Parenteral Nutrition in Hospitalized Patients: Comparison of Two Commercially Available Lipid Emulsions
Phase: PHASE4
Conditions: Obstruction, Cancer, Ileus, Malnutrition, Surgery
Sponsor: Johane Allard

Protocol, March 13, 2014 
 
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Parenteral Nutrition in Hospitalized Patients: Comparison of Two 
Commercially Available Lipid Emulsions 
 
 
NCT01943409 
 
Version date: 13-March-2014 

Protocol, March 13, 2014 
 
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Parenteral Nutrition in Hospitalized Patients: Comparison of Two 
Commercially Available Lipid Emulsions 
Date of Protocol: 
 
  13 March 2014 
Sponsor-Investigator:   
Johane P. Allard 
University Health Network, Toronto, ON  
Expected Study Start Date:   01 June 2013 
Expected Study End Date:    01 December 2015 
Study Coordinator:  
Sultan Alenezi, MScAHN 
Introduction 
Parenteral nutrition (PN) is an important therapy in patients´ recovery. It is indicated when 
the gastrointestinal tract is not functional or cannot be accessed, or the patients´ nutrient 
needs are greater than those achieved using the gastrointestinal tract (1) . Specific 
indications include complete intestinal obstruction, ileus or severe dysmotility, severe 
pancreatitis, high-output intestinal fistulae, short bowel syndrome or severe intestinal 
inflammatory disease (2,3). 
It is important to indicate that PN need to be used in the appropriate setting, since it is a 
costly treatment and is not free of complications. Some of the complications secondary to 
PN are: catheter infections, hyperglycemia, hepatic dysfunction, hyperlipidemia and 
refeeding syndrome (2,4,5). Also, PN is associated with gut atrophy, reduced gut 
absorption, loss of gut barrier, altered gut microflora, increased bacterial adherence, 
increased microbe translocation, B and T cell dysfunction (3,6) 
Bloodstream infections (BSI) rates vary widely among PN patients from 1.3-39% (7,8) 
even though there is evidence on how to reduce catheter-related infections  (9). Still, there 
are studies that have found high rates of catheter-related infections in patients with 
parenteral nutrition. There is a cohort study in patients with central venous catheters, with 
or without PN, this study found that PN was an independent risk factor for BSI (10). 
Another study in 19 Canadian hospitals found that the rates of BSI among patients with PN 
were 4 times higher than those not receiving PN (11). The most common organisms in 
hospitalized patients are coagulase-negative staphylococcus, Staphylococcus aureus, 
Enterococcus, Candida spp, Klebsiella pneumoniae, and Pseudomonas aeruginosa (8) 
Until recently, Intralipid, a soybean oil-based lipid emulsion, has been the only available 
lipid for intravenous use in Canada. In 2010, ClinOleic, a new, predominantly olive oil 
based emulsion, has been approved by Health Canada as an alternative lipid.  
 

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There is an increasing need for hospitals to do quality-assurance studies for in-patient PN to 
assess indications, PN prescription, complications, clinical outcomes and costs. The only 
in-patient population that is well studied is the intensive care unit (ICU) population. Several 
meta-analyses showed that PN was associated with higher infection rate, longer length of 
stay and higher mortality when compared with enteral nutrition (12,13). Results from these 
and other studies were the basis for the Canadian ICU Guidelines (13-17).  
The aims of this study (already approved CAPCR 12/5174/AE) ) were to determine if PN 
prescribed in in-patients follows existing guidelines in terms of timing of nutrition support, 
prescription and monitoring and, whether it is associated with complications. In addition, 
clinical outcomes such as length of stay and mortality are assessed.  
In addition, we will evaluate, in this cohort of patients, the effect of 2 different lipid 
emulsions, both approved by Health Canada (Intralipid based on soybean oil and ClinOleic 
based on olive oil). These lipid emulsions, readily available through our provider, will be 
prescribed alternatively according to standards of care.  We also plan to do additional 
measurements relevant to nutrition which include: C-reactive protein [CRP], pre-albumin, 
subjective global assessment, hand grip strength and arm circumference at beginning and 
10 days of PN (or at discontinuation if less than 10days). We will also monitor diagnoses of 
infections during PN, including 1 week after PN discontinuation if patients remain in 
hospital. We were advised to re-submit as a new study rather than as an amendment. 
Background 
In a prospective quality control study in Switzerland, 200 patients receiving PN were 
evaluated to see if PN prescription was justified according to the 2002 ASPEN guidelines. 
They were recruited during 18 weeks from Medicine, Surgery and Intensive Care Units. In 
this study, the Nutrition Support Team did not interfere with the PN prescriptions which 
were made by the medical staff of the different wards. They concluded that PN prescription 
was justified in all but 14 patients (7%). The energy supply was adequate only in 31.5% of 
the patients and overfeeding was more frequently observed. Women, thin and elderly 
patients were at more risk for overfeeding. The same happened with the protein supply, 
only 21% of the patients received an adequate supply and 65.5% received excess proteins. 
Also, 23.5% of the patients did not receive supplementation of vitamins and/or trace 
elements in their PN(18). This study shows the need to establish nutrition support 
protocols, particularly for PN. 
In one Canadian study (19), the authors conducted a cross-sectional national survey of 
dietitians working in ICUs and identified interventions to target for quality improvement 
initiatives. In this study, 24% of the sites that responded reported the presence of a nutrition 
support team. The enteral route was the main route of administering nutrition support and 
of the 702 patients studied, 7.1% received parenteral nutrition only. Underfeeding seemed 

Protocol, March 13, 2014 
 
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to be a significant problem in the group of patients that stayed in the ICU for more than 3 
days since 16% of these patients did not receive any nutrition support. Furthermore, of 
those that received nutrition support the average of calories and proteins received was 56% 
to 62% of their estimated needs over the first 12 days in the ICU. Another study conducted 
in Canadian ICUs evaluated whether an auditing practice and providing feedback is an 
effective strategy to improve adherence to nutrition guidelines. Twenty-six ICUs 
participated in an audit in 2007 and were given a feedback of their performance compared 
with the Canadian Critical Care Nutrition guidelines. The authors observed improvement in 
some nutrition practices in many ICUs after the reaudit in 2008  (20).  
There is another study from Spain that shows the development and implementation of an 
audit tool for quality control of PN(21). In 1995, this quality control program was 
implemented by the Pharmacy Service and became a tool that measured compliance with 
accepted standards in the literature. The authors show the results of 5 audits during the past 
10 years. This study was made in hospitalized patients with PN with the exception of ICU 
patients, pediatric patients and patients with chronic renal dysfunction. The authors 
concluded that in the last audit 9 out of 22 criteria reached the predefined standards, but 
also found some they needed to improve such as the indication of PN, assessment at the 
beginning of nutrition support and infectious complications.  
The last study found(22), describes the approach taken by one hospital in California to 
improve safety and quality of PN. Process improvement strategies included revisions to the 
PN order form, education of clinicians, increased collaboration between pharmacists and 
registered dietitians and initiation of PN rounds. These process strategies positively 
impacted quality and costs. There was improvement in compliance with safe practice 
standards, percentage of patients with appropriate indication for PN, glycemic 
management, laboratory monitoring. The average number of patients receiving PN 
decreased from approximately 15 to less than 5 per day, this decreased the costs 
significantly. 
In Canada, there are guidelines for nutrition support in mechanically ventilated critically ill 
adults. These guidelines were made by searching in four bibliographic databases 
randomized clinical trials or meta-analysis of randomized controlled trials that included any 
form of enteral or parenteral nutrition and the outcomes were: mortality, length of stay, 
quality of life, complications and cost. The search was done between the years 1980 to 
2002. With respect to PN, the authors concluded that it should not be indicated until all 
strategies to maximize enteral nutrition delivery have been attempted. Also, when PN is 
indicated, glutamine should be used as a parenteral supplement if it is available. They also 
concluded that in patients who are not malnourished, are tolerating some enteral nutrition or 
when PN is indicated for short-term use (<10 days), hypocaloric PN and also withholding 
lipids should be considered in these specific setting. In surgical critically ill patients with 

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nutrition support, intensive insulin therapy to achieve blood glucose levels between 4.4 and 
6.1 mmol/L should be considered(16) 
The literature has mentioned that there is an overprescription of PN in patients with 
functional gastrointestinal tracts. It is important to mention that PN is associated with 
adverse events when compared to enteral nutrition. One review analyzed randomized 
clinical trials and concluded that there are more infections and longer lengths of stay in ICU 
patients receiving PN than those receiving enteral nutrition. Major complications such as: 
pneumothorax and air embolus are greater in parenterally fed patients. Also, the cost of PN 
is higher (6). Kudsk and colleagues reported pneumonia, abscesses, line infection or all 
three in 40% of parenterally fed patients versus 16% of enterally fed patients (23). 
It is also known that PN is an expensive treatment and its cost differs among countries. In 
Europe, the daily cost of one compounded PN bag for neonates is around 55 Euros. An 
average cost per bag for infants <2 year was around 84 Euros. A major proportion of the 
cost is due to staff time(24). In the United States, when comparing compounded PN versus 
multi-chamber PN based on the underlying bloodstream infection risk the daily mean PN 
acquisition cost for patients receiving multi-chamber PN was US $164 compared with US 
$239 for patients receiving compounded PN(25). In Toronto General Hospital, the cost of a 
bag of parenteral nutrition is around $140 CAD per day. 
Intralipid is a soybean oil (SO) intravenous fat emulsion, available since 1961,  rich in 
omega-6 polyunsaturated fatty acids (PUFA) and may enhance the generation of 
arachidonic acid-derived eicosanoids that could exaggerate the inflammatory response 
during stress and trauma (26). This pro-inflammatory effect may be detrimental. For 
example, in a prospective, randomized, controlled study comparing the vascular, metabolic, 
immune and inflammatory effects of 24h- infusion of parenteral nutrition (PN) with SO-
based lipid emulsion (Intralipid), olive oil-based lipid emulsion (ClinOleic), lipid free and 
normal saline in 12 healthy subjects, the authors found that Intralipid increased blood 
pressure and altered endothelial function  (27). A recent ASPEN position paper (28) 
reviewed the literature on lipid emulsions. While the current available, standard SO-based 
lipid emulsion like Intralipids meet the needs of most PN patients, alternative oil-based fat 
emulsions, like olive oil (OO) are used extensively in Europe and have been shown to be 
less proinflammatory and immunosuppressive due to different metabolic pathways. Patients 
receiving these alternative lipid emulsions may have better clinical outcomes but further 
research is needed to identify which type of lipid emulsion or which combination of oils 
may be most clinically useful for specific patient populations. SO lipid emulsions have 
plant sterols known as phytosterols, these are thought to alter hepatic function and have 
been associated with cholestasis in children on long-term PN (29,30). Also, most SO lipid 
emulsions have small amounts of α-tocopherol, a known antioxidant. Studies have shown 
that vitamin E has a role in the prevention of hepatic injury in animal models(31), but there 
is still deficit in human data.   

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ClinOleic is a lipid emulsion composed of OO (80%) and SO (20%) (27,32). It is a third-
generation of lipids and was introduced in Europe in the 1990s (28) . It has more 
monounsaturated fatty acids (MUFA) than PUFA, in a proportion of 65% MUFA and 20% 
PUFA (32). Even though it has a lower proportion of PUFA, no significant changes in 
plasma fatty acid profile and no deficiency of essential fatty acids have been reported (33). 
However, this was observed in a mouse model (34).  ClinOleic is also rich in α-tocopherol, 
and MUFAs are resistant to lipid peroxidation so this intravenous lipid emulsion is 
potentially beneficial in subjects with risk of oxidative stress (32). There is a lack of studies 
that critically evaluate indications and outcomes regarding parenteral nutrition in different 
hospital units and in a wider variety of pathologies. There are very few studies published 
that compare two types of intravenous lipid emulsions and all have limited number of 
patients. There is a need to elucidate if the new lipid generations are a better option than the 
classic SO-based lipid emulsions and which patient populations will benefit most from 
them. This and our personal need for evaluating the indications and outcomes of patients 
with parenteral nutrition motivated us to do this study in our own center. 
Part A: 
Primary Objective    
 To evaluate parenteral nutrition prescriptions in hospitalized patients 
 Secondary Objectives 
 Describe patient population according to the pathology that caused the 
hospitalization  
 Record the indication that determined the need for PN and whether they are 
medical, surgical or ICU patients 
 Assess updated Charlson co-morbidity index (CCI) 
 Record the number of days with intakes less than 50% of requirements or NPO 
before PN was prescribed 
 Perform a nutritional assessment which includes: weight at admission (if recorded 
in chart) and at time of starting PN, height, body mass index (BMI), Subjective 
Global Assessment (SGA), albumin and estimate of nutritional requirements.  
 Record the initial PN prescription in terms of energy and proteins 
 Record how many days it took to reach the nutritional requirements estimated by 
the dietitian 
 Compare energy received as a goal with calculated energy requirements using 
published equations 
 Record the number of times PN was interrupted 
 Record the total number of PN days the patient received 
 Determine the type of line (central or peripheral) and number of days with 
peripheral and/or central lines. 

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 Determine the type of vascular access (if central line) 
 Record laboratory results once a week to assess potential metabolic complications 
associated with PN 
 Record  catheter related infections, whether suspected or confirmed 
 Record any other complications deemed related to PN 
 Record number of antibiotic-days to treat catheter-associated infections 
 Record the reason why PN was discontinued  
 Record total length of stay 
 Record in-hospital mortality and cause of mortality during PN as well as during 
entire hospital stay 
 
 
Part B: Intralipid vs ClinOleic  
Primary Objective 
To evaluate metabolic, nutritional, infectious and inflammatory parameters in 
patients receiving SO-based lipid emulsion compared to those of patients receiving 
OO -based lipid emulsion.  
 Primary Outcome: length of stay 
 Secondary Outcomes: mortality, nutritional parameters (anthropometry, 
handgrip-strength, mid-arm circumference, , pre-albumin), inflammation 
(high sensitivity C-reactive protein; hs-CRP), documented infections, ICU 
stay, antibiotic-days, liver enzymes, essential fatty acid status 
Study design 
This is a prospective study that will evaluate the indications of parenteral nutrition in an 
inpatient setting. As part of their PN prescription, patients will receive either standard lipid 
(Intralipid) or OO-based lipid emulsion (ClinOleic), alternately depending on their time 
point of PN start, i.e. one person will receive Intralipid, the next one ClinOleic, etc. We will 
collect information from patients that have started with parenteral nutrition during their 
hospitalization and that are hospitalized in medical, surgical or ICU wards. We will also 
collect retrospective data of 100 patients to compare if the actions of the nutrition team and 
results change with respect to the prospective data.   
Inclusion Criteria: 
 Patients 18 years or older 

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 Patients that are expected to require PN for 5 days or more during their 
hospitalization  
 Patients hospitalized in medical, surgical or ICU wards 
 Signed informed consent either from the patient, their legally authorized 
representative or a direct family member 
Exclusion Criteria: 
 Patients without PN during their hospitalization 
Part A: Patients will be approached when they start with PN during their hospitalization 
and will be followed until their last day of PN or, if occurred before PN ends, death. Part 
B: For the proposed study, we will start PN as usual, according to the patients needs. We 
will randomly assign patients to receive either Intralipid or ClinOleic as the lipid emulsion 
in the PN. The amount of calories from the lipid emulsion will be equivalent.  
Patients will be followed for one week after their last day on PN and, in addition, major 
outcomes such as mortality and length of stay will be assessed during the entire 
hospitalization.    
Information regarding the patients nutrition will be obtained from the hospital chart and by 
direct communication with the PN team (dietitian, nurse, pharmacist) after signed informed 
consent. 
We will analyze the nutritional indications and laboratory results of patients hospitalized in 
different units who are starting with PN alone or in combination with enteral or oral feeding 
twice a week. We will use a registry to enter the data. 
Measurements: :Part A 1) Patient demography: age, sex; 2) Type of patient: medical, 
surgical and/or ICU patients; 3) Type of any surgery the patient has during hospitalization; 
4) Primary indications related to parenteral nutrition, comorbidities, updated CCI (31,32); 
5) Nutritional assessment: weight, height, BMI, SGA, estimated energy and protein 
requirements; 6) comparison of energy received as a goal vs calculated energy requirements 
using published equations; 7) Energy, dextrose, aminoacids and lipids received by PN. 
Total energy and proteins received including enteral nutrition and oral intake. Energy 
provided by Propofol, if received. In case of enteral nutrition, name and amount of product 
used; 8) Type of line used (peripheral or central); 9) Vascular access; 10) Reason for 
ending PN; 11) Number of times and reasons for interruption of PN; 12) Weekly PN related 
laboratory results; 13) Complications secondary to PN; 14) Outcome of patient  
Part B: We will include the same measurements as in part A, but will add some additional 
nutritional parameters which will be done at baseline (Day 0) and after 10 days (Day 10) 

Protocol, March 13, 2014 
 
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with PN. Baseline or day 0 assessments to be done prior to or within 24 hours of PN 
initiation. Day 10 measurements to be done on day 10 of PN administration. If the PN ends 
before day 10, we will consider a cutoff at day 7 of PN. This means that if the PN ends 
before day 7, we will not repeat the measurements or blood work. If PN ends between days 
7-9 we will repeat the measurements instead of doing them on day 10 for this special cases. 
The parameters to measure will be: hand grip strength (kg), mid arm circumference (cm), 
SGA and weight as measures of nutritional status. We will also add hs-CRP, pre-albumin, 
and fatty acid profile in red blood cells (RBC) and plasma to the laboratory results at both 
time points. Clinical outcomes (documented infections, antibiotic-days or other adverse 
events) will be monitored for one week post-PN. In addition, mortality and length of stay 
will be documented for the entire hospitalization.   
There are numerous studies that try to elucidate which equation is the best to estimate the 
energy requirements of hospitalized and healthy people, but none have shown to be 
comparable to indirect calorimetry, which is considered the gold-standard. The ASPEN 
guidelines refer to the non-obese critically ill patient and suggest using 25 kcal/kg actual 
body weight per day, published equations, or to measure energy requirements using indirect 
calorimetry (35). Moreover, the ESPEN guidelines also suggest prescribing 25 kcal/kg in 
the ICU population increasing to target over the next 2-3 days (36). In the case of obese 
critically ill patients,  ASPEN guidelines suggest a hypocaloric feeding and they mention 
that the goal of the enteral nutrition regimen should not exceed 60-70% of target energy 
requirements,11-14 kcal/kg actual body weight per day or 22-25 kcal/kg ideal body weight 
(35) .  Recently published studies have found that the Penn State equation can be used in 
patients with mechanical ventilation and that the Penn State modified can be used in older 
obese patients with mechanical ventilation (37-40).  
For non-Icu population, ASPEN and ESPEN guidelines agree in using weight based 
formulas to calculate energy requirements. The estimated energy requirements should be 
between 20-40 kcal/kg, depending on the pathology (41-45). At the same time, both 
guidelines suggest using ideal body weight (IBW) in case of obesity and ESPEN adds 
ascites as another condition were IBW should be used (35,42,45). For the calculation of 
IBW we will use Hamwi’s equation (46).We will use Penn State formula for ICU ventilated 
patients and weight based formulas for all other patient populations. Ideal body weight will 
be used in patients with ascites, obesity or in cases of edema were body weight with edema 
is much more than usual body weight or body weight at admission. Actual body weight will 
be used for undernourished or normal weight population. 
Blood sample collection and processing: 
Blood will be collected in the morning during the routine blood draw on the wards. 
Samples for plasma and RBC fatty acids will be collected in EDTA containing tubes, and 

Protocol, March 13, 2014 
 
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samples for pre-albumin and hs-CRP in tubes without anticoagulant. The tubes will be 
centrifuged (910 × g, 10 min), and serum and plasma will be aliquoted and stored at -80°C 
until analysis.  
From the plasma tube, all remaining plasma and the buffy coat, which shows on top of the 
erythrocyte sediment as a white ring will be discarded. The remaining packed RBC will be 
aliquoted and frozen at -80°C until analysis. 
Pre-albumin and hs-CRP will be measured by routine methods at an accredited laboratory 
(Hospitals In-Common Laboratory Inc., Toronto). 
Red blood cell and plasma fatty acid profile will be assessed using gas chromatography. 
Briefly, total lipids will be extracted from RBC or plasma into chloroform/methanol (47) , 
containing butylated hydroxytoluene as antioxidant. Extracted lipids will be  saponified and 
transmethylated using boron-triflouride (48) . Fatty acid methyl esters were then separated 
using an Agilent 6890 gas chromatograph equipped with a flame ionization detector (49). 
Peaks will be identified from C14:0 to C22:6n-3. The relative amount of the essential fatty 
acids, alpha-linoleic acid and linolenic acid will be reported as % of total lipids. 
Statistical analysis 
Part A: Descriptive statistics will be performed. Results will be expressed as absolute 
numbers and percentages, mean ±standard deviation (SD) or median (minimum; maximum) 
depending on the variable types and distributions, separately for the prospective and the 
restrospective dataset.For the prospective study, multivariate logistic regression will be 
performed to identify risk factors associated with specific PN prescription: for example, 
inadequate administration of PN. In addition, data from the prospective study and the 
retrospective chart review will be compared by unpaired t-test, Mann-Whitney-test or chi-
square test as appropriate. A p value <0.05 will be considered statistically significant. Part 
B: For the Intralipid and the ClinOleic analysis, all variables will be tested for normal 
distribution (Shapiro Wilks test). Primary outcome is length of stay (in days). The Intralipid 
and ClinOleic groups will initially be compared with unpaired t-test or Mann-Whitney test 
as appropriate. Secondary outcomes: other clinical outcomes (days in ICU, antibiotic-days, 
infections, mortality) will also be analyzed the same way initially. For secondary outcomes 
that may change over time, i.e. hs-CRP, pre-albumin and other laboratory results, BMI,   
arm circumference, hand grip strength, changes will be compared between groups using 
unpaired t-test or Mann-Whitney test as appropriate. To account for possible covariate 
effects (eg. age, baseline BMI, Charlson comorbidity index), regression methods such as 
generalized linear models will be employed. All tests will be based on two-sided 
alternatives and a test will be considered statistically significant using alpha=0.05. SAS 
Enterprise Guide 4.1 software (SAS Institute Inc., Cary, NC, USA) will be used. 
 

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Feasibility and Sample Size 
Part A: Based on previous studies, there are about 200 in-patients per year receiving PN. 
All patients will be assessed as per standard medical guidelines for PN and it is expected 
that 90% will agree to participate in the project. We calculate that we will have enrolled 
about 50 patients for Part A, before we start with part B. We will later include 150 more 
patients from Part B to have a total of 200 patients. We will compare the data obtained with 
100 retrospective patients to see if the actions of the nutrition team changed since we 
started the project.  
Part B: When we receive the ClinOleic in the hospital, patients will receive either SO-
based lipid emulsion (Intralipid= 150 patients) or OO-based lipid emulsion (ClinOleic=150 
patients) on an alternate basis (one-to-one) for the duration of the PN.  
The total number of patients including part A and part B is estimated to be 350 patients. It 
is expected to take about one and a half years to recruit this number of patients.  
For the Intralipid and ClinOleic analysis, we based our sample size on a study that 
evaluated the use of either SO or SO + fish oil (FO) in 206 patients with 
gastrointestinal or colonic cancer during 7 days after surgery and found that the 
patients that were given the FO treatment had significantly shorter length of stay than 
the SO group (Mean (SD) 15(5) versus 17(8) p= 0.041). Also, they had fewer 
infectious complications (50). Another study compared soybean oil and soybean 
oil+FO in 57 elderly patients with colorectal cancer. In the treatment group, there were 
fewer infectious complications and incidences of systemic inflammatory response 
syndrome (SIRS), and shorter lengths of hospital stay were observed(51).  
Based on this, we estimate that a sample size of 150 in each group with a power of 0.8 
and alpha of 0.05 will be sufficient to show a similar difference in length of stay 
between the two groups (soybean or ClinOleic) using the online sample size 
calculation provided by G.W. Snedecor & W.G. Cochran  
http://www.biomath.info/power/ttest.htm.   
Significance 
There are currently no data prospectively collected in Canada that evaluate the indications 
and outcomes of hospitalized patients with PN in different hospital units. There is a need 
for prospective interventional studies to compare clinical outcomes between the traditional 
soybean oil-based lipid emulsion and the olive oil-based lipid emulsion. The results of this 
project will help establish standards of practice and this will greatly benefit the inpatient 
population requiring PN. 
 

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