1. Clinical decision to initiate parenteral nutrition based on determination by medical team Yes No 2. Gestational age ≥ 36 weeks
Yes No 3. Weight ≥ 2500 grams Yes No 4. Indwelling urinary catheter for urine collection Yes No 5. Central venous access for parenteral nutrition Exclusion Criteria: To be monitored throughout study period Yes No 1. Hepatic failure defined as ALT and AST >500 UL, with an INR >2.5, not accounted for by
therapeutic anticoagulation Yes No 2. Renal failure defined as creatinine 2x the upper limit of normal for age. Yes No 3. Sepsis defined as a clinical confirmation of a positive blood culture as a systemic infection
treated with antibiotics Yes No 4. Excessive blood loss from chest tubes (5 ml/kg/hr) that has not resolved within six hours following admission to the CCCU; as indicated by the need for frequent blood transfusion
Yes No 5. Requiring extracorporeal membrane oxygenation (ECMO) support.
Enrolment date and time: └───┴───┘ │ └──────┘ │ └───┴───┘ └───┴───┘ : └───┴───┘ D D MON Y Y H H M M Randomization date and time: └───┴───┘ │ └──────┘ │ └───┴───┘ └───┴───┘ : └───┴───┘ D D MON Y Y H H M M
92
Demographic and Baseline Information 1. Age: _____ weeks 2. Gestational age: weeks 3. Age at time of surgery: weeks 4. Date & Time of CCCU Admit: _____/_____/________ at _______: _______ DD MM YYYY HH MM 5. Date & Time of Subject Enrolment: _____/_____/________ at _______: _______ DD MM YYYY HH MM 6. Gender: Female Male
Chromosome abnormality: 7. Admission Diagnosis:
6. Surgical Procedure:
Anthropometrics 1. Birth weight: kg
Birth length: cm
Birth head circumference: cm
2. Preoperative weight: kg
Preoperative length: cm
Preoperative head circumference: cm
3. CCCU discharge weight: kg
93
Nutrition DA PN Adaptation Period PN START date & time: _____/_____/________ at _______: ______ DD MM YYYY HH MM PN END date & time: _____/_____/________ at _______: _______ DD MM YYYY HH MM Amino Acid Dextrose Lipid Content g/L
Rate: ml/hr
Total volume mL/d
Hours given HH:MM
______ : _______
______ : _______
______: _______
PN D1 PN study solution START date & time: _____/_____/________ at _______:_______ DD MM YYYY HH MM PN study solution END date & time: _____/_____/________ at _______: _______ DD MM YYYY HH MM Amino Acid Dextrose Lipid Content g/L
Rate: ml/hr
Total volume ml/d
Hours given HH:MM
______ : _______
______ : _______
______: _______
Notes:
EN D1 EN START date & time: _____/_____/________ at _______: _______ DD MM YYYY HH MM Enteral Feed Protein g/ml Calories /ml Volume ml/d
PN D2 PN Study solution START date & time: _____/_____/________ at _______: ______ DD MM YYYY HH MM PN Study solution END date & time: _____/_____/________ at _______: _______ DD MM YYYY HH MM Amino Acid Dextrose Lipid Content g/L
Rate: ml/hr
Total volume ml/d
Hours given HH:MM
______ : _______
______ : _______
______: _______
Notes:
EN D2 EN START date & time: _____/_____/________ at _______: _______ DD MM YYYY HH MM Enteral Feed Protein g/ml Calories /ml Volume ml/d
95 PN D3 PN study solution START date & time: _____/_____/________ at _______:_______ DD MM YYYY HH MM PN study solution END date & time: _____/_____/________ at _______: _______ DD MM YYYY HH MM Amino Acid Dextrose Lipid Content g/L
Rate: ml/hr
Total volume ml/d
Hours given HH:MM
______ : _______
______ : _______
______: _______
Notes:
EN D3 EN START date & time: _____/_____/________ at _______: _______ DD MM YYYY HH MM Enteral Feed Protein g/ml Calories /ml Volume