How does SMOFlipid compare to Intralipid for hospitalized patients on TPN?

Comment by InpharmD Researcher

There is limited evidence examining the use of SMOFlipid compared to Intralipid in total parenteral nutrition (TPN) for hospitalized patients. Due to SMOFlipid’s oil-blend components, it may provide positive immunomodulatory and anti-inflammatory effects in contrast to Intralipid, where its high ω-6 fatty acid content may lead to a greater risk of inflammation and immunosuppression. SMOFlipid’s lipid components may also translate to hyperlipidemia prevention, improved liver function, and shorter hospital stays without an increased risk of bleeds and coagulation. However, identified studies are mainly retrospective in nature, and have either found no difference between the use of SMOFlipid or without, or have reported mixed outcomes.

Background

The American Society for Parenteral and Enteral Nutrition (ASPEN) published 2020 recommendations regarding the safe use of lipid injectable emulsions. The optimal blend of oils for critically ill patients remains uncertain. However, there is a growing consensus that a blend of oils to create a lower ratio of ω-6 and ω-3 polyunsaturated fatty acids (PUFA) has been suggested. When compared to SMOFlipid, the oil source of Intralipid is primarily comprised of soybean (100%), while SMOFlipid is a four-oil blend (soybean 30%; medium-chain triglycerides 30%; olive oil 25%; fish oil 15%). Intralipid has been associated with a greater risk of inflammation and immunosuppression, supposedly due to its high ω-6 FA content. The ω-3-to-ω-6 PUFA ratio for SMOFlipid is stated to be 2.5:1, while the ratio for Intralipid is 7:1. Because of this, ASPEN recommends that once critically ill patients are stable, it may be reasonable to switch from soybean oil lipid emulsion to the oil-blend emulsion (i.e., SMOFlipid). Even though Intralipid contains only soybeans, the risk of cross-reactivity means it shares similar contraindication warnings with SMOFlipid due to hypersensitivity (e.g., allergy to soy, peanuts, fish, and eggs). Unfortunately, further discussion seems limited regarding the pros and cons for individual lipid emulsions. [1]

A 2021 meta-analysis was conducted to assess the SMOFlipid with other lipid agents in hospitalized patients, including Intralipid, Lipoven, ClinOleic, Lipofundin, and Lipovenoes. The combination of oils in the SMOFlipid is stated to optimize the ω-3-to-ω-6 PUFA ratio, which could translate to less potent inflammatory effects. ω-3 PUFA produces intracellular signaling molecules that possess pro- or anti-inflammatory effects compared to ω-6 PUFA, which tends to develop strictly pro-inflammatory cytokines. While the meta-analysis did not exclusively compare between SMOFlipid and Intralipid, the overall results suggest that SMOFlipid is prone to prevent hyperlipidemia with no difference in adverse events compared to the other lipids. SMOFlipid may also reduce the hospital's length of stay. How these outcomes would differ in patients who are on concomitant total parenteral nutrition (TPN) is uncertain. [2]

According to a 2018 article, SMOFlipid provides several potential pros over Intralipid for critically ill patients requiring parenteral nutrition. SMOFlipid contains multiple fatty acid sources, including omega-3 fish oil, which has been reported to provide positive immunomodulatory and anti-inflammatory effects that help reduce the length of hospital stay and nosocomial infections. Several reports cited demonstrated benefits of SMOFlipid use, including improved liver function and lowering of liver enzymes. While a few minor studies found no differences or were mixed, the article presented largely positive findings on the clinical impact from the use of SMOFlipid. Despite the higher cost of SMOFlipid versus Intralipid, evidence from pharmacoeconomic analyses suggest reduced overall treatment expenses driven by shorter hospitalizations. [3]

Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

What are the pros and cons of SMOFlipid over Intralipid for hospitalized patients on TPN?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-5 for your response.

SMOFlipid vs Intralipid 20%: Effect of Mixed-Oil vs Soybean-Oil Emulsion on Parenteral Nutrition–Associated Cholestasis in the Neonatal Population
Design	Single-center, retrospective, cohort study N= 136
Objective	To compare the incidence of parenteral nutrition (PN)-associated cholestasis (PNAC) in patients admitted to the neonatal intensive care unit (NICU) who received either Intralipid 20% or SMOFlipid
Study Groups	Intralipid group (n= 55) SMOFlipid group (n = 81)
Inclusion Criteria	NICU patients who received PN for ≥ 14 days
Exclusion Criteria	Diagnosis of cytomegalovirus, preexisting hepatobiliary disease, chromosomal disorders, or inborn errors of metabolism After initial IRB approval, an amendment was submitted to remove the exclusion criteria of receiving 1 or more blood transfusions and diagnosis of neonatal sepsis from the protocol to increase sample size and improve external validity.
Methods	Patient demographics, diagnoses, and laboratory values were obtained from the electronic medical record. Patients who received SMOFlipid (SO, MCT, OO, FO-ILE) were compared with those who received Intralipid (SO-ILE). The incidence of PN-induced cholestasis was defined as direct bilirubin > 2 mg/dL, or direct bilirubin > 20% of total bilirubin, when total bilirubin is > 5 mg/dL, on or before 30 days post initiation of PN.
Duration	June 2014 to October 2018
Outcome Measures	Primary: incidence of PNAC Secondary: prevalence of elevated liver function tests; effect on select laboratory parameters; development of PNAC by age; and incidence of retinopathy of prematurity (ROP)
Baseline Characteristics		Intralipid group (n= 55)	SMOFlipid group (n = 81)
	Gestational age at birth, wk ≤24 24.1–26 26.1–28 28.1–30 30.1–32 ≥32.1	11 11 10 9 4 10	8 21 24 11 9 8
	Female	22	35
	Birth height, cm (P25–P75)	35.1 (32.3–41.1)	35.1 (32.5–38.1)
	Birth weight, kg (P25–P75)	0.9 (0.7–1.6)	0.9 (0.8–1.2)
	Race White African American Unavailable	46 1 6	49 1 29
	Median LOS, days	80 (24–143)	87 (18–160)
	Diagnoses during hospital stay Congenital duodenal atresia Hemolytic disease Sepsis	5% 2% 29%	1% 0 30%
	LOS, length of stay; P25, 25th percentile; P75, 75th percentile
	Weight at baseline (p= 0.96), 14 days (p= 0.51), and 30 days (p= 0.34) was not statistically different between groups. There were also no differences found at the beginning of therapy, after 2 weeks of therapy, and at 30 days for median serum albumin or platelet levels. Most patients that developed PNAC were 28 weeks of age or younger when PN was initiated, apart from 2 patients that received Intralipid therapy beginning at >32.1 weeks of age. ROP diagnoses trended higher in the SMOFlipid group (27 of 81 patients, 33.3%) when compared with the Intralipid group (12 of 55 patients, 21.8%); however, this was not a statistically significant difference (p= 0.18).
Results	Endpoint	Intralipid group (n= 55)	SMOFlipid group (n = 81)	p-value
	Direct bilirubin > 2 mg/dL before 30 days post TPN initiation	5 (9.1%)	2 (2.5%)	0.12
	Direct bilirubin > 20% of T bili	7 (12.7%)	2 (2.5%)	0.03
	Cholestasis (composite)	9 (16.4%)	2 (2.5%)	0.007
	Prevalence of elevated liver function tests ^a Elevated at baseline Elevated at 14 days Elevated at 30 days	20 (36.4%) 2 (3.6%) 6 (10.9%)	13 (16.0%) 7 (8.6%) 5 (6.2%)	0.008 0.31 0.35
	^aDefined as alanine transaminase (ALT) or aspartate transaminase (AST) > 55 IU/L in females and ALT/AST > 60 IU/L in males.
Adverse Events	See results
Study Author Conclusions	Use of SMOFlipid as the lipid emulsion component of PN may be beneficial in prevention of PNAC in NICU patients that are receiving PN for ≥2 weeks.
InpharmD Researcher Critique	Study limitations include modified exclusion criteria (e.g., sepsis, blood product use) due to practical challenges. Over the four-year study, changes in the electronic medical record system and ICD coding, along with diverse practices among over 30 weekly NICU providers, may have introduced potential confounders. Notably, total lipid and enteral nutrition during the transition from parenteral nutrition were not assessed, restricting conclusions on these variables between groups.

References:

Jackson RL, White PZ, Zalla J. SMOFlipid vs Intralipid 20%: Effect of Mixed-Oil vs Soybean-Oil Emulsion on Parenteral Nutrition-Associated Cholestasis in the Neonatal Population. JPEN J Parenter Enteral Nutr. 2021;45(2):339-346. doi:10.1002/jpen.1843

SMOFlipid versus Intralipid in Postoperative ICU Patients
Design	Prospective, randomized, double-blinded study (Egypt) N= 83
Objective	To study the effect of traditional Intralipid versus SMOFlipid on interleukin-6 in postoperative patients needing total parenteral nutrition (TPN)
Study Groups	Intralipid (n= 42) SMOFlipid (n= 41)
Inclusion Criteria	Admitted to the surgical intensive care unit
Exclusion Criteria	Allergy to egg, soybean protein, or other content of the lipid emulsion; general contraindication to parenteral therapy; pregnancy or breastfeeding; severe coagulopathy; shock; diabetes mellitus with ketoacidosis presented within 7 days; abnormal renal or liver function; type IV hyperlipidemia, disorder of lipid metabolism, or hypertriglyceridemia (>354 mg/dL); unconsciousness or uncooperativeness
Methods	Patients were randomized to group 1, which is the use of Intralipid 20% (Fresenius Kabi Deutschland GmbH, Bad Homburg vor der Höhe, Germany; control group) or group 2, which is the use of SMOFlipid 20% emulsion (Fresenius Kabi Deutschland GmbH; experimental group). Postoperatively, all patients received parenteral nutrition > 7 consecutive days through a peripheral or indwelling central venous catheter. Infusion pumps provided glucose, aminoacids, vitamins, and trace elements to both groupos for 12-16 h daily. Fat content did not exceed 1.5 g/kg/day. The lipid emulsions were given separately with the infusion pump to control the infusion duration for 12-16 h (not to exceed 0.125 g/kg/h). The nutrition in both groups was isonitrogenous and isocaloric.
Duration	Between September 2012 and April 2014 Follow-up: 1 month
Outcome Measures	Clinical outcomes, laboratory parameters, IL-6 levels
Baseline Characteristics		Intralipid (n= 42)	SMOFlipid (n= 41)
	Age, years	58.2 ± 11.3	56.8 ± 10.8
	Female	47.67%	43.9%
	Body mass index, kg/m2	28.1 ± 2.1	27.9 ± 1.9
	SAPS II	46.7 ± 5.2	43.5 ± 4.8
	Organ failure score	8.7 ± 1.1	8.9 ± 1.3
	Abbreviations: SAPS, Simplified Acute Physiology Score
Results	Vital signs, lipid profile, IL-6 measurement	Measurements between groups for baseline values, values at day 4, and values at day 7 were all non-significant with the exception of IL-6, which showed a non-significant difference between both study groups at admission, but showed a significantly lower level at day 4 of admission (p< 0.05) and highly significant lower level at day 7 of admission (p< 0.01) in the SMOF group vs. the Intralipid group. Levels of IL-6 were depicted in a chart.
	Routine laboratory parameters	Measurements between groups for baseline values, values at day 4, and values at day 7 were all non-significant.
	Clinical outcomes	The clinical outcomes included duration of ventilation, days of ICU stay, days of hospital stay, 1 week mortality, and 1 month mortality. Measurements between groups showed a non-significant difference.
Adverse Events	Not disclosed
Study Author Conclusions	On comparing intralipid versus SMOFlipid, we have discovered that SMOFlipid group showed low level of IL6 which is as a single agent gives an indication of reduced inflammatory response with SMOFlipid but with a weak proof and need more studies for bigger scale of inflammatory indicators.
InpharmD Researcher Critique	The sole use of IL-6 markers to gauge inflammation may be a factor to the non-significance found between groups. Additionally, the small sample size and the patient population (surgical patients with a short-term hospitalization period) reduce the generalizability of these results to hospitalized patients overall.

References:

Metry AA, Abdelaal W, Ragaei M, Refaat M, Nakhla G (2014) SMOFlipid versus Intralipid in Postoperative ICU Patients. Enliven: J Anesthesiol Crit Care Med 1(6): 015.

Change From Intralipid To SMOF Lipid Is Associated With Improved Liver Function In Infants With PN Associated Liver Disease
Design	Retrospective cohort review (United Kingdom) N= 14
Objective	To investigate the effects of a change in lipid formulation, from Intralipid (IL) to SMOF, on liver function in infants with parenteral nutrition-associated liver disease (PNALD)
Study Groups	Study cohort (N= 14)
Inclusion Criteria	Infants with PNALD (conjugated bilirubin [CB] >50 μmol/L) commenced initially on IL and subsequently changed to SMOF, as per Unit protocol
Methods	This retrospective analysis was carried out after a preliminary pilot study. Data were gathered by reviewing infant case notes.
Duration	N/A
Outcome Measures	Liver function (CB, AST, ALT levels, and the change in each of these per week: ΔCB, ΔAST, ΔALT) before and after the change in lipid
Baseline Characteristics		Study cohort (N= 14)
	Gestation age, weeks (median)	29 (24 to 40)
	Birth weight, kg	1.23 (0.53 to 3.66)
	Duration of parenteral nutrition, days (median)	89 (19 to 212)
	Median age at change from IL to SMOF, days	50 (22 to 142)
Results	Endpoint	Study cohort (N= 14)
		Pre SMOF	2 weeks of SMOF	4 weeks of SMOF
	Change per week, umol/L/week Change in CB Change in ALT Change in AST	12.2 ± 13.3 13.2 ± 21.9 6.61 ± 32.2	0.3 ± 13.9* 24.7 ± 78.8 35.3 ± 130.6	−0.6 ± 10.6* 0.24 ± 11.6 0.24 ± 11.6
	Mean level, umol/L CB ALT AST	80.7 ± 30.4 158 ± 337 317 ± 781	79.8 ± 24.7 95 ± 142 152 ± 269	87.5 ± 29.0 60 ± 42 78 ± 36
	*p< 0.05 compared to Pre SMOF
Adverse Events	Not disclosed
Study Author Conclusions	Change from IL to SMOF was associated with improved liver function in infants with PNALD. This data supports the use of SMOF in infants requiring long-term PN therapy to minimize PNALD. Further study is required to determine the optimum timing for the commencement of SMOF use
InpharmD Researcher Critique	The trial's retrospective design introduces the risk of recall and or reporting bias. The single-center design and small sample size may limit the generalizability of the results. It is also important to note that only the abstract was available for data extrapolation.

References:

Attard MI, Patel N, Simpson J. Change from intralipid to SMOF lipid is associated with improved liver function in infants with PN associated liver disease. Archives of Disease in Childhood. 2012;97(Suppl 1):A54.2-A55. doi:https://doi.org/10.1136/archdischild-2012-301885.132

The impact of a lipid injectable emulsion (SMOF) on conjugated bilirubin levels in children receiving prolonged parenteral nutrition: A large single center experience
Design	Retrospective chart review N= 150
Objective	To compare the impact of SMOFlipid on conjugated bilirubin (CB) levels in children receiving prolonged parenteral nutrition (PN)
Study Groups	Intralipid (n= 72) SMOFlipid (n= 88)
Inclusion Criteria	Infants (< 1 year old) admitted to the hospital and treated with PN, have received either lipid emulsions for ≥ 28 consecutive days
Exclusion Criteria	Not disclosed
Methods	Medical charts of all infants treated with Intralipid or SMOFlipid were reviewed. Intravenous lipid emulsion (ILE) initiation, ranging from 1.0 to 2.0 g/kg/day, began either on the first day of life or upon admission. Progression with other macronutrients aimed to meet complete requirements, capped at 3.5 g/kg for both products. Cholestasis was defined as conjugated bilirubin elevation (>3.0 μmol/L). Weekly PN blood work was done, covering triglycerides, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), CB, pre-albumin, albumin, electrolytes, and blood gases. Monthly monitoring included vitamins and trace elements. Elevated triglycerides (>3 mmol/L) led to a temporary lipid emulsion halt (6–24 hours), resuming below 3 mmol/L. If CB exceeded 50 μmol/L, the lipid emulsion shifted to Omegaven® (1 g/kg/day) and Intralipid (1 g/kg/day). Persistent cholestasis resulted in complete Intralipid discontinuation, with close monitoring for essential fatty acid deficiency.
Duration	January 2012 to September 2013 (Intralipid) October 2013 to December 2016 (SMOFlipid)
Outcome Measures	CB levels at the end of ILE administration, the safety of SMOFlipid as the primary ILE
Baseline Characteristics		Intralipid (n= 72)	SMOFlipid (n= 88)
	Birth weight, kg	1.88	1.68
	Gestational age, weeks	33.1	33.3
	Female	51%	42%
	Total days on lipid emulsion	39	35
	Main diagnosis Prematurity Gastrointestinal Respiratory Cardiac Neurologic Genetic Hematologic	7% 37% 8% 15% 12.5% 7% 8%	25% 21.5% 16% 17% 10% 4.5% 2.5%
Results	Endpoint	Intralipid (95% CI)	SMOFlipid (95% CI)
	Incidence of cholestasis	4.5%	20%
	Final conjugated bilirubin levels comparison *	Adjusted mean: 2.5 (2.1 to 2.8) Geometric mean: 12.2 (8.2 to 16.4) n= 73	Adjusted mean: 2.0 (1.7 to 2.2) Geometric mean: 7.4 (5.5 to 9.0) n= 74
	CI, confidence interval * The geometric mean ratio between the groups was 1.7 (95% CI 1.1 to 2.6; p= 0.02).
Adverse Events	No children were managed by a lipid-restriction protocol, and no adverse events were observed with the use of SMOFlipid.
Study Author Conclusions	In a large and heterogenous group of infants receiving PN for ≥28 consecutive days the final levels of CB were significantly lower with SMOFlipid when compared to Intralipid suggesting a protective role of this type of ILE in this high-risk population.
InpharmD Researcher Critique	The study's limitations include its retrospective design, a heterogeneous population, and variability in lipid doses (average 2.5 g/kg/day). Despite no significant differences in lipid intake, the lower final conjugated bilirubin in the SMOFlipid group raises questions about dose impact. Inconsistent data on bilirubin levels before parenteral nutrition initiation, uncertainties in enteral feed progression, and the absence of information on essential fatty acid deficiency are additional limitations. However, the study is notable for representing a large cohort of patients receiving parenteral nutrition for ≥ 28 consecutive days with similar lipid doses, demonstrating a significant benefit of SMOFlipid on conjugated bilirubin levels during prolonged intravenous lipid emulsion administration.

References:

Navaratnarajah N, Girard G, Sant'Anna G, Langlois H, Sant'Anna AM. The impact of a lipid injectable emulsion (SMOF) on conjugated bilirubin levels in children receiving prolonged parenteral nutrition: A large single center experience. Clin Nutr ESPEN. 2022;49:289-294. doi:10.1016/j.clnesp.2022.03.036

Comparative study of the safety and efficacy of SMOFlipid vs non SMOFlipid as TPN for liver transplantation
Design	Retrospective chart review (Taiwan) N= 54
Objective	To evaluate the effect of the SMOFlipid supplement in total parenteral nutrition (TPN) in liver transplant (LT) patients
Study Groups	SMOFlipid group (n= 31) Non-SMOFlipid group (n= 23)
Inclusion Criteria	Aged > 18 years, TPN that was provided in the last 14 days during the peri-transplantation period
Exclusion Criteria	Well-tolerated oral intake, TPN supplement that was discontinued within 10 days, renal dysfunction
Methods	At the institution, TPN and SMOFlipid support were indicated for patients who received nothing by mouth > 3 days. SMOFlipid was discontinued when the platelet count decreased to 40,000/μL or less. Thus, patients who had a pretransplant platelet count < 40,000/μL were assigned to the non-SMOFlipid group, and patients who had a count > 40,000/μL were assigned to the SMOFlipid group. The aPTT level was maintained between 1.5 and 2 times the normal controlled level with heparin for at least 10-14 days. Oral administration of dipyridamole 75 mg four times daily for 3 months was indicated for stimulation of antiplatelet activity when the platelet count increased to ≥ 40,000/μL. Postoperatively, methylprednisolone, tacrolimus, basiliximab, and mycophenolate mofetil were used. Antithrombotic treatment consisted of heparin and PGE1 use for the first 7–14 days.
Duration	Between January 2012 and June 2015 Follow-up: 30 days
Outcome Measures	Coagulation parameters
Baseline Characteristics		SMOFlipid group (n= 31)	Non-SMOFlipid group (n= 23)
	Age, years	53.54 ± 11.77	54.07 ± 10.20
	Female	14	12
	Severity of disease Child-Pugh Score A B C MELD Score	8 12 11 21.42 ± 8.547	5 5 13 23.11 ± 9.42
	Indication of TPN Prolonged NPO Poor oral intake Other	14 13 4	9 11 3
	ICU stay, days	27.81 ± 16.67	28.57 ± 18.56
	Hospital stay, days	89.94 ± 60.89	103.7 ± 81.41
	Abbreviations: ICU, intensive care unit; MELD, Model for End-Stage Liver Disease; NPO, nothing by mouth
Results	Coagulopathy profile and nutrition profile in SMOFlipid group
		7 days vs. 14 days p-value	7 days vs. 30 days p-value	14 days vs. 30 days p-value
	PT, sec	0.124	0.044	0.103
	INR, sec	0.060	0.012	0.042
	aPTT, sec	0.002	0.0001	0.002
	Platelet, 10³/μL	0.022	0.0001	0.187
	Albumin, g/dL	0.280	0.046	0.119
	Cholesterol, mg/dL	0.0001	0.0001	0.0001
	Triglyceride, mg/dL	0.006	0.006	0.360
	Coagulopathy profile and nutrition profile in non-SMOFlipid group
	PT, sec	0.347	0.011	0.064
	INR, sec	0.983	0.021	0.075
	aPTT, sec	0.540	0.0001	0.007
	Platelet, 10³/μL	0.023	0.013	0.992
	Albumin, g/dL	0.101	0.062	0.179
	Cholesterol, mg/dL	0.018	0.0001	0.0001
	Triglyceride, mg/dL	0.451	0.026	0.076
	Data of improvement of coagulation profile after nutrition support in both groups are listed as graphs. All coagulation parameters improved gradually in both arms, but the non-SMOFlipid group exhibited lower platelet count 7 days after TPN support. However, there were no significant differences on 14 and 30 days observed in platelet counts between the groups.
Adverse Events	No bleeding events (e.g., postoperative intra-abdominal bleeding, upper gastrointestinal bleeding, intra-cranial hemorrhage) were reported.
Study Author Conclusions	TPN using SMOFlipid after LT is a good strategy for improving nutritional status without increasing the risks of bleeding and coagulation in patients intolerant of early enteral nutrition. Moreover, SMOFlipid use may not cause coagulopathy up to 14 days after LT. Overall, SMOFlipid provides nutritional benefits without increasing the risk of bleeding.
InpharmD Researcher Critique	The study's limitations include a small sample size (54 out of 147 patients undergoing TPN after LT), introducing potential selection bias. The retrospective design may lead to recall bias and incomplete records. The study does not assess the anti-inflammatory effects of SMOFlipid. Coagulopathy and thrombocytopenia may be influenced by factors beyond nutrition, such as medication usage and complications. The complex composition of SMOFlipid necessitates further analysis to determine the individual effects of each component.

References:

Wu MY, Kuo SC, Chuang SF, et al. Comparative study of the safety and efficacy of SMOFlipid vs non SMOFlipid as TPN for liver transplantation. Ann Med Surg (Lond). 2021;63:102094. Published 2021 Feb 18. doi:10.1016/j.amsu.2021.01.042