Clinical trial NCT03889197
Conditions: Postnatal Growth Disorder
Keywords: Postnatal Growth Disorder Growth and development
Sponsor: Indiana University
Start date: 2019-07-01; Completion date: 2023-08-15
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Postnatal growth failure occurs in up to 50% of very low birth weight (VLBW, \<1500 grams at birth) infants as assessed by discharge weight. This study will evaluate if a sodium supplementation algorithm guided by spot urine sodium measurements can improve postnatal growth.

Detailed description:
Postnatal growth failure is a significant morbidity in very low birth weight (VLBW, \<1500 grams at birth) infants. Efforts to promote growth and optimize nutritional support have included earlier initiation of parenteral nutrition and increased caloric and protein administration. While these advances in nutritional practices have resulted in improved growth, up to 50% of VLBW infants continue to experience postnatal growth failure (defined as discharge weight \<10th percentile by Fenton growth charts) and over 25% experience severe postnatal growth failure (\<3rd percentile). Current nutritional recommendations for sodium provision to preterm infants is 3-5 mEq/kg/d and fails to take into account the degree of renal immaturity present in extremely preterm infants. The investigators hypothesize that the sodium supplementation algorithm will improve in-hospital somatic growth (weight, length, and head circumference) between 2 weeks of postnatal age and 36 weeks postmenstrual age over current sodium replacement practices. The algorithm will be evaluated in a prospective, pragmatic, randomized trial. Infants in the sodium supplementation algorithm group will have a spot urine sodium concentration determined every two weeks beginning on the 14th postnatal day and continuing until 36 weeks postmenstrual age with sodium supplementation provided according to the algorithm.

Arms: arm 1: Standard of care sodium supplementation as directed by the medical care team arm 2: Beginning on the 14th -16th postnatal day and continuing until 36 weeks postmenstrual age, infants randomized to the algorithm will have a spot urine sodium concentration determined every two weeks and sodium supplementation provided according to the algorithm.
Interventions: intervention 1: Sodium supplementation guided by urine sodium concentration algorithm
Intervention descriptions: intervention 1: 4 mEq/kg/d sodium added the first time urine \[Na\] below threshold; for each subsequent time urine \[Na\] below threshold, add additional 2 mEq/kg/d.

Protocol documents:
Prot_SAP_ICF_000.pdf: 
                     Version 9   (October 2022) 
 
 
 
Physiologic Approach to Sodium Supplementation in Premature Infants 
(Salt to Grow) 
 
 
 
 
 
Study Investigator: 
 
Gregory M. Sokol 
 
 
 
Collaborators: 
 
 
Jeffrey L. Segar 
 
 
 
 
 
Medical College of Wisconsin  
 
 
 
 
 
 
William Wai-Lun Wong 
 
 
 
 
 
Baylor College of Medicine 
 
 
 
 
 
Version Date: 
 
 
  October 17, 2022 
 
 
 
Funding:  
 
 
Thrasher Research Fund 
Award Number 14651  
 
 
ClinicalTrials.gov  
 
NCT: 03889197                     
 
 
IRB Number:  
 
 
1902815407 
 
 
 
 
 
 
 


 
2 
CONTENTS: 
 
 
 
Section 1.  
Abstract - 3 
 
Section 2.  
Statement of Problem - 5 
 
Section 3.  
Methods - 11 
 
Section 4.  
Adverse Events and Reporting - 17 
 
Section 5.  
Safety, Data Management, and Analysis Plan - 19 
 
Section 5.  
References – 22 
 
Section 6.              Appendix - 25 
 
 
 
 


 
3 
SECTION 1. 
ABSTRACT 
 
Study Hypothesis/Question 
Aim:  To determine the effects on somatic growth (weight, length, head circumference) of 
adherence to a clinical practice algorithm utilizing urinary sodium concentration to guide sodium 
supplementation as compared to current treatment practices in preterm infants. 
 
Study Design Type 
Prospective, pragmatic, randomized trial comparing a clinical practice algorithm to current 
treatment practices. 
 
Sample Size 
N = 90 patients (Infant and mother dyads) 
 
Eligibility Criteria 
Inclusion: 
1. Infants with gestational age 25 0/7 – 29 6/7 at birth 
2. Birth weight ≥ 500 grams 
3. Admitted within the 1st week of life 
4. < 17 days of age at time of enrollment 
 
Exclusion: 
1. Infants admitted after the 1st week of life 
2. Major congenital anomalies 
3. Structural genitourinary abnormality 
4. Renal dysfunction (serum creatinine > 1.0 mg/dl or an increase of  ≥ 0.3 mg/dl between the 
2 most recent consecutive measurements) immediately prior to the initiation of study 
procedures. 
5. Diuretic use less than 48 hours prior to initiation of study procedures 
6. Infant with an ostomy (infants receiving an ostomy after study entry will be withdrawn) 
7. Infant with a diagnosis or suspicion of diabetes insipidus  
 
This study will also include the mother of the infant to collect information from the mother’s 
chart. 
 
Study Intervention/Methods 
Beginning on the 14-16th postnatal day and continuing until 36 weeks postmenstrual age, infants 
randomized to the algorithm will have a spot urine sodium concentration determined every two 
weeks with additional sodium supplementation provided according to the algorithm.   
Assessment of total body water and energy expenditure will be made at 32 weeks corrected age 
by the doubly-labeled water method on all enrolled patients. 
 
 
 


 
4 
Primary Outcome 
The change in somatic growth (weight gain, head circumference, and length) evaluated by the 
change in Z-score between 2 weeks of age and 36 weeks conceptual age or transfer from NICU. 
 
 
Secondary Outcomes 
1. The change in somatic growth (weight gain, head circumference and length) evaluated by the 
change in Z-score between 2 weeks of age and discharge or transfer from the NICU or 44 
weeks corrected age (whichever occurs first) 
2. Total body water and energy expenditure at 32 weeks corrected age. 
3. Incidence and severity of bronchopulmonary dysplasia 
4. Duration of mechanical ventilation 
5. Need for supplemental oxygen 
6. Use of diuretic therapy 
7. Retinopathy of prematurity 
 
 
 
 
 


 
5 
SECTION 2. 
STATEMENT OF PROBLEM 
 
2.1 
PRIMARY HYPOTHESES OR QUESTIONS 
 
Aim 1.  To determine the effects on somatic growth of adherence to a clinical practice algorithm guiding 
sodium supplementation as compared to current treatment practices in preterm infants.  
 
Aim 2.  To determine the effects on total body water and energy expenditure of adherence to a clinical 
practice algorithm guiding sodium supplementation as compared to current treatment practices in preterm 
infants. 
 
Aim 3.  To assess whether adherence to the algorithm impacts the incidence of secondary outcomes 
including, duration of mechanical ventilation, rates of bronchopulmonary dysplasia, duration of 
supplemental oxygen, severe retinopathy of prematurity (stage ≥3 or requiring treatment), length of 
hospitalization, and neurodevelopmental impairment. 
 
Hypothesis 1.  Use of this innovative algorithm to direct sodium supplementation will result in improved in-
hospital somatic growth (weight, length and head circumference) compared to standard treatment. 
 
Hypothesis 2.  Use of the clinical practice algorithm to guide sodium supplementation in premature infants 
will result in no differences in total body water but decreased energy expenditure compared to the control 
group. 
 
Hypothesis 3.  Use of the algorithm will not negatively impact the incidence of common neonatal 
morbidities, including duration of mechanical ventilation, rates of bronchopulmonary dysplasia, duration of 
supplemental oxygen, severe retinopathy of prematurity, length of hospitalization, and 
neurodevelopmental impairment. 
 
 
2.2 
BACKGROUND AND RATIONAL 
 
Postnatal growth failure is a significant morbidity in very low birth weight (VLBW, <1500 grams at birth) 
infants. Recent efforts to promote growth and optimize nutritional support in this population have included 
earlier initiation of parenteral nutrition and increased caloric and protein administration. While these 
advances in nutritional practices have resulted in improved growth velocity, up to 50% of VLBW infants 
continue to experience postnatal growth failure (defined as discharge weight <10th percentile by Fenton 
growth charts[1]) and over 25% experience severe postnatal growth failure (<3rd percentile)[2, 3]. 
Furthermore, approximately 40% of VLBW infants have a fall in weight Z-score of >1 between birth and 
discharge. Strong associations have been identified between in-hospital growth failure and impaired short 
term (18–22 months) and long-term (up to 25 years) neurodevelopment[4-7]. Thus, it is imperative that 
evidenced-based initiatives be designed to address this major issue impacting the care of preterm infants. 
 
Sodium and Growth 
While recent efforts have focused on increasing caloric and protein intake in VLBW infants, little attention 
has been given to identifying sodium requirements for optimal growth[8, 9]. The need for adequate sodium 
intake to optimize growth is apparent from studies in animals and humans[10-16]. In young, growing rats, 
feeding a sodium deficient diet impairs weight and length gain, diminishes nitrogen retention and decreases 


 
6 
muscle protein synthesis and RNA concentrations[16]. Salt supplementation to sodium depleted animals 
restores normal rates of weight and length growth and protein synthesis[17]. Improved growth resulted from 
increased efficiency of weight gain per gram of food intake; there was no difference in caloric intake. In a 
separate study, weanling rats fed low sodium diets for 5 weeks displayed impaired bone growth, fat-free dry 
weight and total body fat and nitrogen accretion compared to sodium replete animals[11]. Notably, animals 
provided a broad range of sodium intake (0.1 to 3 times the minimal daily requirement of sodium for normal 
growth) displayed similar body water content (% body weight) and serum sodium values. Several groups 
identified that infants with short bowl syndrome at risk for sodium depletion due to intestinal losses 
displayed improved growth with sodium supplementation and sodium repletion[10, 14, 18].  
 
The mechanisms linking sodium depletion and impaired growth and tissue repair have not been fully 
defined.  It is hypothesized that reduced availability of sodium in the extracellular fluid space and a 
decreased transmembrane gradient for sodium results in decreased Na+-H+ antiporter activity across the 
cell membrane, increased intracellular H+ and decreased intracellular pH[13, 19]. In tissue culture, DNA 
synthesis and the action of growth factors on cell growth is inhibited when the sodium concentration in the 
culture medium is reduced; and restored when sodium is replaced[20, 21]. Specifically, reduced sodium 
concentration of culture medium inhibits Na+-H+ exchange, decreasing intracellular pH (pHi) and impairing 
cell growth[20-22].  Ray et al. demonstrated in weanling rats that a sodium-deficient diet results in growth 
restriction and a decrease in muscle pHi [19]. Thus, there appears to be a strong relationship between 
sodium availability and its effects on Na+-H+ exchange activity, pHi, and cell growth, both in vitro and in 
vivo[21, 23-25]. It is therefore not surprising to find that sodium depletion impairs growth during the 
postnatal period. 
Provision of Sodium 
Current nutritional recommendations for preterm infants from the American Academy of Pediatrics include 
enteral or parenteral intake of sodium of 3-5 mEq/kg/d and are based on a factorial approach calculated from 
fetal accretion of body components[26-28]. This recommendation has not been updated since 1985[29] and 
fails to take into account the degree of renal immaturity present in extremely preterm infants who are 
surviving after birth far earlier in gestation now than 30 years ago. Furthermore, many infants fail to receive 
the currently recommended quantity of sodium. In a review of 70 infants with birth weights less than 
1000 grams admitted to a level IV NICU January 2009 through June 2011, only 11% of infants received an 
average sodium intake of over 3 mEq/kg/d from weeks 2 through 12 of life[30]. Growth velocity in this cohort 
averaged only 10.7 g/kg/d, well below the goal outlined by the AAP[29].  Delgado, et al demonstrated that 
infants born at 23-31 weeks gestation and receiving the AAP recommended sodium intake do not 
consistently achieve a state of positive sodium balance (intake > urine sodium losses) until after 32 weeks 
postmenstrual age[31]. Considering these calculations did not account for non-renal sodium losses or sodium 
accretion associated with growth, (approximately 1.4 mEq/kg/d at these gestational ages), it is unlikely 
sufficient sodium was provided at any time point. The University of Iowa Children’s Hospital found average 
daily sodium intake for 26–29 6/7-week gestation infants born during 2014–2015 to be 3.6, 3.8, and 
2.9 mEq/kg/d at 4, 6 and 8 weeks of postnatal age, respectively. Thus, even current recommendations, which 
likely underestimate the needs of many infants, are often not met. Reasons for this likely include that 
formulas designed specifically for premature infants (Enfamil Premature, 2.5 mEq/100 calories; Similac 
Special Care, 1.87 mEq/100 calories) fail to meet the higher end of these recommended requirements as 
does human milk supplemented with commercial fortifiers (2.1 mEq/100 calories, fortification to 24 
kcal/oz)[26]. 
 
Studies in preterm infants suggest sodium supplementation above that provided in the diet may optimize 
weight gain. Vanpee et al provided 4 mEq/kg/d of supplemental sodium chloride to infants with gestational 
age 29-34 weeks from 4-14 days of life[32]. At 2 weeks of age, supplemented infants weighed about 6% 


 
7 
above birthweight while non-supplemented infants were approximately 2% below birthweight (<0.01); fluid 
intake and urine output were similar between groups.  Recently, Isemann et al reported that sodium 
supplementation to infants <32 weeks gestation at a dose of 4 mEq/kg/d from days 7–35 of life enhanced 
weight gain (26.9 ± 3.1 vs. 22.9 ± 4.7 g/kg/d)[33]. Importantly, 79% of patients in the supplemented group 
maintained their Fenton growth curve birth percentile at 6 weeks of age compared to 13% in the non-
supplemented group. This study was limited by its small sample size as well as the lack of a patient-focused 
assessment of the need for supplementation. 
 
Clinical relevance of the study 
A primary issue in preterm infants failing to receive adequate sodium intake is the current lack of a clinical 
measure of total body sodium status. Most neonatologists base the decision to provide supplemental 
sodium on serum sodium levels (personal communication), however the physiologic basis for this practice 
is limited given the poor relationship between serum sodium concentration and body sodium content[34-
37]. Animal and human studies support that i) sodium deficiency impairs growth; ii) many preterm infants 
fail to receive sufficient sodium in their diet; iii) there is currently no accepted approach to identifying 
infants with sodium deficiency; and iv) impaired postnatal growth is associated with impaired 
neurodevelopmental outcome. Sodium supplementation improves growth of preterm infants, however 
previous studies were limited in sample size, provided supplementation for only relatively short period of 
time and failed to identify which infants required supplementation and those in whom supplementation 
was inadequate. As such, there is a vital need for early identification of those infants requiring sodium 
supplementation and to develop a rational, physiology-based approach guiding the amount of 
supplementation. The proposed trial addresses these limitations and gaps in knowledge.  Specifically, this 
pragmatic trial utilizing a sodium supplementation algorithm is powered to address an important, yet 
underappreciated clinical aspect of nutritional management of preterm infants, and will produce 
substantial evidence on which to base recommendations to guide sodium supplementation in extremely 
preterm infants. Results from this trial will have the potential to change clinical practice and result in a 
paradigm shift in how physicians use dietary approaches to optimize growth and potentially 
neurodevelopmental outcomes. 
 
Supportive preliminary data 
An underappreciated though convenient approach to the assessment of sodium homeostasis is the use of 
urine sodium concentration measured from a spot urine sample[38]. While evidence is limited, there is 
general agreement that in patients with normal and mature renal function, urine sodium >30 mEq/L is 
reflective of positive sodium balance, measurements <30 mEq/L represent total body sodium depletion and 
measurements <10 mEq/L indicate severe deficit. Limitations of this approach have recently been 
highlighted as urine sodium excretion is dependent upon diet, fluid consumption and circadian cycle[39]. 
However, in contrast to older children and adults, there is typically a consistent pattern of provision of diet 
and fluid to preterm infants, ameliorating some of this concern.   
 
Several studies have now correlated low urine sodium concentration with poor growth during infancy and 
demonstrated that sodium supplementation to achieve urine sodium >30 mEq/L is associated with 
improved weight gain[10, 14, 18]. Butterworth et al described 39 infants (mean gestational age at birth 
32 weeks and birth weight 1.43 kg) with intestinal stomas in place, 92% had total sodium deficiency 
(defined as urine Na <30 mEq/L) and 64% had severe deficiency (<10 mEq/L)[10]. Sodium repletion and 
maintenance therapy were governed by a clinical guideline primarily using urine sodium values. On 
multiple regression analysis, urine sodium but not serum sodium, caloric or fluid intake was significantly 
associated with weight gain. A separate study of 40 infants <1 year of age with ileostomies reported similar 


 
8 
findings, optimum growth was achieved when urine sodium exceeded 30 mEq/L[14]. These findings 
highlight the correlation between sodium deficit and impaired growth in infants. 
 
Development of algorithm using urine sodium concentrations.  Our novel approach takes advantage of the 
fact that urine sodium concentration is reflective of total body sodium status. However, in the preterm 
population such an approach is confounded by renal functional immaturity. Specifically, preterm neonates 
have a lower glomerular filtration rate (GFR) and higher fractional excretion of sodium (FeNa) compared to 
term infants[40, 41]. Furthermore, there is ongoing 
maturation of renal function with postnatal age; 
GFR and FeNa being inversely correlated with 
postnatal age[40, 41]. To account for these 
maturational changes in developing a 
physiologically based algorithm for guiding sodium 
supplementation in the preterm population, we 
used recently published measures of glomerular 
and tubular function to calculate expected urine 
sodium concentrations with various and advancing 
gestational and postnatal ages. Values for weight 
and length were based on standardized growth 
charts as well as data from our NICU. Body surface 
area was calculated according to a standardized 
formula[42]. Glomerular filtration rate was 
obtained from the literature[41]. GFR in ml/min 
was calculated based on estimated GFR in 
ml/min/1.73 m2 and estimated body surface area 
for each gestational and postnatal age. Total 
filtered volume was calculated from GFR (ml/min) x 
1440 min/day. Filtered sodium was calculated using an 
estimated serum sodium concentration of 135 mEq/L. 
We purposefully chose a value at the lower limit of 
normal to avoid overestimating urine sodium losses. 
Fractional excretion of sodium was based on 
interpolation and extrapolation of recently published 
longitudinal data on FeNa in preterm infants less than 28 weeks and 29–31 weeks gestation[40]. Total urine 
sodium was calculated based on the total amount of filtered sodium and FeNa (filtered sodium x FeNa). The 
value chosen for urine volume was based on values reported in the literature and verified in our own patient 
population. Finally, urine sodium concentrations for each gestational and postnatal age were calculated 
based on total urine sodium and estimated urine volume (UNa (mEq/d)/urine volume (ml/d) x 1000 ml/L). 
 
As expected there is large variation in urine sodium concentration over the ranges of gestational and 
postnatal age. Figure 1 summarizes the calculated urine Na concentrations (top) and daily urine sodium 
losses (bottom) at 2 weeks of postnatal age for a range of gestational ages. Not unexpectedly, the urine 
values consistently equal or exceed the 30 mEq/L value used in children with more mature renal function to 
signify sufficient body sodium. Furthermore, estimated urine sodium losses often exceeded the 3–
5 mEq/kg/d of Na currently recommended by AAP for preterm infants. 
Using these data, we developed a novel algorithm to guide sodium supplementation in infants 25–
29 6/7 weeks gestation. The algorithm has undergone slight modification since its original development, 
although changes have been minimal. The algorithm is as follows: 
Figure 1. Calculated urine sodium 
concentration (top) and daily urine 
sodium losses (bottom) at 2 weeks of age 
for various gestational ages. Values 
calculated as described in text. 


 
9 
Postnatal 
age (weeks) 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
GA (birth) 
 
 
 
 
 
 
 
 
 
 
 
 
 
25 wk 
<50 
 
 
<40 
 
 
<40 
 
 
<40 
 
 
<40 
 
 
<30 
 
<30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
26 - 29 6/7 wk <40 
 
 
<40 
 
 
<40 
 
 
<40 
 
 
<30 
 
 
<30 
 
 
 
i.  Values represent urine [Na], expressed as mEq/L, obtained every other week 
ii.  If urine [Na] is below threshold value, initiate supplementation at 4 mEq/kg/d above current Na intake. 
Adjust supplementation weekly to account for weight gain 
iii.  Increase by 2 mEq/kg at subsequent time points if <urine [Na] goal. (Values should not be  
 
  
 
obtained within 48 hr of use of diuretic agent) 
iv.  Consider supplementation or determination of urine [Na] if serum [Na] is ≤132 mEq/L prior to first 
 
scheduled urine [Na] determination 
v.  Provide supplementation if serum [Na] ≤132 mEq/L, regardless of urine [Na] unless there is evidence of 
 
acute fluid overload (significant increase in weight).  Hyponatremia in presence of high urine [Na] likely 
 
represents a condition of severe urinary sodium loss leading to hyponatremia 
vi.  Continue supplementation unless serum [Na] >144 mEq/L 
vii. Consider discontinuation of supplementation at 38 weeks postmenstrual age 
 
Initial supplementation of 4 mEq/kg/d was chosen based on experience in the literature[33, 43]. These 
studies suggest this degree of supplementation overcomes sodium depletion and improves growth without 
development of hypernatremia.  
This algorithm was initiated as a standardized protocol to guide sodium supplementation at the University 
of Iowa Children’s Hospital NICU in 2016 for infants 26 – 29 6/7 weeks gestation. The algorithm was applied 
to all infants excluding those with underlying renal abnormalities, or other conditions that may affect fluid 
and electrolyte balance. As expected, there was little relationship between serum and urine sodium 
concentrations at 2 weeks of postnatal age (Figure 2). Notable, a significant number of infants with 
“normal” serum sodium concentrations had urine 
sodium concentrations that we interpreted as 
being consistent with sodium depletion, based on 
the algorithm.  
 
To evaluate the impact of adapting the algorithm, 
data were compared for 50 infants, 26 – 29 6/7 
weeks gestation cared for in the 2014-2015, prior 
to implementation of the algorithm and 40 
infants cared for in 2016, after implementation of 
the algorithm. Results from this study have 
recently been published[44].   
 
Figure 2. Serum sodium vs. urine sodium 
concentrations measured at 2 weeks postnatal 


 
10 
Twenty-three (58%) of infants had initial (2-week measurement) urine Na concentration warranting 
supplementation; while another 7 of infants had low urine sodium concentration] at 4 wk, warranting 
supplementation. Thus, 75% of infants cared for using this algorithm received sodium supplementation 
above that in their normal diet. Daily Na intake was similar at 2 wk in both cohorts, but significantly greater 
(p <0.05) at 4, 6 and 8 wk in the 2016 vs. 2014–2015 cohort (Table).  Weight gain, determined as change in 
weight Z-score between 2 and 8 wk of age, was significantly greater in 2016 vs. 2014–2015 cohort (0.32 ± 
0.06 vs. -0.01 ± 0.08, p<0.01).  Caloric, protein and total fluid intakes as well as daily urine output were 
similar between cohorts at the measured time points of 2, 4, 6 and 8 weeks of age (Table).  Use of the 
algorithm did not negatively impact respiratory morbidity at either 28 days of postnatal age (or at 36 weeks 
postmenstrual age (2014-2015 cohort: 60% receiving supplemental oxygen; 2016 cohort: 48% receiving 
supplemental oxygen).  Since initiating use of this algorithm, no infant has required sodium 
supplementation to be discontinued due to hypernatremia (serum [Na] >144 mEq/L). These data suggest 
the physiologically based algorithm to individualize identification of need for sodium supplementation in 
the preterm infant resulted in increased sodium intake and growth in this population. Given the potential 
benefits of this approach on growth and ultimately neurodevelopmental outcome, a randomized controlled 
trial to evaluate the efficacy of 
this approach is needed. 
 
Assumptions regarding the 
approach have been validated.  
Infants at the University of 
Iowa Children’s Hospital NICU, 
have validated several of the 
assumptions implicit in the 
derived algorithm. Fractional 
excretion of sodium (FENa) at 
2 weeks of age is similar to that 
used in the calculations for 
development of the algorithm. 
As previously stated, we found 
little relationship between 
serum [Na] and urine [Na] at 
2 weeks of age. Importantly, 
many infants with urine [Na] 
<40 mEq/L still had serum [Na] 
>135 mEq/L. This represents a group of infants who likely have total body sodium depletion yet would likely 
not be receiving sodium supplementation due to a “normal” serum [Na]. As expected, Na intake correlated 
positively with urine [Na] at and beyond the 2-week time point. Recently Dr. Segar collected urine samples 
4 times over the course of 24 hrs from 10 preterm infants (25-28 weeks gestation) at 2 weeks of postnatal 
age and measured urine sodium concentration and found the coefficient of variation (Standard 
deviation/mean) to be about 0.15. Thus we are confident that a spot urine sodium concentration is 
reflective of daily sodium losses (i.e. those obtained by a 24 hr urine collection). 
 
 
 


 
11 
SECTION 3. 
METHODS 
 
3.1 
STUDY POPULATION 
Premature infants < 17 days of age and their mothers 
 
3.1.1 Inclusion Criteria 
1. Infants with gestational age 25 0/7 – 29 6/7 at birth 
2. Birth weight ≥ 500 grams 
3. Admitted within the 1st week of life 
4. < 17 days of age at time of enrollment 
 
3.1.2 Exclusion Criteria 
1. Infants admitted after the 1st week of life 
2. Major congenital anomalies 
3. Structural genitourinary abnormality 
4. Renal dysfunction (serum creatinine > 1.0 mg/dl or an increase of  ≥ 0.3 mg/dl between the 2 
most recent consecutive measurements) immediately prior to the initiation of study 
procedures. 
5. Diuretic use less than 48 hours prior to initiation of study procedures 
6. Infant with an ostomy (infants receiving an ostomy after study entry will be withdrawn) 
7. Infant with a diagnosis or suspicion of diabetes insipidus 
 
This study will also include the mother of the infant to collect information from the mother’s 
chart. 
 
3.2 
DETAILED STUDY PROCEDURES 
• 
All study events described below have a ±2 day range for execution.  
• Doubly labeled water procedure will  occur from corrected week 32 to corrected week 32 + 
6 days 
• 
Date of birth is considered day 0 
• 
See Appendix for table of events 
 
3.2.1 
Screening 
 
All patients admitted to Riley Hospital at IU Health’s NICUs (Simon Family Tower, Methodist, IU 
North), and Eskenazi Health NICU, will be evaluated for eligibility.  Outborn infants will be included 
if admitted within the first week of life. 
 
3.2.2 
Consent Procedure 
 
Eligible infant’s guardians will be approached for consent by study personnel after the infant’s first 
week of life.   
 


 
12 
 
 
3.2.3 
Randomization Procedure 
 
An infant must meet all inclusion criteria and no exclusion criteria at the time of randomization.  
After meeting eligibility and obtaining consent, randomization will be carried out in REDCap to 
management arms 1:1, using a permutated block scheme stratified by gestational age at birth:    
25 0/7 – 27 6/7 and 28 0/7 – 29 6/7 weeks. 
 
3.2.4 
Study Intervention 
 
Infants randomized to the study algorithm will have their urine [Na] measured at 2 weeks of age 
and every 2 weeks thereafter until 36 weeks corrected age.  They will receive additional sodium 
supplementation after the second week of life if their urine [Na] is below the level in the diagram 
on the following page: 
 
 
Postnatal 
age (weeks) 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
GA (birth) 
 
 
 
 
 
 
 
 
 
 
 
 
 
25 wk 
<50 
 
 
<40 
 
 
<40 
 
 
<40 
 
 
<40 
 
 
<30 
 
<30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
26 - 29 6/7 wk <40 
 
 
<40 
 
 
<40 
 
 
<40 
 
 
<30 
 
 
<30 
 
 
 
i.  Values in table represent urine [Na], expressed as mEq/L, obtained every other week 
ii.  If urine [Na] is below threshold value, initiate supplementation at 4 mEq/kg/d above current Na intake. 
Adjust supplementation weekly to account for weight gain 
iii. Increase supplementation by 2 mEq/kg/d at subsequent biweekly points if <urine [Na] goal. Urine [Na] 
 
should not be obtained within 48 hr of use of diuretic agent 
iv. Provide supplementation if serum [Na] ≤132 mEq/L regardless of urine [Na] unless there is evidence of 
 acute fluid overload (significant increase in weight).  Hyponatremia in presence of high urine [Na] likely 
 represents a condition of severe urinary sodium loss leading to hyponatremia 
v.  Continue supplementation unless serum [Na] >144 mEq/L 
 
 
If serum [Na] 145 – 146 mEq/L; reduce sodium supplement by ½ and consider  
 
 
 
measuring serum [Na] on subsequent day 
 
 
If serum [Na] > 147 mEq/L; discontinue sodium supplementation  
vi. Continuation of supplementation after 38 weeks postmenstrual age will be at the discretion of the 
 
clinical care team 
 
Routes of sodium administration:   
 
We will allow flexibility in how supplemental sodium is delivered since this is not standardized in 
usual care practices. 
 


 
13 
For infants receiving ≤80 ml/kg/d of enteral feedings: The designated amount of sodium 
supplementation will be added to parenteral fluids to be infused over 24 hours. Sodium may be 
provided as sodium chloride acetate/citrate/bicarbonate or any mixture thereof.   
 
For infants receiving >80 ml/kg/d of enteral feedings: The designated amount of sodium will be 
added to the feedings (sole route of supplementation) or provided by a combination of enteral 
and parenteral route. When provided enterally, sodium will be administered in equally divided 
quantities with every other feeding, (i.e., 4 feedings each day for infants fed every 3 hours, 3 
feedings each day for infants fed every 4 hours). Enteral supplemental sodium may be 
administered in the form (sodium chloride, sodium acetate, sodium citrate, sodium bicarbonate, 
or any mixture) chosen by the care team.  
 
3.2.5 
Data collection:   
 
Growth and nutrition data, including fluid, caloric, protein, carbohydrate and lipid intakes and 
weight, will be abstracted from the infants’ medical records and entered on to study data collection 
instruments. Standardized data collection forms will be used for collection all clinical outcome data 
and entered into a REDCap data base as described below. Other variables will be recorded on data 
forms created for this trial. The potential confounding variables include but are not limited to: 
 
• 
Maternal demographic variables: maternal age, maternal education level, maternal 
race/ethnicity, maternal health issues, presence of chorioamnionitis, preeclampsia, reason 
for preterm delivery 
 
• 
Labor and delivery: rupture of membranes, steroid exposure, antibiotics, mode of delivery 
 
• 
Infant health demographic variables: gestational age at birth, birthweight, length, sex, small 
for gestational age status, parity, Apgar scores, delivery room resuscitation, initial respiratory 
support, blood pressure, body temperature, pH, PaO2, FiO2. 
 
• 
Infant neurologic and medical morbidity: death, presence and severity of intracranial 
hemorrhage, presence of periventricular leukomalacia, seizures, patent ductus arteriosus, 
early and late onset sepsis, bronchopulmonary dysplasia, retinopathy of prematurity (stage 
≥3 or requiring treatment), age at final tracheal extubation, length of hospital stay, duration 
of need for supplemental oxygen and diagnosis of hypertension as defined as need for 
scheduled antihypertensive agents. 
 
• 
Nutritional intake data:  Parenteral intake of fluid, protein, lipid, calories and sodium will be 
recorded each Monday, Wednesday and Friday from day of life until 38 weeks postmenstrual 
age or hospital discharge. Enteral intake of milk/formula volume, sodium and calories will 
similarly be recorded each Monday, Wednesday and Friday. Sodium content of breast milk 
will be estimated at 0.8 mEq/100 ml. Milk fortified to 24 and 27 kcal/oz with human milk 
fortifier (HMF) will be estimated to have sodium content of 1.4 and 1.8 mEq/100 ml, 
respectively. Sodium content of formula will be as described by the manufacturer. 
 
• 
Anthropomorphic measurements:  Measurements will be obtained weekly until 
discharge/transfer or until 44 weeks corrected age (whichever occurs first).  Weights will be 


 
14 
extracted from the medical record. Research staff will obtain the length (using a length 
board) and OFC. 
 
 
 
3.2.6 
Measurement of Total Body Water and Energy Expenditure 
 
Total body water (TBW) and energy expenditure (EE) will be determined at 32 weeks 
postmenstrual age. This approach will provide TBW and EE measurements over a range of 
postnatal ages following initial supplementation (i.e. 3 weeks for infants born at 29 weeks 
gestation, 7 weeks for infants born at 25 weeks gestation) allowing an understanding of changes in 
TBW and EE over time after initiating supplemental Na. EE and TBW will be measured using the 
doubly labeled water (DLW, 2H218O) method which has been validated in preterm and term 
infants[53-56]. The method uses non-radioactive isotopes, is non-invasive and does not require 
blood sampling.  The method is based on the principle that labeled hydrogen (2H) is eliminated as 
water, disappearance of the oxygen isotope (18O) is eliminated as water and as expired carbon 
dioxide. By measuring the difference in the elimination rates, carbon dioxide production can be 
calculated according to the following equations: 
 
rCO2 = 0.445N x [(1.01 x ko) – (1.04 x kh] 
where rCO2 is carbon dioxide production rate, N is the mean of the initial and final TBW volume 
calculated as described below, ko and kh are the fractional elimination rates for 18O and 2H2, 
respectively.   
 
Metabolic rate is estimated from rCO2 using Weir’s equation based on the food quotient (FQ) of 
dietary intake: 
 
EE(kcal/d) = 1.44 x [[3.941 x rCO2(ml/min)/FQ] + 1.11 x rCO2(ml/min)] 
Food quotient (FQ), used as an estimate of respiratory quotient is calculated as: 
FQ = (P x 0.81) + (F x 0.71) + (C x 1.00) 
 
Where P, F and C represent the energy contributed by protein (P), fat (F) and carbohydrate (C) 
expressed as a fraction of the total metabolizable energy of the diet[57].  Published values for 
human milk and infant formula will be used as applicable and modified as necessary for any  
dietary supplementation (i.e. human milk fortifier) provided.    
 
TBW (g) is estimated from the dilution of 2H using the following equation as previously described 
by us and others[58-60]. 
TBW =[Dose x W x (dd - dw)]/(D x I0 x 1.041) 
 
where Dose is the weight (g) of the DLW administered, W is the weight (g) of water used to 
prepare the dose dilution, dd is the d2H value (o/oo) of the dose dilution, dw is the d2H value (o/oo) 
of the water used in making the dose dilution, D is the weight (g) of the DLW used to prepare the 
dose dilution, I0 is the zero-time intercept (o/oo) of the 2H enrichment over time,  and 1.041 is the 
correction for deuterium distributed into non-aqueous tissues. Urine 2H2O enrichment at time 0 is 
extrapolated by linear regression analysis after plotting the logarithm of 2H2O enrichment in urine 
versus time. 
 


 
15 
A typical study protocol using the DLW method starts with a baseline urine collection before the 
dose of DLW to determine baseline values for 2H and 18O.  An accurately weighed dose of DLW 
(1.5g/kg body weight, 2H2O (99.9 atom %) and H218O (10.0 atom %) (both from Children’s Nutrition 
Research Center at Baylor College of Medicine) is administered through a nasogastric feeding 
tube. DLW sterility is ensured using microfiltration into single use sterilized serum vials that are 
then covered with parafilm. The dose (approximately 1.5 ml/kg) is flushed through the tube with 2 
ml of sterile water. The syringes containing the isotopes are weighed to the nearest 0.1 mg before 
and after the dose is given. Urine samples are then collected between 6-24 h after dosing and, and 
again 2 and 5 days after dosing.  Timing of urine collection is carefully recorded. These urine 
samples will be analyzed for 2H and 18O enrichment by isotope ratio mass spectrometry, which will 
allow for calculation of TBW and EE as described above[61,62].   
 
Urine will be collected, labelled appropriately, including time after DLW administration, and frozen 
at -20˚C until shipped for analysis.  Samples will be shipped from IU to the USDA/ARS Children 
Nutrition Research Center at Baylor College of Medicine and immediately transferred to the 
Central DLW Laboratory, directed by Dr. William W. Wong, a collaborator on the project. Upon 
arrival, samples will be logged and again frozen at -80˚C until isotope analysis is performed by gas-
isotope-ratio mass spectrometry as performed in Dr. Wong’s laboratory as previously 
described[63]. 
 
3.2.7 
Blinding/Masking 
 
None.  Though randomization will be concealed preventing allocation bias, it is impossible to blind 
caregivers or parents to the intervention.  Interim results will be provided to the Data Safety 
Monitoring Committee (DSMC) with treatment assignments labeled only as group “A” and “B.” We 
will record sodium and fluid intake as well as serum and urine sodium values in order to assess 
protocol compliance. 
 
3.2.8 
Primary Outcome 
 
The change in somatic growth (weight gain, head circumference, and length) evaluated by the 
change in Z-score between 2 weeks of age and 36 weeks conceptual age or transfer from NICU.  
Weights will be extracted from the medical record, consistent study personnel will obtain the 
length (using a length board) and OFC. 
 
3.2.9      Secondary Outcomes 
 
1. The change in somatic growth (weight gain, head circumference and length) evaluated by 
the change in Z-score between 2 weeks of age and discharge or transfer from the NICU or 
44 weeks corrected age (whichever occurs first). 
2. Total body water and energy expenditure at 32 weeks corrected age 
3. Incidence and severity of bronchopulmonary dysplasia 
4. Duration of mechanical ventilation 
5. Need for supplemental oxygen 
6. Use of diuretic therapy 


 
16 
7. Retinopathy of prematurity 
 
SECTION 4. 
ADVERSE EVENTS AND REPORTING 
 
4.1 
Definitions  
An adverse event (AE) is defined as any untoward medical occurrence in a subject in the 
investigation. AEs must be assessed for expectedness, severity, attribution (relatedness to the 
study intervention), and seriousness by the investigator, or another qualified study team member 
as characterized below. AEs deemed related to the intervention must be reported as serious 
adverse events (SAEs) if they become serious (become life-threatening, result in death, or prolong 
hospitalization). Recording of such adverse events will start at the time of the study intervention 
(2 weeks of age) and will stop at 36 weeks PMA or transfer/discharge (whichever occurs later).  
The following criteria will be used to define relatedness:  
Definite: The AE is clearly related to the study intervention  
Probable: The AE is likely related to the study intervention  
Possible: The AE may be related to the study intervention  
Unrelated: The AE is clearly not related to the study intervention 
 
The severity of AEs will be described as: 
Mild: asymptomatic or mild symptoms, no intervention indicated  
Moderate: clinically significant requiring minimal noninvasive intervention 
Severe: severe or medically significant but not immediately life-threatening, need for intensive, 
emergent, or invasive intervention  
Life-threatening: life-threatening physiological consequences, need for intensive or emergent 
invasive intervention 
 
4.2 
Adverse Event Monitoring and Reporting  
Extremely preterm infants commonly have multiple clinical complications and laboratory 
abnormalities associated with prematurity. Those listed as secondary outcomes will be collected in 
the REDCap database and reviewed monthly by the Study Team.  
Published data involving this population and at the dose of sodium supplementation to be 
provided in this study have not shown any harmful effects, including hypernatremia, suggesting 


 
17 
this risk is minimal [33, 43]. In this patient population per routine standard of care, serum [Na] 
concentrations are checked daily to several times/week on infants receiving majority of intake 
parenterally and twice weekly to weekly for infants receiving primarily enteral intake. As this is a 
pragmatic, unmasked study evaluating an algorithm to assist clinicians in preventing total body 
sodium deficiency, AE reporting will specifically focus on states of sodium inadequacy or excess, 
and any additional adverse event monitoring the DSMC requests.  
Adverse event monitoring will include:  
 
Hyponatremia:  mild [Na] 134-130; moderate [Na] 129-125; severe [Na] <125 
Hypernatremia: mild [Na] 146-150; moderate [Na] 151-155; severe [Na] >155 
(To be considered an AE, 2 consecutive measurements of hyper/hyponatremia will be required to 
rule out laboratory measurement variation.) 
 
Common complications of prematurity that are not considered AE’s will be collected and included 
in a Note to File for each participant.  
 
Other events classified as serious and unexpected 
Other events resulting in death or classified as a Serious or Related (to study procedures). 
All SAEs and AEs reported during this study will be followed until resolution or until the 
investigator confirms that the AE/SAE has stabilized and no more follow-up is required.  
All deaths and serious adverse events SAEs that are at least possibly related and all unexpected 
SAEs will be reported to the Chair of the DSMC within 72 hours of awareness. An initial SAE form 
must be as complete as possible, including details of the current serious adverse event, including 
an Investigator assessment of the causal relationship between the event and study procedures. 
Information not available at the time of the initial report must be documented on a follow-up SAE 
form.  
All AEs/SAEs that meet IU HRPP Policy on Reportable Events will be reported to the IRB within 5 
working days.  
 
 
SECTION 5. 
SAFETY, DATA MANAGEMENT, AND ANALYTICAL PLAN 
 
5.1           Protection against risks 
Potential Risks 
The risks from this study are minimal, primarily consisting of mild hypernatremia.  However, 
published data involving this population and at dose of sodium supplementation to be provided in 
this study have not shown any harmful effects, including hypernatremia, suggesting this risk is 
minimal [33, 43].  Additional risks relate to the collection of biological samples, and collection of 
clinical data with the potential for loss of confidentiality. 


 
18 
 
Adequacy of the Protection against Risk 
Recruitment and Informed Consent 
Neonatal research nurses/coordinators are a key element in the success of clinical research 
programs within neonatal intensive care units.  The team of research coordinators will be in 
constant communication with the NICU care team to assist in identification of eligible patients. 
They will screen patients and present to the parents the details of the study and obtain informed 
consent. The experience of the research coordinators results in effective communication about 
protocols and success in recruitment.  Based upon completion of a large number of studies in the 
NICUs, we anticipate approximately a 60% enrollment.  The drop-out rate is likely to be minimal 
given the limited interventions and lack of anticipated side effects from the intervention. 
 
Protecting Confidentiality 
Security measures to protect subject identities include the use of coded files to unlink research 
records from names and other identifiers, locked storage areas, and password-protected 
computer files.  Subjects’ names are linked to their IDs as noted above.  Access to computer 
systems housing sensitive information is strictly regulated.  Credentials permitting access to these 
systems are granted only to essential investigators and research personnel.  All systems are 
secured from external attack through a combination of hardware and software firewalls and are 
updated with necessary security patches as they become available.  Related hardware and back-
up storage media are maintained in a secure environment to which only essential personnel have 
physical access. All consent and research procedures will be compliant with Subpart B of the Code 
of Federal Regulations Title 45, Part 46 - Protection of Human Subjects with Additional Protections 
for Pregnant Women, Human Fetuses and Neonates Involved in Research (66 FR 56778, Nov. 13, 
2001). 
 
5.2.1 
Data management and interpretation 
 
Data will be collected using prepared forms, then entered and managed using REDCap electronic 
capture tools hosted and managed by IUPUI Biostatistics. The REDCap platform is a secure, web-
based application designed to support data capture for research studies, providing: 1) an 
intuitive interface for validated data entry; 2) audit trails for tracking data manipulation and 
export procedures; 3) automated export procedures for seamless data downloads to common 
statistical packages and 4) procedures for importing data from external sources.  Only IRB 
approved research team members will have access to the REDCap data platform. Each team’s 
members will be granted access to the REDCap data system through a secure login. In the 
REDCap data platform, primary data and data backups are secured at separate Indiana 
University Data centers. Operating system security includes: secure logins, data encryption at 
rest, remote system logging and configuration and change management. Data backups are 
encrypted both in flight and at rest. Copies of data are replicated to the remote data center 
every 15 minutes. There are 100+ point-in-time copies of data available at any time. Disaster 
recovery has been tested and confirmed. 
 
Performance Monitoring:  Standard reports will be generated from the study database by the 


 
19 
Data Center. These will include monthly reports that provide the number of infants screened 
and enrolled, missing data, adherence to study protocols, and a variety of performance 
measures, including adverse events. 
 
5.2.2           Statistical analysis 
 
All analyses will be performed on an intent-to-treat basis. The primary analysis (and all analyses 
examining outcomes by treatment) will be adjusted for the stratification variable of gestational 
age. Since the primary outcome is continuous, linear regression will be used to estimate the 
adjusted mean difference in growth between the two treatment groups. Similarly, for secondary 
outcomes, linear regression will be used for continuous outcomes and robust Poisson regression 
for binary or categorical outcomes to obtain adjusted relative risk estimates for the treatment 
effect. 
 
5.2.3 
Sample size and power estimates 
 
Sample size and power calculations for this study are based upon the primary outcome of 
differences in weight gain between the two groups of infants. Using data from our recently 
completed analysis, in which infants 26 – 29 6/7 weeks gestation treated according to the 
algorithm were compared with historical controls, and based upon identifying a difference in 
weight Z-score of 0.25 at 36 weeks postmenstrual age, using a SD of 0.4 with an alpha = 0.05 and 
power of 0.8, we calculate we will need a total sample size of 82 patients (41 per group).  With 
regards to the secondary outcome of EE, and based upon published data of EE estimated in 
preterm infants using the DLW method, a sample size of 41 patients per group will allow us to 
detect a 6% difference in EE, assuming an alpha = 0.05 and a power of 0.80.  With regards to TBW, 
and based upon data from these same investigators who report a mean TBW of 80.8% body 
weight, with SD of 3.1%, this sample size will allow us to detect a difference in TBW of 2.0% 
between groups, assuming an alpha = 0.05 and a power of 0.80.  To acknowledge for study drop 
out, we will plan to enroll up to 90 patients (plus 90 mothers for chart review). 
 
5.3  
DATA SAFETY AND MONITORING PLAN   
 
A Data Safety and Monitoring Committee (DSMC), headed by Dr. Edward Bell, Professor of 
Pediatrics, University of Iowa Carver College of Medicine will monitor the progress of the study 
when 25%, 50% and 75% of the trial subjects have reached hospital discharge. Dr. Bell, who has 
extensive experience with DSMCs, will be responsible for recruiting the necessary individuals with 
expertise in neonatology, biostatistics, bioethics and clinical trials to establish the DSMC. The DSMC 
will review accumulated blinded study data to ensure that the intervention is not leading to harm.  
If there is a significant imbalance of secondary outcome rates between the study arms, the proper 
course of action will be discussed by the study PIs and the DSMC. The DSMC will not be charged 
with assessing efficacy before conclusion of the trial; therefore, no loss of alpha will result from the 
planned interim safety analyses.  


 
20 
Safety outcomes include incidence of mortality up through 36 weeks PMA, BPD, and ROP. The 
DSMC may request other outcomes at their prerogative. The DSMC will examine other safety 
outcomes, including all reported deaths and serious adverse events by treatment group in 
considering a recommendation to suspend the trial for safety reasons.  
 
 
 
 
 


 
21 
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24 
Section 6.        Appendix 
 
 
 
 
Name of form 
< 17 
days 
of 
life 
On 
Study 
Weeks 1-19 on Study (estimate based on birth 
Gestational Age) 
Discharge/Transfer 
or week 44 of life 
corrected 
Eligibility Check 
List 
X 
 
 
 
Informed consent 
X 
 
 
 
Enrollment 
Randomization 
 
X 
 
 
Maternal 
Demographics 
 
X 
 
 
Maternal Health 
Data 
 
X 
 
 
Neonatal 
Demographics 
 
X 
 
 
Neonatal Health 
Data 
 
X 
 
 
Sodium History 
 
X 
 
 
SOC Serum 
Sodium 
 
 
Weekly 
X 
Study Urine 
Sodium – ARM B 
ONLY 
 
 
Weeks 1,3,5,7,9,11,13,15,17,19 
 
Nutrition – 
Enteral/Parenteral 
 
 
Weekly; Monday, Wednesday, Fridays 
 
Body 
Measurements 
 
 
Weekly; Length, OFC, Weight 
X 
Doubly Labeled 
Water 
 
 
Will occur at 32 - 32+6 weeks corrected age 
 
Doubly Labeled 
Water Sample 
 
 
Will collect before procedure, 6-24 hr post, 36-48 hr 
post and 110-130 hr post 
 
Week 36 Status 
 
 
to be completed at 36 weeks postmenstrual age or if 
patient discontinues study early 
 
Outcome Status 
 
 
 
X 
Adverse Event 
 
Will be followed once enrolled to discharge/transfer or week 44 of life (whichever 
occurs first) 


 
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INDIANA UNIVERSITY INFORMED CONSENT STATEMENT FOR RESEARCH 
 
Physiologic Approach to Sodium Supplementation in Premature Infants (Salt to Grow) 
 
ABOUT THIS RESEARCH  
You are being asked to let your baby take part in a research study called Salt to Grow.  Clinicians do 
research to answer important questions which might help change or improve the way we do things in 
the future.  This consent form will give you information about the study to help you decide whether 
you want to let your baby take part.  Please read this form, and ask any questions you have, before 
agreeing to let your baby be in the study. 
 
We are also asking to collect information from your chart as described below in the “What Will Happen 
During the Study?” section. 
 
This study is being done at Riley Hospital for Children (Methodist, Riley Downtown, IU North), and 
Eskenazi Hospital by Dr. Gregory Sokol.  It is being paid for by the Thrasher Research Fund.  
 
TAKING PART IN THIS STUDY IS VOLUNTARY 
You do not have to let your baby take part in the study.  Or, if you let your baby take part, you can 
choose to take them out of the study at any time.   Your decision will not affect your baby’s care or 
treatment at Riley Hospital for Children, Indiana University, or Eskenazi Health.  
 
WHY IS THIS STUDY BEING DONE? 
You are being asked to let your baby take part in this study because they were premature (born very 
early).  Many premature babies do not grow well even though they get enough nutrition.  We know 
low sodium causes poor growth.  Many premature babies get extra sodium while in the hospital.  Their 
kidneys have problems holding on to sodium because they are still developing. 
 
There is no exact way to measure how much sodium is in the total body.  Right now your baby’s doctor 
looks at the sodium in their blood to decide when and how much sodium to give.   
 
The purpose of this study is to see if using a baby’s urine sodium and blood sodium levels to decide 
about giving extra sodium will keep their body’s sodium normal and help them grow better. 
 
HOW MANY BABIES WILL TAKE PART? 
If you decide to let your baby be in this study, they will be one of up to 90 babies taking part. This study 
is only being done at Riley Hospital for Children (Methodist, Riley Downtown, IU North), and Eskenazi 
Health. 
 
WHAT WILL HAPPEN DURING THE STUDY? 
Information We Collect 
At the beginning of the study, we will write down birth information like weight, length, head size, how 
long you were pregnant, your health issues, issues that you developed during your pregnancy and your 
race and ethnic background. 
 


 
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During the study we will check your baby’s chart for their medical history, physical exams, labs, tests, 
feedings (or other nutrition) and medicines given.  We will also note any problems or changes in your 
baby’s health while in the hospital.  
 
Study Groups 
Your baby will be put into one of two study groups. One group will use urine sodium to decide when 
and how much sodium to give.  The other group will get standard (usual) care.  Both groups will have 
their blood sodium measured.  The standard of care is to use the sodium blood test to decide when 
and how much sodium to give.  The standard care group is needed for comparison to help us decide if 
this method of replacing sodium helps babies grow.  Which group your baby is in will be decided by 
chance, like tossing a coin. Your baby will have a 50% chance (1 out of 2 chances) of being in either 
group.  
 
Measuring Urine Sodium  
Babies in the urine sodium group will have a urine sample collected to see how much sodium is in it.  
We will do this about every 2 weeks until they reach the corrected gestational age of 36 weeks. For 
example if your baby was born at 28 weeks and your baby is now 4 weeks old, their corrected 
gestational age is 32 weeks old. 
 
If their urine sodium falls below a certain amount, extra sodium will be added every day to their IV (in 
the vein) fluids or feeding given by mouth or tube.  This process will continue until your baby reaches a 
corrected gestational age of 38 weeks.  Your baby’s care team will decide if they will do it for a longer 
time. 
 
Measuring Body Water and Energy Use  
All babies in the study will have their total body water and energy use measured.  This will be done 
when they are about 32 weeks corrected gestational age.   We will use the “doubly labeled water” 
method.  This method uses non-radioactive water isotopes. This water isotope is a kind of water found 
in nature.  It is in things like drinking water (and other drinks), moisture in the air, rain, snow, lake and 
sea water, and in foods we eat every day.  In fact, the oxygen isotope is found in the air we all breathe.   
 
What we do: 
1. First, we will get a urine sample from your baby.   
2. Then your baby will get about ½ teaspoon of water with the isotope, followed by another ½ 
teaspoon of sterile water through their feeding tube.   
3. Over the next 5 days, we will collect 3 more urine samples. The urine samples will be labeled 
with a special code number.  They will not have your baby’s name, initials or any other 
information that could identify your baby.  
4. The urine samples will be studied.   
 
Measuring Length and Head Size 
A nurse will use a board and measuring tape to check your baby’s length and head size every week 
until they are discharged from the unit, transferred or reach 44 weeks corrected age, which ever 
happen first.  These measurements are usually done on all premature babies.  
 
 


 
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WHAT ARE THE RISKS OF TAKING PART IN THE STUDY? 
Your baby was born very early.  Babies born very early are at risk for many problems including bad 
breathing trouble (maybe needing extra oxygen and/or a breathing machine), bleeding inside the 
brain, infections, necrotizing enterocolitis (a serious infection of the intestine), low or high sodium in 
their blood, poor growth and developmental problems including cerebral palsy.  These are risks 
whether or not your baby takes part in this study.  Below are other possible risks or discomforts from 
participation in the study:  
 
• Your baby may have high sodium in their blood.  The care team will check it often.  Other 
studies like this have not caused a high sodium level.  We will stop giving extra sodium if the 
level gets above normal.   
• Infection can happen when anything is added to your baby’s diet.  In this study, water with the 
isotope is added.  This risk is lowered by putting the water though filters. 
• Loss of confidentiality.  Every effort will be made to protect your infant’s confidential medical 
information, but this cannot be guaranteed.  
• There may be other information about the study we do not yet know.  If we find out any new 
information, including risks, while your baby is in the study, we will tell you right away. 
 
WHAT ARE THE POTENTIAL BENEFITS OF MY BABY TAKING PART IN THE STUDY? 
Your baby may or may not benefit from being in this study.  Some babies may benefit if one treatment 
group shows benefit and your baby is in that group.  But, we do not know whether there is a benefit 
for one group or the other.  It is possible your baby will not benefit. 
We hope the information we get from this study will help treat premature babies in the future.     
 
WHAT ARE THE OTHER TREATMENT OPTIONS? 
Your baby does not have to take part in this study. If you decide you do not want your baby to be in it, 
they will still get regular medical care at Riley Hospital for Children. 
 
HOW WILL MY BABY’S INFORMATION BE PROTECTED? 
Efforts are made to protect all research subjects from inappropriate use of their personal information.  
We will do everything we can to keep your baby’s records confidential, but we cannot guarantee 
absolute confidentiality.  Your baby’s personal information may be shared if required by law.  Your 
baby’s identity will not be shared in reports in which this study may be published.   
Personal health information (PHI) such as name, date of birth, address, email address, and phone 
number will be stored in an IU research clinical management and payment system and database to 
track your study procedures and information, schedule study visits and follow-up activities, distribute 
payments, link study data, and enable chart reviews.   
 
To protect your baby’s identity, your baby will be assigned a unique study ID number which will be 
linked (Coded) to your study information. Your information collected for this study will be kept in a 
password-protected database.  Only research staff and collaborators can see it.   
 
Organizations that may look at and/or copy your baby’s research records for quality assurance and 
data analysis include groups such as the study investigator and their research associates, the Indiana 
University Institutional Review Board or its designees, the Thrasher Research Fund, the Indiana Clinical 


 
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Research Center,, and any state or federal agencies such as the U.S. Food and Drug Administration 
(FDA) who may need to access your baby’s medical and/or research records (as allowed by law). 
 
A description of this clinical trial will be available on ClinicalTrials.gov, as required by U.S. law.  This 
website will not include information that can identify your baby.  At most, the website will include a 
summary of the results.  You can search this website at any time.  
 
WILL MY BABY’S INFORMATION BE USED FOR FUTURE RESEARCH? 
Information collected from your baby for this study may be used for future research studies or shared 
with other researchers for future research.  If this happens, information which could identify your baby 
will be removed before any information is shared.  Since identifying information will be removed, we 
will not ask for your additional consent. 
 
WILL I BE PAID FOR TAKING PART?  
You will not be paid for your baby’s participation in this study. Your baby will receive an age-
appropriate book as a thank you for participating in the study.  
 
WILL IT COST ME ANYTHING FOR MY BABY TO BE IN THE STUDY?  
Neither you nor your insurance company will have to pay for any test or visit that is done only for the 
purpose of this study (urine sodium, total body water and energy use measurements).  The parts of 
your baby’s care that would normally be done as standard treatment will be billed to you or your 
insurance company.  
 
WHO WILL PAY FOR TREATMENT IF MY BABY IS HURT?  
If your baby is hurt because of taking part in this study, they will get any needed medical treatment.  
This treatment will be billed as part of their medical expenses.  As with any medical care your baby 
receives, costs not covered by your insurance company will be your responsibility.  It is also your 
responsibility to check your health care coverage. There is no program in place for other monetary 
compensation for such injuries.  However, you are not giving up any legal rights or benefits to which 
you are otherwise entitled. 
 
WHO SHOULD I CALL WITH QUESTIONS OR PROBLEMS? 
For questions about the study or a research-related injury, call Dr. Gregory Sokol at (317) 274-4768.  If 
you need to reach a neonatologist between the hours of 5pm to 8am call the neonatologist on call at 
(317) 948-4371 
 
For questions about your baby’s rights as a research participant, to discuss problems, complaints, or 
concerns about a research study, or to get information or to offer input, please call the IU Human 
Subjects Office at 800-696-2949 or email irb@iu.edu. 
 
CAN I WITHDRAW MY BABY FROM THE STUDY? 
If you decide to let your baby be in this study, you can change your mind and decide to take them out 
of the study (withdraw) at any time.  The study team will help withdraw your baby from the study 
safely.  If you decide to withdraw, please tell a member of the study team. 
 


 
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The investigator can withdraw your baby from the study without your permission.  If this happens, we 
will tell you.  Possible reasons for withdrawal include:  we find new information that shows the risks of 
the study are greater than the benefits, or if your baby develops a problem that makes us stop the 
study procedures.   
 
You will be told about new information that may affect your baby’s health, welfare, or willingness to 
stay in the study. 
 
 
PARTICIPANT’S CONSENT 
In consideration of all of the above, I give my consent for my baby to take part in this research study.  I 
will get a copy of this informed consent document to keep for my records.  I agree to let my baby take 
part in this study. I agree to the collection of information from my chart as described in this informed 
consent document. 
 
Your Child’s Printed Name: 
 
 
 
Printed Name of Parent/Legal Guardian: 
___________ 
 
Signature of Parent/Legal Guardian: 
Date: 
 
 
 
 
If the mother is under 18 years old please complete: 
 
Printed Name of Parent/Legal Guardian: 
___________ 
 
Signature of Parent/Legal Guardian: 
Date: 
 
 
 
 
Printed Name of Person Obtaining Consent:  
 
 
 
Signature of Person Obtaining Consent: 
Date: