Kirstin Hybsch

April 19, 2017

SMOFlipid IVFE use in parenteral nutrition for

critically ill patients
 I. Introduction

Intravenous fat emulsions (IVFE) contain essential fatty acids and are a non-calorie source of

energy used in parental nutrition (PN). First major IVFE was used in the late 17th century but

coupled with many side effects, leaving plenty of room for improvements in the coming years.1

Fast forward to the 21st century, IVFEs are still used throughout clinical practice and widely used

in critically ill patients.

Soybean oil, medium-chain triglyceride, olive oil, fish oil otherwise known as SMOFlipid is

an IVFE used in PN. It is a fourth generation fat emulsion based on ASPEN guidelines. It has

been used in critically ill patients in Europe for over ten years. However, in the United States we

are hesitant to include this in our clinical practice why? Currently, the United States is

continuing to investigate SMOFlipid efficacy despite significant research conducted. Benefits of

this particular IVFE have been revealed including improvement in liver function (reduced liver

enzymes and total bilirubin), reduction of pro-inflammatory properties, increase in antioxidants,

prevention of cholestasis in preterm infants and reversal of essential fatty acid deficiency

(EFAD) in adults along with its safety and tolerance.

Typically in the United States, long-chain triglycerides (LCT) are utilized in the form of

soybean oil. Commercial lipid emulsions include: Intralipid, Nutralipid, Liposyn III and some

less common including Clinolipid (olive oil and soybean oil). Whereas, Europe not only uses

soybean and olive oil but commonly uses fish oil and medium-chain triglycerides (MCT) in

critically ill patients. The inclusion of MCTs and polyunsaturated fatty acids are oxidized much

faster than with LCTs.2 SMOFlipid is comprised of 30% soybean oil, 30% MCT, 25% olive oil

and 15% fish oil. Research has shown with the inclusion of fish oil in PN solutions it is less pro-

inflammatory than commercial soybean IVFEs. Additionally, the eciosanoids from omega 3
fatty acids in fish oil based emulsions are less inflammatory in comparison to fat emulsions

originating from omega 6 fatty acids in soybean oil IVFEs. Furthermore, fish oil has more

antioxidant properties including a-tocopherol (form of vitamin E) to inhibit the oxidation of fatty

acids.

II. Current state of research

The extensive research to support the use of SMOFlipid in long-term PN, especially in

critically ill patients is overwhelming. A randomized control trial (RCT) performed in patients

with intestinal failure on long-term PN was investigated by Klek, Stanislawm, et al. There were

seventy-three patients age eighteen to eighty-five years old who were in- and outpatients

receiving PN over the course of four-weeks. These patients were randomized to the control

group: Intralipid (soybean oil IVFE) or the treatment group: SMOFlipid. The researchers

evaluated the patients biochemical laboratory values, demographic data and vital signs at

baseline. Furthermore, fatty acid pattern, plasma lipoproteins, vitamin E were evaluated and

assessed.

To further assess the safety and tolerance of this particular IVFE, events were categorized

as adverse events (AE) or serious adverse events (SAE). It was noted that none of the AEs

were serious and were mainly due to infection related to central venous catheter, which is often

common in patients on long-term PN. There were five AEs in the SMOF group and six in the

Intralipid group. There were two SAEs in the SMOF group and eight in the Intralipid group. The

SAEs were defined as serious life threatening events resulting in hospitalization or death and

were documented throughout the length of study. However, it is important to note the researchers
never identified the criteria of a SAE, which is certainly a limitation in this particular study,

although it should be noted that in all cases there was a full recovery reported.

Results showed the patients assigned to the treatment group (SMOFlipid) had a reduction

in liver enzymes (ALT, AST) and total bilirubin in comparison to the control group (Intralipid)

where there was a slight increase in biochemical markers.3 Furthermore, there was an increase in

a-tocopherol in the treatment group as well as eicosapentanoic acid (EPA) and docosahexaenoic

acid (DHA), whereas, the control group was unchanged. The inclusion of fish oil, improves the

balance of the immune response, resulting in a quicker resolution of inflammation and recovery.

Lastly, there was a significant reduction in pro-inflammatory cytokines with the treatment group.

A secondary analysis data from a prospective multicenter study was conducted by

Edmunds, Christina E., et al to further investigate the tolerance to different IVFEs in critically ill

patients. Included subjects were adults admitted into the intensive care unit (ICU) for more than

seventy-two hours and were mechanically ventilated within forty-eight hours. There were four

hundred and fifty one patients included in this study. Additionally, these patients also had to

receive PN for five days or more, and continued receiving the same IVFE during the time of

collecting data.5

In order to further assess critically ill patients, data was obtained including clinical and

demographic information for a total of twelve days or until patient deceased or was discharged

from ICU. Whereas, clinical data was measured and reported for a total of sixty days post ICU

admission. It was not clearly stated how patients were allocated to IVFEs. Patients received

either lipid-free, soybean oil, MCT, olive oil or fish oil in PN. There were seventy patients

(15.5%) in the lipid free group, two hundred and twenty-three (49.5%) in the soybean oil group,
sixty-five (14.4%) in the MCT group, seventy-four (16.4%) in olive oil group and nineteen

(4.9%) in the fish oil group.

Results were evaluated using an adjusted Cox proportional hazard model to further

evaluate the time until mechanical ventilation was discontinued, time until discharge from ICU

and time until discharge from hospital stay. Fish oil group in comparison to lipid free group had a

reduced time on mechanical ventilation alive and a shorter length of stay in the ICU until

discharge. Thus, it was concluded by the researchers that use of fish oil as an alternative IVFE

was associated with improved outcomes in a clinical setting.

Moreover, additional research studies have been conducted in gastrointestinal surgical

patients. A study by Wu, Ming-Hsun, et al compared Smoflipid versus MCT/LCT IVFE in post-

surgical gastrointestinal patients. Patients underwent gastrectomy with or without lymph node

dissection related to gastric adenocarcinoma or gastrointestinal stromal tumor.7 PN was initiated

for five days post-operatively. There were thirty-five patients with a medium age of fifty-seven

years of age included in the study. Patients were excluded from the study if the presented with

any metabolic disease i.e. diabetes or hyperlipidemia; obesity, chronic renal, liver or heart

disease, life-threatening diseases or history of drug/alcohol abuse. Patients were also excluded if

they were hypersensitive to active ingredients in Smoflipid. All patients for monitored and

evaluated based on vital signs, blood serum, and labs. Additionally, oxidative stress was also

assessed via Chemiluminescence Analyzing System.7

At baseline biochemical markers, blood serum and clinical labs were recorded including:

c-reactive protein (CRP), oxidative stress, interleukin-6 (IL-6), interleukin-10 (IL-10), tumor

necrosis factor-alpha (TNF-a), and Transforming Growth Factor-Beta 1 (TGF-B1). IL-6 pro-
inflammatory cytokine and anti-inflammatory mytokine and IL-10 is an anti-inflammatory

cytokine. TNF-a is a major pro-inflammatory cytokine involved in inflammatory events and

TGF-b1 cytokine with potent regulatory and inflammatory activity.

At the end of the study, results indicated no change in inflammatory markers or oxidative

stress among both groups nor did blood glucose change significantly between either groups.

However, there was a significant decrease in triglyceride levels in the Smoflipid group, whereas,

MCT/LCT IVFE had an increase on day 2 and remained elevated throughout the study. The

inclusion of fish oil in Smoflipid helped correct dyslipidemia in patients. Although inflammatory

markers were not drastically different among both groups, Smoflipid was safe and well tolerated

leading to beneficial outcomes in fatty acid profile vs. MCT/LCT IVFE.

An additional double-blind randomized study conducted by Ma, Cheng-Jen, et al

compared the efficacy and safety of a composite versus a conventional IVFE in postsurgical

gastrointestinal tumor patients. There were forty patients included in the study post-elective

surgery. Patients were excluded if they had severe hypoalbuminemia (<2.5g/dL), diabetes

mellitus, or hyperlipidemia (fasting TG >250mg/dL); had a BMI greater than 30kg/m2; abused

drugs alcohol; liver disease, renal disease, heart or other life-threatening disease. Patients were

given 1-2g/kg BW/d lipid varying on the patients condition and infused continuously daily for

twenty-four hours.8 Included participants were randomized to receive composite IVFE

(Smoflipid) or conventional IVFE: MCT/LCT. Both IVFEs were administered for five days

post-surgery. Both were infused for a total of eight hours/day and patients were also on a clear

liquid diet.
 In order to gather more information on the participants included in the study, data was

collected including: vital signs, clinical course, fluid input, medication, concomitant procedure

and AEs between surgery day and end of the study on day six. Blood was obtained from each

patient measuring levels of glucose, triglyceride, albumin, pre-albumin, and cholesterol.

Additionally, inflammation-related cytokines including IL-6, IL-1B, TNF-a, and CRP were

assessed. Lab values including: AST, ALT and total/direct bilirubin were also recorded. All the

collected data was further assessed by a statistical package to evaluate clinical significance.

Results showed similar clinical outcomes in both groups including similar pro-

inflammatory markers post-operatively and mild to moderate AEs in both groups (nausea and

vomiting; both groups recovered and continued 5 day PN course). The length of hospital stay

was similar in both groups. However, groups receiving Smoflipid had significantly lower LDL

levels and cholesterol levels were slightly lower. It was discussed that Smoflipid was just as safe

and well tolerated (if not more) as the conventional IVFE. Smoflipid appeared to have better

triglyceride and cholesterol lowering abilities. The anti-inflammatory composition of Smoflipid

had similar outcomes as the conventional IVFE. However, it is important to note that looking at

the results table provided in the study, Smoflipid did reduce inflammatory markers, although

clinically insignificant due a p-value of .038. It can be concluded that both IVFEs were well

tolerated and had beneficial outcomes in post-surgical gastrointestinal patients.

Although there is significant research supporting efficacy of SMOFlipid use in long-term

PN for adults, there is also data suggesting the same efficacy in critically ill neonates. In Europe,

SMOFlipid was first used in the pediatric and preterm neonate patients. A randomized control

trial conducted by Burrin, Douglas G., et al. investigated the impact of SMOFlipid use on

cellular mechanisms of PN, specifically, associated liver disease in premature neonates. The risk
of cholestasis liver disease is extremely high, and unfortunately very common with PN in

premature neonates. In infants who are on PN for two months or more have a 50% risk of

developing cholestasis liver disease, and could progress further to end stage liver disease or the

need for a liver transplant. Usually this disease can be detected early on by looking at

biochemical markers such as total bilirubin, bile acids and liver transaminases. The researchers

hypothesized that a PN emulsion such as SMOFlipid would be well tolerated as soybean oil

emulsions are, while also influencing the fatty acid profile. Additionally, it was found that the use

of soybean oil as a lipid emulsion are linked to cholestasis.5

There were a total of fifty-three neonates, <34 weeks gestational age randomized to

receive soybean oil emulsion or SMOFlipid for a minimum of seven days on PN. The infusion

rate was gradually increased from 1.0g fat/kg per body weight (BW) on days one-three, and

increased to 2g fat/kg per BW on day four, on day five infusion rate ramped up to 3g fat/kg per

BW and 3.5g fat/kg per BW on days six to fourteen.5 At baseline biochemistry lab values were

assessed and compared to lab values at the end of the study. In both the treatment, and control

group baseline triglyceride concentrations were 0.52 0.16 vs 0.54 0.19 mmol/L. As the study

progressed, both the treatment and control group had similar triglyceride concentrations increase

at a slow pace. Triglyceride concentrations on day eight were 0.69 0.38 vs 0.67 0.36,

resulting in a significant P value of 0.78. Furthermore, there was a significant reduction in total

and direct bilirubin in the group receiving SMOFlipid.

A randomized controlled trial performed by Deshpande, Girish, et al. further investigated

the efficacy of a fish oil lipid emulsion (SMOFlipid) in very preterm neonates (<30 weeks).6

Premature neonates were randomly allocated to receive fish oil IVFE SMOFlipid or olive oil

IVFE Clinoleic. Unlike Clinoleic, SMOFlipid has the appropriate ratio of omega 6 to omega 3
fatty acids (2.5:1), whereas, Clinoleic has a high ratio of omega 6 to omega 3 fatty acids (9:1).

Therefore, Clinoleic is more pro-inflammatory whereas, SMOFlipid isnt due to the more

balanced ratio between essential fatty acids. The researchers in this particular study hypothesized

that the neonatal treatment group receiving the SMOFlipid would have a rise in omega 3 fatty

acid levels and a decrease in oxidative stress versus the control group receiving Clinoleic.6

There were thirty-four preterm neonatal subjects included at the start of the study, and

thirty subjects completed the study. The included subjects were 23-30 weeks gestational age and

were allocated at random to treatment group or control group. At baseline plasma F2-isoprostane

(lipid peroxidation marker), vitamin E and red blood cell fatty acids were evaluated both before

and after. In order to ensure safety among the subjects, blood cultures for sepsis and growth were

monitored and evaluated closely throughout the study.

Results indicated that the preterm neonates tolerated both PN IVFE solutions well

without any medical intolerances or AEs to note. In the treatment group there was a reduction of

plasma F2-isoprostane levels in comparison to the levels at the beginning of the study.

Additionally, vitamin E and EPA were drastically increased in the treatment group. In both the

treatment and control group there was an increase in oleic and linoleic acid. Ultimately, the

researchers hypothesis was spot on in which the neonates receiving SMOFlipid for seven days

had a reduction in lipid oxidative stress and an increase in omega 3 fatty acid levels, supporting

anti pro-inflammatory responses.

These studies suggest the safety, tolerance and extensive benefits SMOFlipid has to offer

in patients on long-term PN who are critically ill. Despite the thorough data provided, there are

discrepancies in the literature that leave readers questioning accuracy. For one, it is astounding
that this fourth generation lipid emulsion has been approved by the FDA in 2016 however, very

few clinical facilities use this lipid emulsion in practice. It is even more interesting to note that

the substantial research conducted throughout the years havent convinced more facilities to

make the switch to SMOFlipid once approved by the FDA. Extensive studies were conducted

across the age range from preterm neonates to critically ill elderly patients. The results were

black and white, showing the substantial benefits using a fish oil lipid emulsion in patients

critically ill. Biochemical labs were significantly reduced when patients received SMOFlipid and

as a result, total and direct bilirubin, triglycerides, and liver enzymes were drastically reduced,

while EPA, DHA and a-tocopherol (vitamin E) were drastically increased. Further proving the

benefits that this IVFE has.

However, it is important to note that one of these studies was co-sponsored by the maker

of SMOFlipid, Fresenius Kabi. This is a major limitation of the study that should be addressed

when assessing the accuracy of the results. Although this study had major success and was

meticulously conducted, the unconscious bias of the co-sponsors could have had the potential to

skew data or exclude information that could fabricate the results of SMOFlipid in practice.

Despite the research and convincing assessments of this particular IVFE, there are a few

key criticisms that may be preventing this product from entering clinical facilities across the U.S.

First off, researchers never mentioned the cost factor of this new, fourth generation lipid

emulsion in PN. In comparison to Intralipid (soybean oil IVFE) most commonly used in clinical

facilities, SMOFlipid costs $13.50 per 500mL, whereas Intralipid costs $11.25 per 500mL.

Although only a $2.25 difference, on a larger scale, it could be the difference between hundreds,

if not thousands of dollars spent, depending on the size of the clinical facility.
 Not only is this new alternative IVFE expensive on average, it can only be purchased in a

three-in-one otherwise known as total nutrient admixtures (TNA). This is a major set back to

this lipid emulsion since some facilities only use two-in-one PNs to have the flexibility of

hanging a third bag of lipid emulsions if needed. There is no flexibility with using TNA because

lipids, dextrose and amino acids are hung as one bag. Additionally, TNAs are commonly used in

stable patients on total parental nutrition (TPN), which is difficult to begin using TNA in

critically ill patients just starting off on nutrition support.

In addition to this IVFEs lack of flexibility in terms of packaging along with the

expense, it should also be noted this particular IVFE is most beneficial in critically ill patients.

Specifically, benefiting patients in the ICU, NICU or PICU. Therefore, smaller hospitals or

facilities without trauma or intensive care units would not need to purchase this IVFE since they

most likely do not have enough patients that would need it. Whereas, an acute trauma center

could benefit from having SMOFlipid in stock as they would go through it quick enough and

also have the potential to reduce length of stay or length of stay in the ICU.

To conclude, the use of SMOFlipid in clinical studies have shown a positive effect on

fatty acid profile, liver function including total and direct bilirubin, AST, ALT along with an

increase in DHA, EPA, a-tocopherol and a better balance of omega 6 to omega 3 fatty acid ratio.

Overall, SMOFlipid use in critically ill adults, and neonates have shown great tolerance and

safety throughout the above studies. Despite the lack of alternative IVFE use in clinical facilities

in the U.S. it is still a topic we as clinicians should ponder in practice. Although this IVFE may

be expensive, and subject to a particular patient demographic, should we not provide it based on

those factors? Or should we advocate for our critically ill patients who could benefit from

receiving this IVFE? Think about the preterm neonates, SMOFlipid could help prevent
cholestasis, or in the critically ill adults SMOFlipid could help reverse EFAD and support anti-

inflammation. The benefits are endless, and we as clinicians need to continue to advocate for our

patients when they dont have the voice themselves to do so.

Reference Page:

1. Anez-Bustillos, Lorenzo, et al. "Intravenous Fat Emulsion Formulations for the Adult and
Pediatric Patient: Understanding the Differences." Nutrition in Clinical Practice 31.5
(2016): 596-609.
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nutrition of intensive care patients: current thinking and future directions. Intensive Care
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3. Klek, Stanislaw, et al. Four-week parenteral nutrition using a third generation lipid
emulsion (SMOFlipid)a double blind, randomized, multicenter study in adults.
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outcomes in critically ill patients." Critical care medicine 42.5 (2014): 1168-1177.
5. Burrin, Douglas G., et al. "Impact of new-generation lipid emulsions on cellular
mechanisms of parenteral nutritionassociated liver disease." Advances in Nutrition: An
International Review Journal 5.1 (2014): 82-91.
6. Deshpande, Girish, et al. "Fish oil (SMOFlipid) and olive oil lipid (clinoleic) in very
preterm neonates." Journal of pediatric gastroenterology and nutrition 58.2 (2014): 177-
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undergoing gastrointestinal surgery." Journal of Parenteral and Enteral Nutrition 38.7
(2014): 800-808.
8. Ma, Cheng-Jen, et al. "A double-blind randomized study comparing the efficacy and
safety of a composite vs a conventional intravenous fat emulsion in postsurgical
gastrointestinal tumor patients." Nutrition in clinical practice 27.3 (2012): 410-415.