Conditions: Parenteral Nutrition Associated Cholestasis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: no

Brief summary:
The Investigators hypothesize that increased cumulative amount of lipid intake causes PNAC in late preterm and term neonates with major GI surgical disorders

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: intravenous lipid
Intervention descriptions: intervention 1: intravenous given daily for 6 weeks

Protocol document:
Prot_SAP_000.pdf: 
1 
Approved January 10, 2019 
EFFECT OF LIPID INTAKE ON DIRECT HYPERBILIRUBINEMIA IN LATE PRETERM 
AND TERM INFANTS WITH GASTROINTESTINAL SURGICAL PROBLEMS 
NCT01555957 
I. PURPOSE OF THE STUDY AND BACKGROUND 
The purpose of the study is to establish a cause and effect relationship between lipid intake and 
the incidence of direct hyperbilirubinemia (cholestasis) in late preterm and term infants with major 
gastro-intestinal (GI) surgical disorders such as gastroschisis omphalocele, volvulus, TE fistula, 
duodenal atresia, jejunal atresia, ileal atresia, hirschsprung’s disease, anorectal malformation, intestinal 
obstruction and GI perforations requiring surgery. Infants with major GI surgical disorders as 
mentioned above will be randomized to receive 1gm/kg/day or 2gm/kg/day of 20% intralipids within 
the first 72 hours after birth. The study is not open to all surgical infants because infants with other 
surgical problems can be fed enterally within few days after surgery and usually do not require TPN for 
prolong periods (>2 weeks). Also infants with major GI surgical disorders have similar clinical course, 
undergo similar type of operative procedures, and have similar  complications  thus eliminating  
potential confounding factors. The primary outcome measure is the incidence rate of parenteral 
nutrition associated cholestasis (PNAC). PNAC will be defined as serum direct bilirubin ≥ 2mg/dl in 
the absence of other known causes of direct hyperbilirubinemia as described under exclusion criteria.  
 
 II. BACKGROUND AND JUSTIFICATION: 
Since its introduction in the late 1960s, total parenteral nutrition (TPN) has established itself as 
an effective mode for parenteral hyperalimentation in patients with acute or chronic intestinal failure. 
Out of the many complications of parenteral nutrition, the most common is the cholestasis often 
referred to as Parenteral Nutrition Associated Cholestasis (PNAC). PNAC is defined clinically using 


2 
Approved January 10, 2019 
direct bilirubin as an index measure in the absence of other known causes of direct hyperbilirubinemia 
(see exclusion criteria). The reported incidence of PNAC in neonates is as high as 84%. [1, 2] 
 PNAC was first described by Peden and colleagues [3] and has long been recognized as a 
major cause of morbidity and mortality in neonates and infants. [4, 5] PNAC can be associated with 
liver dysfunction, cirrhosis, and hepatic carcinoma. The proposed mechanisms that could explain 
cholestasis caused by the total parenteral nutrition are multifactorial. The major mechanisms include 
hemodynamic modifications within the biliary system caused by parenteral administration of nutrients, 
bile stasis resulting from decreased stimulation of gastrointestinal hormones in the absence of any 
enteral intake, direct toxic effects of TPN components, premature biliary system, and bacterial 
overgrowth leading to overproduction of deconjugated bile acids. Very few observational studies done 
earlier have looked at the association of PNAC with various nutritional components of TPN. The 
findings of these studies indicate that PNAC could be associated with increased duration of TPN [6, 7] 
with almost all infants developing PNAC by 6 weeks on TPN [8,9,10 ], higher intake of amino acids 
[11], higher intake of dextrose, intake of trace elements like aluminium [12], copper and manganese 
[13], and cumulative amount of intravenous lipid intake[14]. Several preventive trials have been 
conducted in neonates involving the use of different amounts of protein intake or the use of choleretic 
medications in order to prevent cholestasis. Vileisis and colleagues [11] did not find any difference in 
the incidence of PNAC when they compared amino acids intake of 2.3gm/kg/day vs. 3.6 gm/kg/day. 
Their findings were reciprocated by Clark and colleagues [15] who found no difference in the incidence 
of PNAC when comparing amino acids supplementation of 2.5 vs. 3.5gm/kg/day. Similarly, the use of 
both cholecystokinin (CCK) [16], and ursodeoxycholic acid [17] failed to prevent the development of 
PNAC. Majority of these preventive trials performed in neonates defined PNAC as direct bilirubin 
≥2mg/dL after two weeks on PN [9, 11, 21]. Because these preventive trials failed to identify any 


3 
Approved January 10, 2019 
preventive therapy, there is a need to identify alternative ways to prevent PNAC in high-risk infants.  
Recent literature including our finding from an observational study suggests that cumulative 
lipid intake may be associated with PNAC in high-risk infants with GI surgical disorders. The side 
effects of intravenous lipid infusions on the hepato-billiary system was first suggested in animal studies 
in 1993 when  La Scala et al. described that the addition of lipids increases TPN associated cholestasis 
in rats [18]. Haynes et al. in 2002 published a series of hepatic pathology and described dose dependent 
hepatic changes with prolonged administration of lipid in premature baboons which included steatosis, 
cholestasis, and proliferation of bile ducts [19]. Since then few observational studies in neonates have 
been performed and demonstrated that lipid intake is associated with PNAC. [7, 11] However, a cause 
and effect relationship between lipid intake and PNAC has not been established using a well-designed 
randomized clinical trial.  We hypothesize that increased cumulative amount of lipid intake causes 
PNAC in late preterm and term neonates with major GI surgical disorders. Our objective is to evaluate 
the effect of cumulative amount of lipid intake on the incidence of PNAC in this vulnerable population.   
 
 
III. 
CHARACTERISTICS OF THE RESEARCH POPULATION 
 
1. 
Number of Subjects: This is a prospective randomized clinical trial involving 40 neonates with 
major GI surgical disorders requiring surgery.   
 
2. 
Gender, Age, Race, and Ethnicity:  The University of Rochester Medical Center (URMC) is a 
tertiary care center and consists of a 52 bed Neonatal Intensive Care Unit. Annually, ~25 infants with 
major GI surgical disorders are admitted to the URMC. The NICU population is approximately 52% 


4 
Approved January 10, 2019 
male with a racial distribution of 64% White, 32% African-American, 2% Asian, and 2% other. The 
ethnic distribution is 75% non-Hispanic. The gender, race, and ethnicity distribution of this prospective 
study is expected to follow the distribution of the NICU population. 
 
3. 
 Inclusion Criteria: All neonates ≥ 34 weeks gestational age with major GI surgical disorders  
(gastroschisis, omphalocele, volvulus, trachea-esophageal  fistula, duodenal atresia, jejunal atresia, ileal 
atresia, hirschsprung’s disease, anorectal malformation, intestinal obstruction, and GI perforations) 
requiring surgery admitted to our NICU within first 72 hours will be eligible for this study. 
 
4. 
Exclusion Criteria: Neonates with the following condition will be excluded: 1) If does not 
need TPN by 72 hours; 2) Direct hyperbilirubinemia within the first 72 hours after birth; 3) TORCH 
infections (Toxoplasmosis, CMV, Herpes, Rubella, HIV, etc); 4) Biliary tract disorders leading to direct 
hyperbilirubinemia; 5) Known metabolic disorders that may be associated with direct 
hyperbilirubinemia- such as Galactosemia, α-1 antitrypsin deficiency, etc. 
 
IV. METHODS AND PROCEDURES 
a) Study Design: This is a prospective randomized controlled trial s planned in order to  evaluate 
the incidence rate of PNAC between 1gm/kg/day of 20% intralipid and 2 gm/kg/day of 20% 
intralipid in high-risk neonates ≥ 34 weeks gestational age (GA). PNAC will be defined as serum 
direct bilirubin ≥ 2mg/dl in the absence of other known causes of direct hyperbilirubinemia as 
described in the exclusion criteria.  
 
b) Screening: All neonates ≥ 34 weeks GA and admitted to the NICU at URMC with major GI 
surgical disorders  will be screened for study criteria within 72 hours after birth. Infants will be 


5 
Approved January 10, 2019 
identified by a designated investigator with regularly scheduled screening of admissions, GA, 
postnatal days and admission diagnosis. Screening will take place on an ongoing basis and not less 
than 3 times per week. The screening log will include GA, postnatal days, and type of GI surgical 
disorders, and whether or not the infant was enrolled in the study.  If not enrolled, the reason will be 
recorded. The number and demographic characteristics of eligible subjects not included will be 
collected to assess the representation of the sample of subjects included.  
 
c) Enrollment and Consent: Families will be approached by one of the investigator as soon as 
possible after eligibility is ascertained to allow sufficient time for the family to ask questions 
about the study.  Parental consent may be obtained any time during the first 72 hours after birth.  
Consent will be documented on an IRB approved consent form.  Each subject will be assigned a 
unique study identification number by the investigator after consent is obtained. 
d) Pre-randomization: Once the infant is enrolled in the study, one of the investigators will notify 
the Research Pharmacist (RP) by telephone call during working hours (8AM-5PM) for 
registration and randomization. Information on weight of the infant will be provided to the RP 
for accurate dosing of intravenous lipid on each day.  
e) Registration: A log sheet of subjects registered with their names, study ID numbers, medical 
record number, dates of birth, and dates of randomization will be kept by the RP  
f) Randomization will be to two arms: 1g/kg/day intravenous lipid or 2 g/kg/day for 6 weeks or 
until develops direct bilirubin ≥ 2mg/dl (in the absence of sepsis) or reaches enteral feeds and 
no longer requires parenteral nutrition. A block randomization with 8 subjects in each block 
will be performed. Study group assignments will be made by the RP with the use of a 
randomization scheme provided by the biostatistician. The assignment will be 1:1 ratio.   


6 
Approved January 10, 2019 
g) Route, Frequency, and Duration: The lipids will be given intravenously every day as per the 
standard of care for 6 weeks or until reach one of the study end points (reach enteral feeds and 
no longer require parenteral nutrition or has direct bilirubin ≥ 2 mg/dl in the absence of 
sepsis).All enrolled infants including those randomized to 2 gm/kg/day intravenous lipid will be 
started at 1gm/kg/day of intravenous lipids as per the standard of care on day 2 after birth. The 
procedures for titrating subjects randomized to the higher dose will be consistent with standard 
procedures. The daily intravenous lipid intake will be increased to 2 gm/kg/day in those 
randomized to 2gm/kg/day. The amount of proteins and glucose will be ordered as per the unit 
policy and at the discretion of the attending neonatologist.  
h) Dose Adjustments: Daily assessment of the weight will be performed by the investigator and 
will be reported to the RP for appropriate adjustment to the dosing of the intravenous lipid. 
Each day, the RP will inform the clinical care team of volume of intravenous lipid to be infused 
over the day. The clinical care team will complete the request in the E-record using the 
information provided by the investigator or the RP.  
i) Subjects will receive glucose, protein, vitamins, and trace elements at the discretion of the 
attending neonatologist as per the standard of care.  The unit policy regarding nutrition is to 
gradually increase protein intake to 3 to 4 gm/kg/day and intravenous glucose intake as 
tolerated to provide a caloric intake of 90 – 110 kcal/kg/day. Assuming the average intake of 
120ml/kg/day of TPN, the predicted amount of caloric intake from the non-fat portion of the 
TPN would be ~ 90 kcal/kg/day (assuming protein intake of 3 to 4 gm/kg/day and an average 
dextrose concentration of 15% via the central line). The clinical team will assume an average 
lipid intake of 1.5gm/kg/day for each enrolled infant during the period of the study which is 
equivalent to a caloric intake of 13.5 ± 4.5 kcal/kg/day from lipid intake. Thus the total caloric 


7 
Approved January 10, 2019 
intake for the infants in the study would be 90 + 13.5 ± 4.5 Kcal/kg/day or 103.5 ± 4.5 
Kcal/kg/day. If the enrolled subject does not gain weight despite reaching allowable maximum 
protein supplementation, there will be room for increasing caloric intake by increasing the 
amount of glucose intake (either by increasing dextrose concentration or increasing total fluid 
intake). Increasing glucose intake for weight gain is the standard of care in our NICU while 
limiting lipid intake in neonates at risk for cholestasis. 
j) In case of hypertriglyceridemia, the unit protocol of intravenous lipid intake will be used and 
the RP will be notified. According to the unit policy, the Intravenous lipid intake will be halved 
when the serum triglycerides level is between 250 to 350 mg/dl and would be stopped when the 
serum triglycerides is >350 mg/dl. Once the hypertriglyceridemia has resolved, the assigned 
intravenous lipid intake will be resumed as per the randomization arm. The discontinuation of 
trace elements and the administration of choleretic medications will be done as per the unit 
policy. According to the unit policy, the use of trace elements will be discontinued if direct 
bilirubin is ≥ 2 mg/dl. Similarly, the unit policy is to add choleretic medications when direct 
bilirubin level is ≥ 2 mg/dl. The care team will be requested to adhere to these unit policies 
during the conduct of the study.  
k) Primary Outcome Measures: PNAC will be the primary outcome measure and will be defined as 
direct bilirubin ≥ 2mg/dl developing within one week of the completion of 6 week 
randomization period in the absence of other known causes (discussed earlier).  Total serum 
bilirubin and direct bilirubin concentration will be measured once weekly as part of the standard 
of care when on parenteral nutrition. The direct bilirubin is usually measured until the 
resolution of direct hyperbilirubinemia as part of the standard of care. If parents have consented, 
we will collect blood that is leftover from blood draws that are done as part of standard of care. 


8 
Approved January 10, 2019 
The blood samples will be stored in -80 degree freezer in the PI’s laboratory within the 
Department of Neonatology for possible future research on intravenous nutrition and its effects 
on the liver such as identifying a more sensitive biochemical marker than direct bilirubin 
concentration of liver injury.  Samples will be stored with a study number only and will only be 
linked to the data collected for the purposes of this study. Only study team members will have 
access to the stored blood and will be able to use the samples.  Future research on stored blood 
after completion of this study will only be conducted  by the PI on IRB approval.   
l) Secondary Outcome measures: Secondary outcome measures will include peak direct bilirubin 
concentrations during hospital stay, use of choleretic medications and use of Omegavan during 
the hospital stay and percentage weight gain during the 6 week study period.  
m) Data Safety Monitoring:  There are several reasons why independent data safety monitoring and 
stopping rules were not considered for this study as described below:  
1) In this study, the outcome measure, direct hyperbilirubinemia >2.0mg/dL, is the potential 
side effect of interest secondary to intravenous lipid intake. As per the standard of care, the 
intravenous lipid intake of 1-2 gm/kg/day is routinely used in the presence of direct 
hyperbilirubinemia of 2 mg/dL to provide essential calories and prevent essential fatty acid 
deficiency. Usually, choleretic medications such as cholecystokinin are used to resolve 
PNAC at this point.   
2) Our hypothesis is that the development of PNAC is causally related to the cumulative lipid 
intake, however, protein and glucose intake may modify the association between lipid intake 
and PNAC. In addition, sepsis and prematurity are confounding risk factors. The sample 
size calculated (n=40) to evaluate the outcome measure (or the adverse event) accounts for 
the variable duration of the TPN (cumulative lipid intake) and presence of confounding risk 
factors. Therefore, meaningful statistical analysis is not possible with an interim analysis of 
less than 40 subjects.  
3) As suggested by our observational study, a mean cumulative dose of 55gm/kg (SD 15) of 
intravenous lipid is required before the development of PNAC in late preterm and term 


9 
Approved January 10, 2019 
infants.  Thus, it is expected that an infant on 1gm/kg/day of intravenous lipid arm will take 
~ 55 days to develop PNAC.  Therefore, considering the fact that TPN intake will often be 
less than 42 days among study subjects, not all infants in either group are expected to 
develop PNAC. PNAC, the study outcome, as defined for the purpose of the study, is the 
earliest when any medications are used to treat PNAC as per the standard of care.  Severe 
PNAC is defined when direct bilirubin concentration is > 10 mg/dL and is very rare. The 
randomization of intravenous lipid intake will be stopped long before severe PNAC may be 
seen among enrolled subjects.   
4) Performing interim analyses will require more stringent significance level which will 
increase the sample size required to perform the study. This is a pilot study performed as 
part of fellow’s project for which 40 subjects are required for meaningful analysis of 
outcome (or adverse event)    
5) This study has been designed as a block randomization with each block having 8 subjects 
with 1:1 assignment, so even if all enrolled infants were to develop PNAC, it will suggest 
that there is no difference between the two groups and there is no causal association 
between intravenous lipid intake and cholestasis.  
Because of reasons mentioned even if the first 20 subjects (50%) hit the direct bilirubin 
endpoint, interim analysis is unlikely to allow meaningful analysis of the causation between 
lipid intake and the outcome measure (or adverse event) as provided in the protocol. In other 
words, it is unlikely to reach adjusted statistical significance required for interim analyses. 
Thus, since the outcome measure and the adverse event are the same and the sample size 
required to evaluate the association (or the adverse event) controlling for other factors is 40, 
no interim analysis and stopping rules were considered for this pilot study.   For trial 
management, the investigation team will track enrollment and protocol compliance and 
review every 3 months.  
 
V. DATA COLLECTION:  The baseline data on demographics and clinical factors (antenatal and 
postnatal) before randomization on each subject will be collected. Similarly, data on clinical factors 
will be collected during the 6 week study period or until the subject is receiving intravenous lipid as per 


10 
Approved January 10, 2019 
randomization or until the subject develops PNAC (direct bilirubin ≥ 2 mg/dl in the absence of 
concurrent infection).   
The information on TPN components, specifically amount of lipid, protein, and glucose intake 
on each day will be prospectively collected using pharmacy and TPN records.  Information on 
cumulative amount of lipid intake, cumulative amount of protein intake, and cumulative amount of 
glucose intake will be determined for all enrolled subjects. The additional information that will be 
collected is duration (days) of TPN, use of trace elements, duration (days) of NPO, type of enteral feeds 
(maternal breast milk vs. Formula) duration (days) of antibiotic use, onset and duration of choleretic 
medications, sepsis defined as blood culture positivity or clinical signs and symptoms of sepsis with the 
use of antibiotics for > 3 days, day of life when the infant reaches an enteral intake of 120 ml/kg/day, 
duration (days) of mechanical ventilation, duration of CPAP, duration of oxygen supplementation, and 
amount of  erythrocyte transfusions during the study period. However, use of choleretic medications 
and discontinuation of trace elements from the TPN is not expected during the study period based on 
the unit policy as delineated earlier. 
 
VI. SAMPLE SIZE CALCULATION: Assuming a 4-week median follow-up time and an incidence 
rate of 40% for 6 weeks in control group, a two-sided log rank test with an overall sample size of 40 
subjects (20 per group) achieves 80.0% power at a 0.050 significance level to detect a hazard ratio of 
3.6.  
 
 
 
 
Power 
Incidence 
Rate 
N 
Control 
N  
Study 
Haz 
Ratio 
(HR) 
0.8 
40% 
20 
20 
3.6 
0.8 
50% 
20 
20 
3.26 
0.8 
60% 
20 
20 
3.02 


11 
Approved January 10, 2019 
Kaplan-Meier (KM) estimates of survival function will be provided and compared between groups. 
Log-rank test will also be used to compare time to endpoint. Cox proportional hazards model will be 
fitted after controlling for covariates which are found to be imbalanced in preliminary analysis. 
Estimate of hazard ratio and associated confidence interval will be obtained.  
 
 
VII. DATA ANALYSES AND MONITORING:  
a) Randomization: Upon successful completion of necessary screening assessments and being 
confirmed to be eligible by the investigator, subjects will be randomized in 1:1 ratio to two groups: 1) 1 
g/kg/day intravenous lipid and 2) 2 g/kg/day intravenous lipid.  Each subject will be assigned a unique 
sequential subject number for identification throughout the entire course of the study. The subject 
number will not be reused for any other participant in the study. Subjects who are discontinued or 
withdrawn from the study prior to randomization will be replaced. In addition, subjects who are 
identified to have direct hyperbilirubinemia from causes other than parenteral nutrition or did not 
require parenteral nutrition for more than 2 weeks will be considered screen failure and will also be 
replaced.  We anticipate a total number of 52 subjects to participate in the study to complete the study 
on 40 subjects. During the study, the treatment assignments will be available only to the RP.    
c) Samples for Analysis: The “Intent-to-Treat” sample includes all subjects who are randomized into 
the study. Subjects will be grouped according to the treatment to which they are randomized.  
d) Statistical Analyses: 
 General statistical Considerations:  


12 
Approved January 10, 2019 
All statistical analyses will be conducted using Version 10 of the SAS System for Windows 
(Copyright © 2002-2003 SAS Institute Inc., Cary, NC, USA.) by a biostatistician. Descriptive statistics 
will be used to summarize outcomes by treatment groups.  For continuous variables, descriptive 
statistics will include the mean, median, standard deviation, minimum, maximum, number of available 
observations, and number of missing observations. For discrete variables, descriptive statistics will 
include frequencies and percentages, number of available observations and numbers of missing 
observations.  
We will determine whether there are important baseline differences between the two groups 
despite randomization with respect to participant characteristics (e.g., gender, race/ethnicity, GA at 
birth, SGA[<10th percentile]). If any important differences are found, the primary analyses will be 
repeated after statistically adjusting for these differences. If distributional assumptions associated with 
a particular statistical procedure are violated, appropriate transformations will be made or non-
parametric alternatives will be used (e.g., Wilcoxon rank sum tests in place of two-sample t-tests). 
Infants enrolled but subsequently found to meet exclusion criteria will be analyzed separately.  
The incidence rate of PNAC will be compared between the 2 groups using Kaplan Meier 
curves. Subjects who reach full enteral feeds before 6 weeks of study period will be censored. Kaplan-
Meier (KM) estimates of survival function will be provided and compared between groups. Log-rank 
test will also be used to compare time to endpoint. Cox proportional hazards model will be fitted after 
controlling for covariates which are found to be imbalanced in preliminary analysis. Estimate of hazard 
ratio and associated confidence interval will be obtained. 
The potential confounders are sepsis, use of choleretic medications and trace elements. 
Incidence of nosocomial sepsis has decreased remarkably over the last few years in our unit and with 


13 
Approved January 10, 2019 
randomization we do not anticipate significant group differences in the incidence of sepsis. The use of 
choleretic medications and discontinuation of trace elements should occur after the development of 
primary outcome as per the unit policy and therefore these factors are unlikely to confound the 
relationship between the lipid intake and PNAC. 
 
VIII. DATA STORAGE AND CONFIDENTIALITY: We will use unique subject identification 
number to ensure confidentiality of data collected. The file linking the study identification number with 
identifiers will be stored in a locked cabinet accessible only to the investigators. Hard copies of data 
collection forms will be stored in a locked cabinet. All links to subject identifiers will be decoded to 
protect privacy of subjects. The records will be kept for 5 years after completing the study and 
publication of the findings.   
IX. RISK/BENEFIT ASSESSMENT 
This prospective study has been designed to minimize the risks to the patients enrolled.  
Intravenous lipid intake in the range of 1-2 gm/kg/day is commonly used in high-risk neonates with 
major GI surgical disorders.  PNAC is a common side effect of parenteral nutrition. Although severe 
cholestasis is defined as direct bilirubin > 10 mg/dl [20] but for the purpose of the study to avoid any 
risk, we have defined our primary outcome measure as direct bilirubin ≥ 2 mg/dl. Infants with direct 
bilirubin ≥ 2 mg/dl (reaching primary outcome) will no longer receive randomized lipid intake and the 
clinical care team will be informed. The lipid intake will then be at the discretion of the attending 
neonatologist.   To protect privacy of subjects, all links to subject identifiers will be decoded and 
subject data will be stored in locked cabinets. 
There is a potential benefit to the study subjects .The benefits to future babies involve more 
judicious administration of lipids in TPN to avoid cholestasis without depriving them of essential fatty 


14 
Approved January 10, 2019 
acids and calories. The findings on the role of cumulative lipid intake for PNAC will be useful for 
future babies as this intervention may help us to decrease the incidence of PNAC without affecting 
caloric intake.       
 
 
X. SUBJECT IDENTIFICATION, RECRUITMENT AND CONSENT 
All neonates ≥ 34 weeks GA and admitted to the NICU at URMC with major GI surgical disorders 
as listed under the inclusion criteria will be screened for study criteria within 72 hours after birth. 
Infants will be identified by the investigator with regularly scheduled screening of admissions, GA, 
postnatal days and admission diagnosis. Screening will take place on an ongoing basis and not less 
than 3 times per week. The screening log will include GA, postnatal days, and type of GI surgical 
disorders, and whether or not the infant was enrolled in the study.  If not enrolled, the reason will be 
recorded. The number and demographic characteristics of eligible subjects not included will be 
collected to assess the representation of the sample of subjects included.  
Families will be approached by one of the investigator as soon as possible after eligibility is 
ascertained to allow sufficient time for the family to ask questions about the study.  Parental 
consent may be obtained any time during the first 3 days after birth.  Consent will be documented 
on an IRB approved consent form. Each subject will be assigned a unique study identification 
number by the investigator after consent is obtained. A log sheet of subjects registered with their 
names, study ID numbers, medical record number, dates of birth, and dates of randomization will 
be kept by the RP. 
  
 


15 
Approved January 10, 2019 
 
 
 
 
 
 
BIBLIOGRAPHY 
 
1. 
Francesco William Guglielmi, MD, PhD.Clin Liver Dis 12 (2008) 97–110 , Cholestasis Induced                    
by Total Parenteral Nutrition  
2. 
Kelly DA. Nutrition.1998 Jan; 14(1):153-7. Liver complications of pediatric parenteral nutrition     
– epidemiology. 
3. 
Peden VH, Witzleben CL, Skelton MA. Total parenteral nutrition. J Pediatr 1971; 78:180–1. 
4. 
 Kubota A, Okada A, Nezu R, et al. Hyperbilirubinemia in neonates associated with total 
parenteral nutrition. JPEN J Parenter Enteral Nutr 1988; 12:602–6. 
5. 
Pereira GR, Sherman MS, DiGiacomo J, et al. Hyperalimentation-induced cholestasis: 
increased incidence and severity in premature infants. Am J Dis Child 1981; 135:842–7. 
6. 
Blau J, et al. effect of protein/nonprotein caloric intake on parentral nutrition associated 
cholestasis in premature infants weighing 600-1000 grams. JPEN; 2007; 31: 487-490. 
7. 
 Hsieh MH et al: Parentral nutrition-associated cholestasis in premature babies: risk factors and 
predictors. Pediatr Neonatal 2009; 50(5): 202-207. 
8. 
Healy CM, Campbell JR, Zaccaria E, Baker CJ. Fluconazole prophylaxis in extremely low birth 
weight neonates reduces invasive candidiasis mortality rates without emergence of fluconazole-


16 
Approved January 10, 2019 
resistant Candida species. Pediatrics. 2008;121:703-710 
9. 
Wright K, Ernst KD, Gaylord MS, Dawson JP, Burnette TM. Increased incidence of parenteral 
nutrition-associated cholestasis with aminosyn PF compared to trophamine. J Perinatol. 2003;23:444-
450. 
10. 
Koglmeier J, Day C, Puntis JW. Clinical outcome in patients from a single region who were 
dependent on parenteral nutrition for 28 days or more. Arch Dis Child. 2008; 93:300-302. 
 
 
.  
11. 
Vileisis RA et al. prospective control led study of parentral nutrition-associated cholestatic 
jaundice: effect of protein intake. J Pediatr 1980; 96: 893-897 
12. 
 Arnold CJ et al: Parentral nutrition-associated cholestasis in neonates: the role of aluminum. 
Nutrition. 2003; 61(9): 306-310 
13. 
 Fell JM, Reynolds AP, Meadows N, et al. Manganese toxicity in children receiving long-term 
parenteral nutrition. Lancet 1996;347:1218–21 
14. 
Shin JI et al: Could lipid infusion be a risk for parentral nutrition-associated cholestasis in low 
birth weight neonates?. Eur J Pediatr 2008 167: 197-20a2 
15. 
Clark RH, Chace DH, Spitzer AR. Effects of two different doses of amino acid supplementation 
on growth and blood amino acid levels in premature neonates admitted to the neonatal intensive care 
unit: A randomized, controlled trial. Pediatrics. 2007;120:1286-1296. 
16. 
Teitelbaum DH, Tracy TF, Jr, Aouthmany MM, Llanos A, Brown MB, Yu S, Brown MR, 
Shulman RJ, Hirschl RB, Derusso PA, Cox J, Dahlgren J, Groner JI, Strouse PJ. Use of 
cholecystokinin-octapeptide for the prevention of parenteral nutrition-associated cholestasis. 
Pediatrics. 2005;115:1332-1340 


17 
Approved January 10, 2019 
17. 
Arslanoglu S, Moro GE, Tauschel HD, Boehm G. Ursodeoxycholic acid treatment in preterm 
infants: A pilot study for the prevention of cholestasis associated with total parenteral nutrition. J 
Pediatr Gastroenterol Nutr. 2008;46:228-231 
18. 
La Scala GC, Le Coultre C, Roche BG, Bugmann P, Belli DC (1993)  The  addition  of  lipids  
increases  the  TPN-associated cholestasis in the rat. Eur J Pediatr Surg 3:224 – 227 
19. 
 Haynes  MJ,  Stahlman  MT,  Bradley  YB,  Jacqueline  CJ  (2002) Hepatic  pathology  in  
extremely  low  birth  weight  baboons receiving long term intralipid. Pediatr Res 51:287A 
20. 
Willis TC, Carter BA, Rogers SP, Hawthorne KM, Hicks PD, Abrams SA. High rates of 
mortality and morbidity occur in infants with parenteral nutrition-associated cholestasis. JPEN J 
Parenter Enteral Nutr. 2010; 34:32-37. 
21. 
Ng PC, Lee CH, Wong SP, Lam HS, Liu FY, So KW, Lee CY, Fok TF. High-dose oral 
erythromycin decreased the incidence of parenteral nutrition-associated cholestasis in preterm infants. 
Gastroenterology. 2007; 132:1726-1739. 
 
 
 
 
 

ICF_001.pdf: 
RSRB 40153 
Page 1 of 5 
1/19/2018 
 
PARENTAL PERMISSION 
Study Title:  Intravenous Nutrition and Liver Problems in Newborn Infants with 
Gastrointestinal Surgical Problems 
 
Investigators: Sanjiv B. Amin M.D, M.S,  
 
Introduction: 
This consent form describes a research study and what you may expect if you decide your baby 
will participate. You are encouraged to read this consent form carefully and to ask the person 
who presents it, any further questions you may have before making your decision whether or not 
to have your baby participate. 
 
This study is being conducted by Dr. Sanjiv B. Amin of the University of Rochester’s 
Department of Pediatrics. 
 
You are being asked to allow your baby to participate in this study because they are receiving 
intravenous nutrition including fat, glucose and protein as part of their routine care.   
 
Purpose of the Study: 
The purpose of this study is to learn more about the effects of the fat given as part of intravenous 
nutrition on the liver. Intravenous nutrition is required because feeding by mouth is not possible 
at this time. Your baby will need intravenous nutrition until we are able to provide all nutrition 
by mouth which may vary from a few days to several weeks or longer.  Nutrition is necessary to 
help your baby grow, heal, and improve the function of the intestine.  
 
The use of intravenous nutrition may be associated with injury to liver. The main components of 
intravenous nutrition include protein, fat, and glucose but we do not know which of these three 
components is associated with liver injury.  Liver injury is evaluated by measuring bilirubin 
concentration in the blood. We routinely evaluate for this complication once every week when 
babies are on intravenous nutrition.  
 
Newborn babies usually receive 1 to 2 gm/kg/day of intravenous fat to provide enough calories 
to grow, develop, and heal. We believe that fat intake may have a bigger role in causing liver 
injury however this has not been proven. With this study we plan to compare two different 
amounts of fat intake (both within the range of what is normally given) with respect to the 
development of liver injury. 
 
Description of the Study Procedures : 
If you agree to have your baby participate in the study, the following things will happen: 
 
1. Your baby will be randomized into one of the two study groups described below. 
Randomization means that the group assignment will be chosen by a matter of chance (just 
like flipping a coin). One group will receive fat intake as part of intravenous nutrition at a 
lower dose (1gm/kg/day) and the other group will receive fat intake at a higher dose 
(2gm/kg/day). You will not be informed which group your baby has been assigned to.  


RSRB 40153 
Page 2 of 5 
1/19/2018 
2. Your baby will continue to receive their assigned dose of fat intake until your baby no 
longer require intravenous nutrition or has received it for 6 weeks, or develops signs of liver 
injury (whichever occurs first).  If your baby develops signs of liver injury, your baby will 
receive the standard care for this problem and the fat intake will be at the discretion of the 
clinical care team.   
 
3. A research team member will review certain parts of your baby’s medical records and 
collect information about your baby’s hospital course, problems, feeding, growth, 
medications, laboratory results and other significant events. By signing this consent you are 
giving your permission for the research team to request and receive this information about 
your child’s medical conditions and course. 
 
4. All the laboratory tests and other procedures needed for the study are already a part of the 
standard care in our NICU, so this study will not require any extra blood work or procedures. 
We would also like to store a sample of your baby’s blood for future research on intravenous 
nutrition and its effects on the liver.  We will only collect blood that is leftover from blood 
draws that are done as part of your baby’s regular care.  No extra blood will be drawn for the 
purposes of this study. 
 
Allowing the study team to store your baby’s blood is optional.  You may still participate in 
the study without providing permission for blood storage.  If you decide now that your 
baby’s blood can be used for future research, you can change your mind at any time.  If you 
do change your mind, please contact Dr. Sanjiv Amin at 585-2732696.  Any blood that 
remains at that time will then be discarded. Samples that have been already used or any data 
that has been generated as a result of testing done on your sample will not be able to be 
retrieved or destroyed. You will be asked to indicate your preferences regarding blood 
storage at the end of this consent form. 
 
Number of Subjects: 
We expect to enroll about 52 babies over the next two and half years. 
 
Risks of Participation: 
Intravenous fat is routinely given to babies to provide necessary calories for growth and 
development. Liver injury is extremely common among newborn babies who receive intravenous 
nutrition beyond a few weeks. We do not anticipate additional risk of liver injury other than what 
is normally observed in babies with the same problems as yours. Liver injury usually resolves 
once the intravenous nutrition is stopped. However, if your baby develops liver injury secondary 
to intravenous fat intake, the clinical team will be informed and your baby will be removed from 
the study. The fat intake your baby receives thereafter will be at the discretion of the physician 
treating your baby.  
 
Every effort will be taken to protect your and your baby’s privacy during the study. To protect 
the privacy of subjects, all links to subject identifiers will be decoded by assigning your baby a 
study number. Subject data will also be stored in a secure manner and only research team 
members will have access to this information. If you decide to allow us to store your baby’s 
leftover blood, the sample will be labeled only with a subject number and stored indefinitely 


RSRB 40153 
Page 3 of 5 
1/19/2018 
within the Department of Neonatology. Only study team members will have access to these 
samples. 
 
Benefits of Participation: 
Your baby may or may not benefit from being in this study.  
 
Compensation for Injury:   
If your baby is directly injured by the drugs or clinical procedures solely required to participate 
in the study, you may need to pay for treatment of their injuries, but you will not be required to 
pay for emergency medical treatment provided at Strong Memorial Hospital or Highland 
Hospital.  The University may seek payment for this care from your baby’s health insurer or third 
parties.  Decisions regarding care and compensation for any other research related injury will be 
made on a case-by-case basis. 
 
Alternatives to Participation: 
If you do not participate in the study, your baby will still receive intravenous fat intake of 1 to 2 
gm/kg/day to provide calories.  The amount of fat intake they receive will be at the discretion of 
the physician treating your baby.   
 
Costs of Participation: 
You and/or your baby’s insurance provider will be responsible for the costs of the regular 
medical care, including the costs of intravenous nutrition, your baby receives during their 
hospital stay. There are no additional costs for participation in this study. 
 
Confidentiality of Records and HIPAA Authorization: 
Information identifying your baby as a participant in this study will become part of their Strong 
Memorial Hospital electronic medical record. 
 
While we will make every effort to keep information we learn about you and your baby private, 
this cannot be guaranteed. Other people may need to see the information. While they normally 
protect the privacy of the information, they may not be required to do so by law. Results of the 
research may be presented at meetings or in publications, but your child’s name will not be used. 
 
The federal Health Insurance Portability and Accountability Act (HIPAA) require us to get your 
permission to use health information about your baby that we either create or use as part of the 
research.  This permission is called an Authorization.  We will use your baby’s research record, 
related information from your child’s medical records, results of laboratory tests and both 
clinical and research observations made while your child takes part in the research. 
 
We will use your baby’s health information to conduct the study, to determine research results, 
to monitor your baby’s health status, and possibly to develop new tests, procedures and 
commercial products. Health information is used to report results of research to sponsors and 
federal regulators.  It may be audited to make sure we are following regulations, policies and 
study plans. Strong Health policies let you see and copy health information after the study ends, 
but not until the study is completed.  If you have never received a copy of the Strong Health 
HIPAA Notice, please ask the investigator for one.  


RSRB 40153 
Page 4 of 5 
1/19/2018 
 
To meet regulations or for reasons related to this research, the study investigator may share a 
copy of this consent form and records that identify you and your baby with the following people: 
The University of Rochester, the Department of Health and Human Service and the Food and 
Drug Administration (FDA). 
 
If you decide to take part, your Authorization for this study will not expire unless you cancel 
(revoke) it.  The information collected during your baby’s participation will be kept for 5 years 
after completion of the study and the publication of the findings. You can always cancel this 
Authorization by writing to the study investigator. If you cancel your Authorization, your baby 
will also be removed from the study.  However, standard medical care and any other benefits to 
which you are otherwise entitled will not be affected.  Canceling your Authorization only affects 
uses and sharing of information after the study investigator gets your written request.  
Information gathered before then may need to be used and given to others.  By Federal law, we 
must send study information to the FDA for drug studies it regulates.  Information that may need 
to be reported to FDA cannot be removed from your research records. 
 
As stated in the section on Voluntary Participation below, you can also refuse to sign this 
consent/Authorization and not be part of the study. You can also tell us you want to leave the 
study at any time without canceling the Authorization.   By signing this consent form, you give 
us permission to use and/or share your baby’s health information as stated above.  
 
Contact Persons: 
For more information concerning this research or if you feel that your child’s participation has 
resulted in a research related injury, emotional or physical discomfort please contact: Dr. Sanjiv 
B. Amin, M.D at 585-273-2696 
 
If you have any questions about your child’s rights as a research subject, or any concerns or 
complaints, you may contact the Human Subjects Protection Specialist at the University of 
Rochester Research Subjects Review Board, Box 315, 601 Elmwood Avenue, Rochester, NY 
14642-8315, Telephone (585) 276-0005.  For long-distance, you may call toll-free, (877) 449-
4441.  You may also call these numbers if you cannot reach the research staff or wish to talk to 
someone else.    


RSRB 40153 
Page 5 of 5 
1/19/2018 
 
Signature/Dates  
Parent Permission  
I have read (or have had read to me) the contents of this permission form and have been 
encouraged to ask questions.  I have received answers to my questions.  I agree to allow my child 
to participate in this study.  I have received (or will receive) a copy of this form for my records 
and future reference. 
 
Please check one of the boxes below regarding blood storage:  
 
  Yes, I agree to allow my baby’s leftover blood to be stored for future research.  
 
 
  No, I do not want my baby’s blood to be stored for future research.   
 
 
 
Research Subject (Child’s Name): ________________________________Print Name 
 
 
Parent’s Name:  _______________________________________________Print Name 
 
 
Parent’s Signature ________________________________ Date   _____________ 
 
 
 
 
Person Obtaining Permission  
I have read this form to the parent and/or the parent has read this form.  I will provide the parent 
with a copy of this permission form.  An explanation of the research was given and questions 
from the parent were solicited and answered to the parent’s satisfaction.  In my judgment, the 
parent has demonstrated comprehension of the information.  I have given the parent adequate 
opportunity to read the permission form before signing. 
 
 
________________________________________ Print Name and Title 
 
 
________________________________________  Signature      ______________Date