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Fish Oil (SMOFlipid) and Olive Oil Lipid (Clinoleic) in Very Preterm Neonates

Deshpande, Girish*; Simmer, Karen*; Deshmukh, Mangesh*; Mori, Trevor A.; Croft, Kevin D.; Kristensen, Judy

Journal of Pediatric Gastroenterology and Nutrition: February 2014 - Volume 58 - Issue 2 - p 177–182
doi: 10.1097/MPG.0000000000000174
Original Articles: Hepatology and Nutrition

Objectives: Fat emulsions used in Australia for parenteral nutrition in preterm neonates have been based on either soybean oil or olive oil (OO). OO lipid Clinoleic has a high ratio of n-6 to n-3 fatty acids (9:1); this may not be ideal for long-chain polyunsaturated fatty acids supply. Newly available SMOFlipid has an appropriate ratio of n-6 to n-3 fatty acids (2.5:1). SMOFlipid also contains OO (25%), coconut oil (30%), and soybean oil (30%). The aims of the study were to evaluate the safety of the SMOFlipid and to test the hypothesis that SMOFlipid would lead to increased omega-3 long-chain polyunsaturated fatty acid levels and reduced oxidative stress as compared with Clinoleic in preterm neonates (<30 weeks).

Methods: Preterm neonates (23–30 weeks) were randomised to receive Clinoleic or SMOFlipid emulsion for 7 days. Investigators and outcome assessors were masked to allocation. Plasma F2-isoprostanes (lipid peroxidation marker), red blood cell fatty acids, and vitamin E were measured before and after the study. Blood culture positive sepsis and growth were monitored for safety.

Results: Thirty of 34 participants completed the study. Both emulsions were well tolerated without any adverse events. F2-isoprostane levels were reduced in the SMOFlipid group as compared with baseline. Eicosapentanoic acid and vitamin E levels were significantly increased in the SMOFlipid group. Oleic acid and linoleic acid levels were increased in both groups. No significant differences were noted in poststudy docosahexaenoic acid levels in both groups despite higher levels of docosahexaenoic acid in SMOFlipid.

Conclusions: SMOFlipid was safe, well tolerated, and showed beneficial effect in terms of reduction of oxidative stress by reducing lipid peroxidation levels in high-risk preterm neonates.

*Department of Neonatal Paediatrics, King Edward Memorial Hospital Western Australia

School of Medicine and Pharmacology, University of Western Australia

Department of Pharmacy, King Edward Memorial Hospital for Women, Perth, Australia.

Address correspondence and reprint requests to Dr Girish Deshpande, FRACP, MSc (e-mail:

Received 1 February, 2013

Accepted 27 August, 2013

Abstract presented at the following meetings: oral presentation at PSANZ 2012 (published as an abstract in J Paediatr Child Health 2012; 48: A143), oral presentation at PAS/SPR 2012 (published in Proc SPR/PAS 2012, abstr no. 2775.4).

This study was funded by a new investigator research grant from the Women's and Infant's Research Institute (grant no. RG510).

Australia New Zealand clinical trial registration no. ACTRN12609001017213.

G.D., K.S., T.A.M., and K.D.C. have received partial funding from Fresenius Kabi and Baxter Health Care for 2 similar studies. Both trials are investigator-initiated trials and none of the companies had any influence on design, conduct, and reporting of the trials. The other authors report no conflicts of interest.

In the postsurfactant era, survival of high-risk preterm neonates has improved significantly. Postnatal growth restriction is an extremely significant issue in these neonates related mainly to feed intolerance and necrotising enterocolitis. Long-term parenteral nutrition (PN) is crucial for this population of neonates to provide optimal nutrition at a critical stage of development (1). Lipid emulsion is an important component of PN, being a concentrated source of energy, essential fatty acids (EFAs), and of long-chain polyunsaturated fatty acids (LC-PUFAs), whose endogenous synthesis is extremely limited (2).

Depending on their structure, lipid emulsions also influence immune cell functions at various levels, including cell membrane properties, phagocytosis, and production of bioactive substances such as cytokines (3).

Lipid emulsions based on soybean oil (SO) are still commonly used; however, more recently, many neonatal units including Australian units have switched to olive oil (OO)–based lipid emulsions (OL) (4,5). SO is rich in omega-6 PUFAs such as linoleic acid (LA) with the potential to increase lipid peroxidation and inflammation. OL (Clinoleic) are rich in monounsaturated fatty acids (MUFAs) and have a higher omega-6:omega-3 ratio because of the lower omega-3 PUFAs content (9:1), which may not be ideal for supporting the needs of a developing infant (6,7).

A novel lipid emulsion SMOFlipid is based on a mixture of SO (30%), medium-chain triglycerides (30%), OO (25%), and fish oil (FO) (15%), which provides a good source of EFA, energy, MUFAs, and omega-3 fatty acids, respectively. It is also supplemented with antioxidant α-tocopherol (200 mg/L), and has a lower omega-6:omega-3 ratio (2.5:1) (8,9) (Table 1).



The potential advantages of the new lipid emulsions are rapid lipid clearance, reducing the risk of cholestasis; reduced oxidative stress; reduced lipid peroxidation and presence of appropriate amounts of antioxidant α-tocopherol and MUFAs, and provision of essential LC-PUFAs, which are critical in neonatal neurodevelopment and vision; an optimal omega-6:omega-3 ratio and reduced immune activity; and anti-inflammatory effects because of its omega-3 PUFA content (9–16). We hypothesised that the SMOFlipid emulsion (FO–based emulsion) would lead to increased omega-3 LC-PUFA levels and reduced oxidative stress in high-risk preterm neonates dependent on PN support as compared with an OL.

The aim of this double-blind randomised controlled trial (RCT) in a regional tertiary neonatal intensive care unit (King Edward Memorial Hospital for Women) was to compare the efficacy (increased LC-PUFA) and safety of the FO emulsion with OL in preterm neonates with gestation <30 weeks.

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Inclusion criteria are preterm neonates (<30 weeks) admitted in the neonatal unit at the Princess Margaret Hospital for Children, requiring PN providing >75% of energy expenditure requirements for ≥7 days; postnatal age <7 days. Exclusion criteria were blood culture positive sepsis; thrombocytopenia (platelet count <150 × 109 cells/L); unconjugated hyperbilirubinemia (requiring exchange transfusion); metabolic disorders including lactic and/or uncompensated acidosis; no parenteral consent; administration of intravenous lipid infusion before study; postnatal age >7 days; bleeding disorder.

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Study Protocol

Institutional ethics approval (King Edward Memorial Hospital for Women: 1674/EW), Therapeutic Goods Administration Australia notification (during the study period SMOFlipid was approved for paediatric use only in Australia), and written informed parental consent were obtained before enrolment by the research fellow or the research nurse.

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Randomisation, Allocation Concealment, and Blinding

The coordinating pharmacist who was not directly involved in patient care randomised neonates (by using a computer-generated randomization list) prepared coded ready-to-use syringes of either OO (20% Clinoleic Baxter, S.A. Belgium) or FO (20% SMOFlipid Fresenius Kabi, Pymble, Australia) lipid emulsion (Table 1). Given this strategy and the identical appearance of the coded, ready-to-use identical syringes, the researcher and other team members were blinded to the allocation status and the content of syringes.

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Lipid Infusion Dosages, Duration, and Administration

The dose protocol (20% Clinoleic or 20% SMOFlipid) was day 1, 1 g · kg−1 · day−1; day 2, 2 g · kg−1 · day−1; day 3, 3 g · kg−1 · day−1; and day 4 to 7, 3 g · kg−1 · day−1. The duration of study was 7 days, after which all of the participants received Clinoleic lipid emulsion, which is the present standard of practice in the nursery. Intravenous lipids were continued as long as PN support was determined necessary by the attending neonatologist. The emulsions were dispensed in amber-coloured coded syringes and amber-coloured infusion lines suitable for infusion pumps and infused intravenously through a central or peripheral line.

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Routine Management

The nature and standard of day-to-day care was common to all enrolled neonates as per unit policy. Enrolled neonates received starter total PN solutions containing 10% glucose and amino acids (Primene, Baxter Health Care, Old Toongabbie, Australia) as soon as possible and lipids were added the next day as per the study protocol. Participants received standard trace elements and vitamins (Cernivit Baxter/Clintec Parenteral, Montargis, France) in PN as per the unit policy. Minimal enteral feeds were introduced early followed by a standardised enteral feeding regimen. Neonates receiving enteral energy >25% of total energy intake at any time were withdrawn from the trial.

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Primary outcomes were levels (mean ± standard deviation [SD]) of LC-PUFA in red cell membrane and lipid peroxidation status measured by plasma F2-isoprostane levels (mean ± SD) as picomole per litre. Secondary outcomes were weight, head circumference, and length at birth at study entry, exit, and at discharge; enteral versus PN proportion; number of episodes of blood culture positive sepsis; intraventricular haemorrhage; duration of hospital stay, mechanical ventilation, and PN support; mortality; and vitamin E levels.

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Laboratory Observations

Red blood cell (RBC) membrane fatty acid levels and plasma F2-isoprostane levels were measured on a 1-mL blood sample (ethylenediaminetetraacetic acid tube) taken before and at the end of the study period as per the method described previously (17,18). Plasma vitamin E level was measured by high-performance liquid chromatography in the Path West laboratory (Queen Elizabeth II Medical Centre, Perth, Western Australia). Routine blood investigations as part of intensive care such as full blood cell count, C-reactive proteins, urea, creatinine, electrolytes, and bilirubin levels were recorded.

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Statistical Considerations

Primary endpoints in the evaluation of efficacy of the lipid emulsions were RBC omega-3 LC-PUFA (eicosapentanoic acid [EPA], docosahexaenoic acid [DHA]) levels (percentage of total fatty acids) and plasma F2-isoprostanes (picomoles per litre). Based on the baseline levels of omega-3 LC-PUFA and F2-isoprostanes, our previous trials (4) reported estimated sample size of 15 neonates per group to allow detecting a difference of 1 SD in RBC omega-3 LC-PUFA levels and plasma F2-isoprostanes between the study groups with 90% power when using a univariate t test with a significance level of 0.05 (PASS 2008, Power and Sample Size Program for Windows, Kaysville, UT).

The data were analysed without breaking the code to ensure masking of statistical analysers. The analysis was based on the principle of intention to treat. Descriptive statistics of continuous data was based on means and SD. Harmonic mean was used where distribution was non-normal with high SDs. Categorical data were summarised using frequency distributions. Baseline comparisons between the 2 groups were performed by using univariate t test and Mann-Whitney test depending on normality of distribution. A similar principle was used to compare the day 8 versus the baseline levels of fatty acids and F2-isoprostanes in the individual groups. Analysis of variance was used to compare the difference between day 8 levels of F2-isoprostanes, fatty acids, and selected safety biochemical indicators across treatment groups after adjusting for baseline values. STATA 9.1 (StataCorp, College Station, TX) software was used to conduct statistical analyses.

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During the study period (January 2010–June 2011), 125 preterm neonates (younger than 30 weeks) were admitted at KEMH. Details of patient flow are shown in Figure 1. We could not enrol the neonates during the weekend/public holidays because of the unavailability of a research pharmacist who could randomise and prepare the syringes for study lipids. Hence, 55 parents could not be approached. Four neonates, 2 in each group, did not receive the full 7 days of study lipids because enteral feeds were tolerated quickly. Therefore, 2 additional neonates were enrolled in each group and all 34 neonates were analysed according to the intention-to-treat principle. There were no significant differences between groups in the baseline characteristics and secondary outcomes (Tables 2 and 3), including gestation, ventilation, sepsis, total energy intake, enteral and PN proportion, total lipid intake, and anthropometry. Baseline plasma F2-isoprostane levels were similar in both groups (Table 4); however; day 8 F2-isoprostane levels were significantly reduced in the FO group as compared with OL after adjusting for baseline levels (FO: 2051.7 [377.6]; OL: 2642.8 [738.6]; P = 0.037). Baseline RBC fatty acid levels (Table 4) were comparable in both groups (except C22:5n6 levels, which were significantly higher in the FO group). Poststudy day 8 RBC linoleic and oleic acids were increased in both groups and were comparable. Mean day 8 EPA levels were reduced in the OL group as compared with baseline; however, in the FO group day 8, EPA levels increased as compared with baseline and the difference was statistically significant as compared with the OL group (FO: 2.29 [0.81] vs OL: 1.07 [0.38]; P = 0.0001). Other LC-PUFA levels on day 8 including arachidonic acid (AA) and DHA were reduced as compared with baseline and similar in both groups. Day 8 plasma vitamin E levels were increased in both groups; however, they were significantly higher in the FO group (FO: 123.25 [50.01]; OL: 84.6 [32.98]; P = 0.009).









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Safety Analysis

There were no significant differences between the groups in measures of biological safety, including blood urea nitrogen, creatinine, electrolytes, total bilirubin, and conjugated billirubin. Liver enzymes (alanine transaminase and γ-glutamyl transferase) were not significantly different and within the normal range in both groups. Full blood cell counts, including platelet count, C-reactive protein, and blood culture positive sepsis, were not significantly different in both groups. There were no significant differences in weight, head circumference, and total length at baseline and at the end of the study. Total lipid intake during 7 days was similar in both the groups (Table 3).

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SO lipid emulsions have been a major component of neonatal PN for decades; however, there are concerns about its excess PUFA and low vitamin E content in these emulsions (9,19,20). OO emulsions are rich in MUFAs, vitamin E, and reduced in PUFAs compared with SO emulsions (8). In addition to MUFA-rich OO, SMOFlipid has omega-3 fatty acids and has a higher vitamin E concentration, which could be beneficial to reduce oxidative stress in high-risk preterm neonates and provide much-needed omega-3 LC-PUFAs such as DHA and EPA; however, there is little information available on the safety and efficacy of FO-based lipid emulsions in very preterm neonates. To our knowledge, this is the first study comparing OL and FO-based lipid emulsions in very preterm neonates, who are at a higher risk for oxidative stress and need longer-term PN.

One of the primary outcomes of our study was to examine the effect on oxidative stress in preterm neonates. Preterm neonates are particularly vulnerable to the effects of oxidative stress because they are exposed to an environment that includes ventilation, oxygen, and nosocomial infections and they have an immature antioxidant system as compared with term infants. High levels of oxidative stress in preterm neonates are typically seen in conditions such as chronic lung diseases, retinopathy of prematurity, periventricular leucomalacia, and necrotising enterocolitis (11). Plasma F2-isoprostanes were used as a marker of in vivo oxidative stress and lipid peroxidation because they are specifically formed by free radical–catalysed peroxidation of arachidonic acid and hence considered reliable compared with other markers (21–23). F2-isoprostanes levels were extremely high at baseline (OO: 2630.8 [604.79] vs FO: 2818 [698.1]) compared with a study in term neonates indicating an extreme oxidative stress in the immediate postnatal period (24). On day 8 of the study, after adjusting for baseline levels, F2-isoprostane levels were significantly lower in the FO group (OO: 2642.8 [738.6] vs FO: 2051.7 [377.6]) as compared with the OL group. These findings were different as compared with another study comparing SMOFlipid and Intralipid (SO-based lipid emulsion in preterm neonates [<34 weeks but >1000 g]) (25). In a similar study by Skouroliakou et al (26), 38 preterm neonates (gestation <32 weeks, birth weight <1500 g) were randomised to receive SMOFlipid emulsion or Intralipid for at least 7 days. Significant reduction in oxidative stress in the SMOFlipid group was documented by a significant rise in α-tocopherol and total antioxidant potential levels compared with standard Intralipid.

There could be several reasons for this potential benefit in reducing oxidative stress in very preterm neonates. Poststudy levels of vitamin E were significantly higher in the FO group, and vitamin E is well known for significant anti-inflammatory properties (27). It is also well documented that preterm very-low-birth-weight neonates have vitamin E deficiency (28). Also, SMOFlipid has high levels of omega-3 LC-PUFAs, including EPA and DHA. In our study, day 8 levels of EPA were significantly higher as compared with the OL group. Omega-3 LC-PUFAs including EPA are known to stimulate an anti-inflammatory response (16). Owing to limitations of the amount of blood we could draw from very preterm neonates, we could not perform any immunological studies. In a randomised clinical trial involving critically ill postoperative adult patients, Schade et al (29) have evaluated the efficacy of OL (Clinoleic) and SMOFlipid emulsions. The levels of proinflammatory cytokines such as interleukin-6 and tumour necrosis factor-α were significantly lower in the SMOFlipid group as compared with Clinoleic.

In our study, both lipid emulsions were found to be safe and well tolerated by very preterm neonates without any adverse effects. There were no significant changes in renal function or haematology. Several observational studies have shown beneficial effects of FO-based lipid emulsions in the treatment of neonatal cholestasis because of prolonged PN (30–32). Our study was not designed to look at preterm neonates requiring long-term PN; however, there was no significant difference in liver enzymes or conjugated bilirubin levels in both groups, and they were within normal limits.

LC-PUFAs such as DHA and AA have an important role in the neurodevelopment and vision of preterm neonates, but their endogenous synthesis is extremely limited (2,33). The majority of the DHA accretion occurs in the last trimester of pregnancy, which preterm neonates may not receive (34). Although SMOFlipid has much higher levels of DHA and EPA compared with Clinoleic, there was no significant difference in day 8 poststudy levels of RBC DHA levels in both groups. This can be explained by 2 different mechanisms. First, there may be relatively poor tissue uptake in preterm neonates. We did not have enough plasma to measure plasma DHA levels to prove this hypothesis; however, RBC EPA levels were significantly higher in the SMOFlipid group, so this proves relatively good EPA tissue uptake. The second possibility is that very preterm neonates may have a significantly high requirement of DHA than previously thought and the amount of DHA in SMOFlipid was not enough to influence RBC DHA during study duration (35). This seems a more reasonable explanation. A randomised clinical trial in postoperative adults comparing SMOFlipid and SO-based lipid emulsion for 5 days documented significantly higher levels of DHA in the SMOFlipid group (15). Some experts, however, have argued that blood cells including RBCs may not be suitable for evaluating overall DHA status because they may not reflect the actual intake (26). There is an urgent need to search for a better model to study tissue uptake of LC-PUFAs in preterm neonates.

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The standard Clinoleic and the new SMOFlipid emulsion were safe and well tolerated in very preterm (gestation <30 weeks) neonates during the study period. Beneficial effects in terms of significant reduction in oxidative stress levels were noted in high-risk preterm neonates. Poststudy RBC EPA levels and vitamin E with anti-inflammatory properties were significantly higher in the SMOFlipid group; however, there was no difference in DHA levels. Further research is required to study the specific effects of fish oil-based lipids on the immune systems of high-risk preterm neonates and the long-term effects on neurodevelopmental outcomes.

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intravenous; isoprostanes; lipid emulsions; parenteral nutrition; premature infants

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