Improving the usability of lipid emulsions and optimizing their user-friendliness: a narrative review

Keisuke Kubota; Natsuko Ichikawa; Kazuhiro Isoda; Misato Enomoto; Miyoko Kosugi; Mari Tanabe; Naoya Sakuraba; Sayuri Endo; Atsushi Suzuki; Masanori Hashimoto

doi:10.15747/ACNM.25.0015

Articles

Page Path: HOME > Ann Clin Nutr Metab > Volume 17(2); 2025 > Article

Review Improving the usability of lipid emulsions and optimizing their user-friendliness: a narrative review: Keisuke Kubota¹, Natsuko Ichikawa², Kazuhiro Isoda³, Misato Enomoto³, Miyoko Kosugi⁴, Mari Tanabe⁵, Naoya Sakuraba⁶, Sayuri Endo², Atsushi Suzuki⁷, Masanori Hashimoto⁸; Annals of Clinical Nutrition and Metabolism 2025;17(2):104-113.
DOI: https://doi.org/10.15747/ACNM.25.0015
Published online: August 1, 2025

¹Department of Esophageal and Gastric Surgery, Nutrition Support Team, Japan Community Healthcare Organization Tokyo Yamate Medical Center, Tokyo, Japan

²Nutrition Management Office, Nutrition Support Team, Japan Community Healthcare Organization Tokyo Yamate Medical Center, Tokyo, Japan

³Department of Pharmacy, Nutrition Support Team, Japan Community Healthcare Organization Tokyo Yamate Medical Center, Tokyo, Japan

⁴Department of Nursing, Nutrition Support Team, Japan Community Healthcare Organization Tokyo Yamate Medical Center, Tokyo, Japan

⁵Department of Rehabilitation, Nutrition Support Team, Japan Community Healthcare Organization Tokyo Yamate Medical Center, Tokyo, Japan

⁶Department of Clinical Laboratory, Nutrition Support Team, Japan Community Healthcare Organization Tokyo Yamate Medical Center, Tokyo, Japan

⁷Department of Nephrology, Nutrition Support Team, Japan Community Healthcare Organization Tokyo Yamate Medical Center, Tokyo, Japan

⁸Department of Breast Surgery, Nutrition Support Team, Japan Community Healthcare Organization Tokyo Yamate Medical Center, Tokyo, Japan

Corresponding author: Keisuke Kubota email: kubota-keisuke@yamate.jcho.go.jp

This article is a secondary publication of an article in Japanese published in the Japanese Journal of Surgical Metabolism and Nutrition, 2024;58(1):41-49. https://doi.org/10.11638/jssmn.58.1_41. The editors of both journals have granted permission for secondary publication.

This paper was presented at the 60th Annual Meeting of the Japanese Society for Surgical Metabolism and Nutrition, held on July 7, 2023, in Tokyo, Japan.

• Received: May 19, 2025 • Revised: July 1, 2025 • Accepted: July 4, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

146 Views
3 Download

prev next

Full Article

Download PDF

Abstract
Introduction
Clinical application of lipid emulsions
Conclusion
Notes
References

Abstract

Purpose
Reluctance to administer lipid emulsions to patients receiving treatment, or as recommended by a nutritional support team, often stems from various restrictions or concerns about potential adverse effects. This paper aims to discuss the appropriate clinical use of lipid emulsions to enhance both patient safety and convenience.
Current concept
We conducted a literature review to assess the importance of nutritional therapy and nutritional intervention, the advantages and disadvantages of lipid-emulsion administration, the current situation in Japan, and differences between lipid formulations. Here, we address issues regarding lipid-emulsion use, including: administration rate, drug mixing, administration in critically ill patients, and early postoperative use. Our findings suggest the following solutions to each issue: although a rate below 0.1 g/kg/hr is generally recommended, faster administration is possible if needed, depending on the case; administration via a piggy tube to basic infusion formulations is unproblematic; second- and third-generation fat emulsions are safe for critically ill patients, though soybean oil should be used with caution; and while fat emulsion administration is feasible immediately after surgery, due to endogenous energy mobilization, it is preferable to initiate administration from the third to fourth postoperative day.
Conclusion
The provisional conclusions of this study are as follows: the introduction of medium-chain triglyceride formulations and fish oil (second- and third-generation lipid emulsions), which are not yet available in Japan, is urgently needed; and individualized administration is essential due to substantial interindividual variability in lipid emulsion usage.
Keywords: Emulsions; Glycine max; Parenteral nutrition; Patient safety; Soybean oil

Introduction

Background

Just as a nutritionally balanced diet is recommended in daily life, the balanced provision of nutrients is equally crucial in hospital-based nutritional therapy, particularly in parenteral nutrition (PN). Large-scale trials have validated the importance of such nutritional interventions, notably the EFFORT study conducted by Schuetz et al. [1]. In that randomized controlled trial, 1,050 patients with nutrition risk screening scores ≥3 assigned to the intervention group were compared with 1,038 control patients. The nutritional intervention group experienced significantly fewer adverse events (23% vs. 27%, P=0.023) and lower mortality (7% vs. 10%, P=0.011), with no significant difference in nutrition-related side effects (16% vs. 14%). Although the necessity of nutritional intervention is beyond dispute, a universally accepted standard protocol has not yet been established.

Objectives

In this paper, we first reaffirm the significance of nutritional therapy and the clinical utility of lipid-emulsion administration. We then address several practical issues surrounding lipid emulsions by structuring key discussion points, reviewing current guidelines, and referencing the latest evidence. Throughout, we highlight particularly exemplary publications as “recommended articles.” The EFFORT trial by Schuetz et al. [1] is among these references and is highly recommended for further reading.

Ethics statement

This is a literature-based study. Institutional Review Board approval was not required, as the research did not involve human subjects.

Benefits and harms of PN

As Terashima stated [2], "Because nutritional therapy intervenes in a purposefully functioning biological defense system and inherently risks disrupting that system, inappropriate nutritional therapy may have deleterious effects. In particular, PN—which is forced nutrition administered directly into the vasculature—tends to make these problems more overt.” In other words, compared to enteral feeding, PN has long been linked to complications such as hepatic dysfunction, intestinal mucosal atrophy, and bacterial translocation. These concerns continue to be explored [3], and Wichman et al. [4] have elucidated the mechanisms underlying these harmful effects of PN. Conversely, Rosseel et al. [5] have argued in favor of PN in critically ill patients, concluding that in cases of sepsis or heart failure, liver dysfunction is attributable to the underlying illness rather than PN itself. Similarly, Webb et al. [6] have shown that supplemental nutrition has a modest but real benefit in oncology patients, while emphasizing the need to consider cost-effectiveness.

Benefits and harms of lipid emulsions and their current use

Among macronutrients, lipid formulations are indispensable. Lipid-free, high-calorie infusions can lead to essential fatty acid deficiency and promote fatty liver, primarily due to excessive glucose administration. Lipid emulsions can also mitigate acute hyperglycemia in patients with impaired glucose tolerance, deliver high caloric content in small volumes—which is advantageous in fluid-restricted states such as heart failure—and lower the respiratory quotient in chronic obstructive pulmonary disease. These properties are particularly useful in specific clinical contexts. Recent studies have demonstrated improved outcomes associated with lipid emulsion use and have noted worse prognoses when lipids are withheld [7,8]. Tota et al. [9] have emphasized that “the outdated notion that lipid emulsions are harmful in critically ill patients must be abandoned”. In Japan, Yasuda et al. [10] reported reduced mortality among intensive care unit (ICU) patients who received lipid emulsions. Although the benefit during the acute phase remains under debate, other authors contend that long-term essential fatty acid deficiency necessitates supplementation [11].

Despite this evidence, real-world clinical practice often diverges from established guidelines. Using DPC (Diagnosis Procedure Combination) data, Sasabuchi et al. [12] analyzed 54,687 Japanese adult patients with central venous catheters and found that total PN (TPN) regimens typically provided 10–20 kcal/kg/day of energy, 0.5–1.0 g/kg/day of amino acids, and 0 g/kg/day of lipids—indicating a lack of adherence to guideline recommendations regarding lipid administration. In a subsequent report [13], the same group compared three cohorts—those meeting targets (energy >20 kcal/kg/day, amino acids >1.0 g/kg/day, lipids >2.5 g/day; n=3,694), partial achievers (n=29,610), and non-achievers (n=21,383)—and observed in-hospital mortality rates of 17.2% versus 25.5% versus 34.5% (P=0.001), activities of daily living (ADL) deterioration rates of 8.4% versus 10.3% versus 10.4% (P=0.001), and no significant difference in readmission rates (4.8% vs. 5.1% vs. 4.8%). These results confirm that lipid administration improves both clinical outcomes and prognosis.

Types of lipid emulsions

While Europe offers a diverse array of clinically available lipid emulsions, it is important to recognize that in Japan, the United States, and Canada, only soybean oil-based (ω-6 long-chain triglyceride [LCT]) formulations are approved. Recent evidence has now almost definitively established that “soybean oil carries numerous drawbacks, whereas medium-chain triglycerides (MCTs), fish oil (ω-3 LCT), and their composite formulations (i.e., second- and third-generation lipid emulsions) offer greater clinical benefit” [9,14]. Tota et al. [9] provide a comprehensive history of PN, infectious complications, and the evolution of lipid emulsions, and strongly recommend both all-in-one bag formulations and second-/third-generation lipid emulsions. Among many recent studies, Pradelli et al. have reported not only improved patient outcomes and prognoses [15,16] but also reductions in healthcare costs [17], demonstrating their utility in the United States [18]. In their systematic review of 49 randomized controlled trials, Pradelli et al. [15] showed that PN regimens enriched with ω-3 fatty acids significantly reduce the risk of infection and peritonitis while also shortening both ICU and overall hospital length of stay. Accordingly, there is a pressing clinical imperative for second- and third-generation lipid emulsions containing MCT and fish oil to become available in Japan.

Clinical application of lipid emulsions

Although debate continues regarding the necessity and risks of lipid emulsions, we proceed on the premise that lipid emulsions are both necessary and beneficial. Various contraindications and precautions concerning their use and safety are documented in product labeling (Table 1). These restrictions can limit practical application in clinical settings, occasionally causing clinicians to hesitate or even avoid lipid-emulsion administration.

In routine nutrition support team (NST) practice, several recurring challenges arise: (1) because lipid emulsions cannot be mixed with other solutions, a separate intravenous line must be secured; however, obtaining additional vascular access can be difficult for many patients; (2) lipid-emulsion infusions are time-consuming, and if only a single line is available, lipid administration may interfere with primary infusion schedules; prolonged continuous infusions also risk impeding patients’ ADLs; (3) although admixture with other drugs is contraindicated, is administration via a side port acceptable? If a side-port infusion is feasible, concerns regarding infusion rate could be alleviated; and (4) some attending physicians and nurses express greater concern about potential adverse effects than the benefits of lipid emulsions, particularly in critically ill or early postoperative patients, making it difficult for the NST to provide definitive recommendations.

To promote wider and safer use of lipid emulsions, we have organized the administration-related issues as follows and will examine whether each can be addressed to facilitate simplified, secure utilization: (1) optimal infusion rate, (2) side-port administration, (3) administration in the context of physiological stress, and (4) use immediately postoperatively.

For each topic, we will (1) reference existing guideline recommendations, (2) review clinical studies underpinning those recommendations, (3) supplement and revise based on the most recent evidence, and (4) summarize current best-practice recommendations.

Literature search and selection methods: we systematically searched the Igaku-Chuo-Zasshi (ICHUSHI) and PubMed databases. In ICHUSHI, our keywords included “脂肪乳剤 (lipid emulsion)” combined with terms such as “投与速度 (infusion rate),” “側管投与 (side-port administration),” “配合変化 (compatibility),” “侵襲下 (under stress),” “ICU,” “重症 (critical illness),” “ARDS,” “敗血症 (sepsis),” “周術期 (perioperative),” and “早期静脈栄養 (early parenteral nutrition).” In PubMed, we used “fat OR lipid” plus “parenteral nutrition” combined with “rate,” “piggyback,” “ARDS,” “sepsis,” “ICU,” “trauma,” “critically ill,” and “early nutrition.” We limited our search to adult clinical studies on lipid-emulsion use, published within the past 3 years (2020–2023). We excluded studies on neonates or infants, case reports, in vitro studies, and animal experiments, focusing instead on evidence-based clinical trials and observational studies. Selected articles were categorized and analyzed by theme, including lipid-emulsion dosage, formulation type, infusion rates, and timing of administration.

Optimal infusion rate

Guideline recommendations

The Japanese Society for Parenteral and Enteral Nutrition (JSPEN) Parenteral and Enteral Nutrition Guidelines state that lipid emulsions should be administered at a rate of ≤0.1 g/kg/hr. Iriyama et al. [19] employed a triglyceride clamp method and found that, at an infusion rate of 0.3 g/kg/hr, serum triglyceride levels increased, whereas rates of ≤0.1 g/kg/hr did not cause triglyceride elevation; therefore, an infusion rate of ≤0.1 g/kg/hr is recommended.

The European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines similarly recommend the use of “all-in-one bag formulations” and “routine lipid administration,” and specify that “the safe dosing range for soybean oil-based lipid emulsions is 0.7–1.5 g/kg given over 12–24 hours” [20].

Critical appraisal of guideline evidence

The JSPEN recommendation is based on Iriyama et al.’s study [19], which demonstrated—using a triglyceride clamp technique—that an infusion rate of 0.3 g/kg/hr led to elevated serum triglyceride levels, whereas rates of ≤0.1 g/kg/hr did not. Thus, the authors concluded that lipid emulsions should be infused at ≤0.1 g/kg/hr. A subsequent report by Iriyama et al. [21] determined that, to maintain serum triglyceride concentrations within the 2–5 mmol/L range, infusion rates must be 0.10–0.14 g/kg/hr. Unfortunately, these studies involved only small cohorts of healthy volunteers, limiting their generalizability to clinical populations.

Another source cited by JSPEN is the review by Klein and Miles [22], which reported multiple adverse events when infusion rates exceeded 0.11 g/kg/hr. However, this review spans just two pages and references a limited number of primary studies, resulting in relatively weak evidentiary strength.

The ESPEN guidelines reference Wichmann et al.’s randomized controlled trial [23], which compared fish oil- and soybean oil-based lipid emulsions administered over 24 hours; however, this investigation did not directly isolate infusion rate as the primary variable.

The survey conducted by Ali et al. [24] further illustrates real-world variability: across 67 Australian hospitals, the median actual lipid infusion rate was 2.0 g/kg/day (interquartile range 1.0–3.5 g/kg/day), indicating that clinicians frequently deviate from guideline recommendations due to insufficient evidence.

The review by Carpentier and Hacquebard [25] provides extensive information on the clinical benefits of fish oil-containing lipid emulsions; however, it does not offer specific guidance regarding optimal infusion rates.

Recent findings

Fukushima et al. [26] from Kobe University employed a triglyceride kinetic model to estimate each patient’s maximal tolerable infusion rate. Among 83 individuals, 30 patients (36%) could theoretically tolerate rates ≥0.2 g/kg/hr, while eight patients (10%) required rates <0.05 g/kg/hr. These findings highlight substantial interindividual variability in lipid-emulsion tolerance and emphasize the necessity and feasibility of personalized dosing regimens. A multicenter collaborative study is currently underway to validate and expand these findings.

Reappraisal of current recommendations

At present, no universally accepted standard for lipid-emulsion infusion rates exists. Existing guidelines generally recommend administration at ≤0.1 g/kg/hr; however, the supporting evidence is limited and inconsistent across studies. Future research and accumulated clinical experience are expected to establish more precise recommendations for infusion rates. In the interim, clinicians should “adhere to guideline recommendations while carefully tailoring lipid-emulsion infusion rates to each patient’s unique clinical status” [summary]. Specifically, when a faster infusion is necessary to accommodate time constraints or minimize interference with ADL, gradual rate escalation—guided by close monitoring of the patient’s overall clinical condition and serial serum triglyceride measurements—may be appropriate.

Side-port administration

Guideline recommendations

The JSPEN Textbook on Parenteral and Enteral Nutrition states: “Mixing total parenteral nutrition (TPN) base solutions with lipid emulsions can lead to oil droplet separation and coalescence of lipid particles. Enlarged particles may be phagocytosed by reticuloendothelial cells, thereby suppressing immune function and provoking pneumonia or respiratory complications; there is also a risk of pulmonary embolism” [27].

Critical appraisal of guideline evidence

Studies by Inoue et al. [28] and Myotoku [29] are cited in support of this recommendation. Inoue et al. [28] infused lipid emulsions via a side port on the central venous TPN line and measured lipid-droplet particle size, concluding that admixture did not pose a problem. Although these data suggest that mixing may not be universally contraindicated, clinical validation remains necessary. Furthermore, compatibility assessments must be performed for each concomitant medication—such as vitamins, insulin, antimicrobials, and vasoactive agents—before combining them with lipid emulsions.

Recent findings

Myotoku [30] and Ishikawa et al. [31] reported that certain admixtures of lipid emulsions are generally acceptable, but specific cautions must be observed. Additionally, common clinical practice involves line flushing—before and after lipid-emulsion infusion—when a single intravenous route is used to avoid admixture; this practice also reduces intraluminal bacterial load [32].

Reappraisal of current recommendations

Current evidence supports that administering lipid emulsions via a side port into the primary TPN line is clinically acceptable. However, compatibility with other medications—such as vitamins, insulin, and vasoactive drugs—remains an open question and requires individual evaluation. As foundational research progresses and clinical validation accumulates, optimized protocols to mitigate complication risks and enhance safety are anticipated. Ultimately, the choice of lipid-emulsion administration method must always prioritize patient safety.

Administration under physiological stress

Guideline recommendations

The JSPEN Parenteral and Enteral Nutrition Guidelines state: “Lipids are essential to supply indispensable fatty acids; however, depending on the administration method, they may adversely affect immune function and the respiratory and cardiovascular systems. Some reports indicate that lipid‐emulsion infusion in trauma patients is associated with increased infectious complications, yet meta‐analyses have not demonstrated a direct link between lipid administration and immune suppression or increased mortality. Although deleterious respiratory and circulatory effects remain a theoretical concern, studies in acute respiratory distress syndrome (ARDS) patients have shown no deterioration in pulmonary status following lipid‐emulsion administration. The current consensus is that, if infusion rate is properly controlled, lipid emulsions can be administered without impairing immune function or respiratory and circulatory homeostasis. Specifically, infusion rates of ≤0.1 g/kg/hr have been reported to maintain stable serum triglyceride levels and permit safe administration; therefore, lipid infusion is strongly recommended under these conditions” [27]. The 2009 American Society for Parenteral and Enteral Nutrition (ASPEN) guidelines recommend: “Do not co‐administer soybean oil-based lipid emulsions within the first week of ICU admission” [33].

Critical appraisal of guideline evidence

The JSPEN recommendation to withhold lipids in specific contexts cites the randomized controlled trial by Battistella et al. [34]. In that study, 30 multiply injured patients (L group) received standard doses of soybean oil-based lipid emulsion, whereas 27 patients (NL group) did not receive lipids for the initial 10‐day period. The L group experienced longer hospital stays (39 days vs. 27 days), prolonged ICU duration (29 days vs. 18 days), extended ventilator dependency (27 days vs. 15 days), and a higher incidence of infectious complications (72 events vs. 39 events, with some patients experiencing multiple events), along with demonstrable T‐cell dysfunction in the L group—strongly suggesting that lipid administration exacerbated infectious risk and worsened outcomes. However, as discussed below, later analyses have questioned whether these findings were overstated.

For instance, Wanten and Calder [35] noted that lipid-emulsion concentration and infusion rates varied widely across studies, rendering the data controversial; the author concluded that safety cannot be unequivocally asserted.

Conversely, numerous reports support the safe use of lipid emulsions under stress. Wichmann’s meta-analysis [36] found no evidence directly linking lipid emulsions to immune suppression or increased mortality and concluded that lipid infusion is “not problematic.” Among the 14 studies referenced by Wichmann regarding administration under stress, only a minority addressed clinical outcomes:

• Ota (JPEN J Parenter Enteral Nutr 1985) studied 40 malnourished patients and found no difference in infection rates between those receiving lipids and controls [37].

• Da Pont (Minerva Gastroenterol Dietol 1994) reported no hepatobiliary or metabolic complications; lipid recipients' nutritional status and prealbumin levels improved [38].

• Gelas (JPEN J Parenter Enteral Nutr 1998) conducted a placebo‐controlled randomized controlled trial of 33 AIDS patients; the clinical courses were equivalent, and body weight increased uniformly, though immune modulation was observed [39].

• Garnacho‐Montero (Nutrition 2002) found no worsening of mortality or ICU stay among 72 septic patients receiving lipids [40].

• Versleijen (Am J Clin Nutr 2008) demonstrated that lipid infusion did not alter leukocyte counts or functional activity [41]. However, these studies provide limited direct evidence to assert safety categorically.

The ASPEN guidelines’ recommendation is based on a small Level II randomized controlled trial (RCT; Van den Berghe et al.), predating widespread intensive insulin protocols, and is therefore graded as a Grade D recommendation [42]. ASPEN also cites Battistella et al. [34] as underpinning the safety concern. Heyland’s meta-analysis [43], another ASPEN reference, concluded that while lipid emulsions may potentially increase infectious complications, the evidence is insufficient to confirm this risk.

By contrast, McCowen et al. [44] conducted an RCT in ICU patients with sepsis-induced ARDS; they found no differences in hyperglycemia or infectious events (including wound, catheter-related, intra-abdominal, or pulmonary infections) between lipid and non-lipid groups, and demonstrated improved nitrogen balance among lipid recipients.

Recent findings

The recommendation by Tota et al. [9]—that "we must abandon the entrenched belief that lipids are harmful in critically ill patients"—remains highly relevant. Based on the latest evidence, they assert that concerns over bloodstream infection risk cannot justify excluding lipid emulsions from PN; indeed, provision of essential fatty acids may improve clinical outcomes. They emphasize the need to understand the true risk factors for sepsis during PN and call for up-to-date nutritional education at all levels of medical training. Moreover, Haji [14] suggest that, in septic or severely stressed surgical patients, the use of non-soybean oil lipid emulsions is recommended, while soybean oil emulsions may be considered acceptable to a lesser extent. Overall, the preponderance of evidence favors safety rather than risk.

In a recent conference presentation, Tateishi [45] from Gunma University compared ICU patients who received lipid emulsions with those who did not and found no significant differences in in-hospital mortality, incidence of infectious complications, or thromboembolic events. Although somewhat dated, Faucher et al.’s study [46] in ARDS patients remains highly informative. No deterioration in oxygenation was observed among 18 patients who received lipid emulsions at 0.2 g/kg/hr. Faucher et al. [46] systematically compared prior reports while accounting for infusion rate; their analysis revealed that roughly half of the published studies deemed lipid administration "safe" and half "risky," suggesting neither lipid-emulsion type nor infusion rate alone can predict safety. Instead, interindividual variability likely determines outcomes.

Current recommendations

Despite evidence from several studies—including large trials—suggesting that lipid emulsions can be safely administered to critically ill and inflamed patients, certain investigations continue to report an increased risk of infectious complications. Continued research is therefore warranted, and clinicians must carefully evaluate appropriate lipid-emulsion administration methods in this population. From the most recent data, two provisional conclusions emerge: (1) second- and third-generation lipid emulsions containing ω-3 fatty acids or MCT appear markedly safer than soybean oil emulsions; and (2) significant interpatient variability necessitates individualized dosing strategies. Because it remains challenging to predict safety a priori, lipid emulsions should be initiated only when anticipated benefits outweigh potential risks, with close monitoring of the patient’s clinical status.

Use immediately postoperatively

Guideline recommendations

The JSPEN Textbook on Parenteral and Enteral Nutrition advocates enteral nutrition as the primary modality and advises that “if no nutritional deficits are present, underfeeding—defined as provision of fewer calories than estimated energy expenditure—should be maintained during the first postoperative week. For patients with preexisting malnutrition, the optimal caloric target is unknown; energy delivery should be set so as not to exacerbate caloric debt (full feeding).” Regarding supplemental PN, the text states: “When a patient has no preexisting malnutrition and enteral nutrition can be initiated early, aggressive PN from the outset is not recommended—there is no clear evidence of improved outcomes, and costs increase. If malnutrition is present before severe illness or if enteral nutrition cannot be started within the first week of ICU admission, PN should be considered while remaining vigilant for refeeding syndrome” [27].

Critical appraisal of guideline evidence

The JSPEN recommendation draws on the RCT by Doig et al. [47]. In that study, 1,372 critically ill postoperative patients who could not tolerate early enteral nutrition were randomized to receive either standard PN beginning on postoperative days 2–3 (n=686) or early PN beginning on day 0 (n=686). At 60 days, mortality was similar (22.8% vs. 21.5%, no statistically significant difference), health-related quality of life (as measured by the RAND-36 General Health Status score) showed no clinically meaningful difference (45.5 vs. 49.8), and duration of mechanical ventilation was slightly shorter in the early PN group (7.26 days vs. 7.73 days). Subjective global assessment metrics demonstrated less muscle wasting (0.27 vs. 0.43) and fat loss (0.31 vs. 0.44) in the early PN cohort [47]. Although these data suggest some benefit, the authors ultimately declined to endorse routine immediate PN, likely because the study was designed with expectations of more pronounced outcome improvements.

Casaer et al. [48] compared late PN—initiated on ICU day 8 (n=2,328)—with early nutrition started on ICU day 3 (n=2,312). While 90-day survival and ICU mortality did not differ, the late PN group experienced shorter ICU and hospital stays, reduced infection rates, fewer days on mechanical ventilation, less need for renal replacement therapy, and lower overall healthcare costs.

Heidegger et al. [49] randomized 305 ICU patients with insufficient enteral intake by day 3 to receive supplemental PN (25–30 kcal/kg/day) starting on day 4 (n=153) versus continued enteral nutrition alone (n=152). The supplemental PN group significantly reduced nosocomial infections.

Recent findings

Terashima [2] revisited early postoperative metabolic responses, highlighting that European and American guidelines often fail to account for the unique catabolic surge and endogenous energy mobilization occurring immediately after surgery. They argue that nutritional plans must explicitly incorporate endogenous energy production when initiated in the immediate postoperative period.

We identified four additional clinical studies examining immediate postoperative lipid-emulsion administration [50,51]. Gao et al. [52] compared supplemental PN initiated on postoperative day 3 versus day 8 in surgical ICU patients. The early PN cohort demonstrated a lower incidence of infectious complications, shorter duration of antibiotic therapy, and higher serum prealbumin and albumin levels.

Niihara and Hiki [53] emphasized that “the term ‘immediately postoperative’ should not be used generically; the degree of surgical invasiveness must be stratified by procedure type”. They proposed that differentiating high- versus low-invasiveness procedures enables more precise timing of nutritional interventions. Taken together, these findings suggest that early postoperative nutrition, including lipids, may improve clinical outcomes when endogenous catabolism is acknowledged.

Current recommendations

Immediate postoperative administration of lipid emulsions can be beneficial if the timing and patient selection are carefully considered; however, some studies remain equivocal or negative. Drawing on existing evidence, we propose the following interim guidance:

Leverage tight glycemic control and endogenous energy mobilization: In the immediate postoperative phase, rigorous blood glucose management and recognition of intrinsic energy mobilization are paramount. Early lipid infusion can be advantageous when these factors are incorporated into nutritional planning.

Stratify by surgical invasiveness: The magnitude of operative stress varies significantly by procedure. For highly invasive operations, supplemental nutrition—including lipids—should be introduced by postoperative days 3–4 to mitigate catabolism; for lower-invasiveness procedures, initiation may be tailored to individual recovery trajectories.

Immediate lipid safety window: If lipid emulsions are administered within the framework mentioned above—namely, blood sugar control, endogenous energy awareness, and appropriate procedure-based timing—there is no evidence of harm associated with immediate postoperative lipid use.

In summary, tailored strategies that consider patient physiology, surgical stress, and real-time metabolic markers are needed. As further data emerge, these provisional recommendations should be refined to optimize safety and efficacy in immediate postoperative lipid administration.

Conclusion

The most salient conclusions drawn from our examination of lipid-emulsion administration are twofold: (1) the urgent need to introduce second- and third-generation lipid emulsions containing MCT and fish oil (ω‐3 fatty acids), and (2) the substantial interindividual variability in tolerance to lipid infusions.

Based on our analysis of specific clinical issues, we present a proposed framework for recommended lipid-emulsion administration, complete with cautions and practical considerations (Table 2). In addressing the question posed by the title, “Exploring Safe and Simplified Administration of Lipid Emulsions,” we must conclude that, although some individual cases may permit more streamlined and secure infusion strategies, it is currently challenging to implement widespread, radical changes in clinical practice. In other words, when clinicians lack complete confidence regarding the applicability or method of lipid-emulsion delivery for a given patient, the prudent approach is to proceed conservatively—“attempt administration while closely monitoring the patient’s condition.” Conversely, if no significant contraindications are present, it is equally valid to state that “administering lipids according to guideline recommendations remains the safest course.”

This review has sought to optimize lipid-emulsion use by synthesizing current guideline directives alongside the latest peer-reviewed evidence to enhance convenience and safety in routine practice. We hope these recommendations will serve as a valuable resource for clinicians incorporating lipid emulsions into daily patient care.

Authors’ contribution

Conceptualization: KK. Data curation: KK, NI, KI. Methodology/formal analysis/validation: KK, SE, MH. Project administration: KK, NI, KI, ME, MK, MT, NS, AS. Funding acquisition: Not applicable. Writing–original draft: KK. Writing–review & editing: KK, NI, KI, ME, MK, MT, NS, SE, AS, MH. All authors read and approved the final manuscript.

Conflict of interest

The authors of this manuscript have no conflicts of interest to disclose.

Funding

None.

Data availability

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Acknowledgments

None.

Supplementary materials

None.

Table 1.

Excerpt from the package insert of a lipid emulsion (Intralipos)

Item	Precise use
Dosage and administration	250 mL (20% solution) per day by intravenous drip infusion over at least 3 hours
Contraindications	Thrombosis, severe hepatic dysfunction, severe coagulation disorders, hyperlipidemia, diabetes mellitus with acidosis
Use with caution	Hepatic dysfunction, coagulation disorders, respiratory disorders, low birth weight infants, severe sepsis
General precautions	Mixing with other drugs, “Avoid administration within 96 hours after administration of plasma expanders (such as dextran, gelatin preparations, etc.)”
Cautions for concomitant use	Warfarin

Table 2.

Proposed methods and precautions for the use of lipid emulsions

Process	Details
1. Consider increasing nutritional administration	Especially in the following special conditions: essential fatty acid deficiency; fatty liver or hepatic dysfunction due to excessive glucose administration; impaired glucose tolerance; congestive heart failure; chronic obstructive pulmonary disease, etc.
1. Consider increasing nutritional administration	→ Consider using a lipid emulsion
2. Confirm patient status	1) Under significant stress (invasive phase)
	→ Apply as appropriate for each case; observe carefully
	2) Early postoperative period
	→ Although administration is technically possible immediately postoperative, necessity is low; begin from postoperative days 3–4
3. For all other situations, start administration per guidelines	Begin infusion via a dedicated line at a rate of 0.1 g/kg/hr.
4. If clinical complications arise	In situations such as difficulty securing a line or decreased activities of daily living:
	→ If the primary infusion is standard intravenous fluids, the lipid emulsion can be given via a side port
	→ Gradually increase infusion rate while monitoring overall patient condition and triglyceride levels

References

1. Schuetz P, Fehr R, Baechli V, Geiser M, Deiss M, Gomes F, et al. Individualised nutritional support in medical inpatients at nutritional risk: a randomised clinical trial. Lancet 2019;393:2312-21. Article PubMed
2. Terashima H. The pros and cons of early parenteral nutrition in the acute phase of stress: the truth behind the debate. Jpn J Surg Metab Nutr 2016;50:111-26.
3. Madnawat H, Welu AL, Gilbert EJ, Taylor DB, Jain S, Manithody C, et al. Mechanisms of parenteral nutrition-associated liver and gut injury. Nutr Clin Pract 2020;35:63-71. Article PubMed PMC PDF
4. Wichman BE, Nilson J, Govindan S, Chen A, Jain A, Arun V, et al. Beyond lipids: novel mechanisms for parenteral nutrition-associated liver disease. Nutr Clin Pract 2022;37:265-73. Article PubMed PMC PDF
5. Rosseel Z, Cortoos PJ, Jonckheer J, Cools W, Vinken M, Reynaert H, et al. Parenteral nutrition, sepsis, acute heart failure and hepatotoxic drugs are related to liver test disturbances in critically ill patients. Nutrients 2023;15:2612.Article PubMed PMC
6. Webb N, Fricke J, Hancock E, Trueman D, Ghosh S, Winstone J, et al. The clinical and cost-effectiveness of supplemental parenteral nutrition in oncology. ESMO Open 2020;5:e000709. Article PubMed PMC
7. Guirgis FW, Black LP, DeVos E, Henson M, Ferreira J, Miller T, et al. Lipid intensive drug therapy for sepsis pilot: a Bayesian phase I clinical trial. J Am Coll Emerg Physicians Open 2020;1:1332-40. Article PubMed PMC PDF
8. Wu SC, Chen TA, Cheng HT, Chang YJ, Wang YC, Tzeng CW, et al. Lipid-free PN is associated with an increased risk of hyperbilirubinemia in surgical critically ill patients with admission hepatic disorder: a retrospective observational study. Ther Clin Risk Manag 2021;17:1001-10. Article PubMed PMC PDF
9. Tota A, Serra A, Raoul P, Gasbarrini A, Rinninella E, Mele MC. Lipid-enriched parenteral nutrition and bloodstream infections in hospitalized patients: is it a real concern? Medicina (Kaunas) 2022;58:885.Article PubMed PMC
10. Yasuda H, Horikoshi Y, Kamoshita S, Kuroda A, Moriya T. Injectable lipid emulsion and clinical outcomes in patients exclusively receiving parenteral nutrition in an ICU: a retrospective cohort study using a Japanese medical claims database. Nutrients 2023;15:2797.Article PubMed PMC
11. Skorepa P, Sobotka O, Vanek J, Ticha A, Fortunato J, Manak J, et al. The impact of glucose-based or lipid-based total parenteral nutrition on the free fatty acids profile in critically ill patients. Nutrients 2020;12:1373.Article PubMed PMC
12. Sasabuchi Y, Ono S, Kamoshita S, Tsuda T, Murano H, Kuroda A. A survey on total parenteral nutrition in 55,000 hospitalized patients: retrospective cohort study using a medical claims database. Clin Nutr ESPEN 2020;39:198-205. Article PubMed
13. Sasabuchi Y, Ono S, Kamoshita S, Tsuda T, Kuroda A. Clinical impact of prescribed doses of nutrients for patients exclusively receiving parenteral nutrition in Japanese hospitals: a retrospective cohort study. JPEN J Parenter Enteral Nutr 2021;45:1514-22. Article PubMed PMC PDF
14. Haji S. The pros and cons of lipid emulsion administration during the perioperative period and under stress. Jpn J Surg Metab Nutr 2020;54:26-30.
15. Pradelli L, Mayer K, Klek S, Omar Alsaleh AJ, Clark RA, Rosenthal MD, et al. ω-3 Fatty-acid enriched parenteral nutrition in hospitalized patients: systematic review with meta-analysis and trial sequential analysis. JPEN J Parenter Enteral Nutr 2020;44:44-57. Article PubMed PMC PDF
16. Pradelli L, Mayer K, Klek S, Rosenthal MD, Povero M, Heller AR, et al. Omega-3 fatty acids in parenteral nutrition: a systematic review with network meta-analysis on clinical outcomes. Clin Nutr 2023;42:590-9. Article PubMed
17. Pradelli L, Klek S, Mayer K, Omar Alsaleh AJ, Rosenthal MD, Heller AR, et al. Omega-3 fatty acid-containing parenteral nutrition in ICU patients: systematic review with meta-analysis and cost-effectiveness analysis. Crit Care 2020;24:634.Article PubMed PMC PDF
18. Pradelli L, Klek S, Mayer K, Omar Alsaleh AJ, Rosenthal MD, Heller AR, et al. Cost-effectiveness of parenteral nutrition containing ω-3 fatty acids in hospitalized adult patients from 5 European countries and the US. JPEN J Parenter Enteral Nutr 2021;45:999-1008. Article PubMed PMC PDF
19. Iriyama K, Tonouchi H, Azuma T, Suzuki H, Carpentier YA. Capacity of high-density lipoprotein for donating apolipoproteins to fat particles in hypertriglyceridemia induced by fat infusion. Nutrition 1991;7:355-7. PubMed
20. Singer P, Berger MM, Van den Berghe G, Biolo G, Calder P, Forbes A, et al. ESPEN Guidelines on Parenteral Nutrition: intensive care. Clin Nutr 2009;28:387-400. Article PubMed
21. Iriyama K, Tsuchibashi T, Miki C, Kalembeyi I, Li H, Urata H, et al. Elimination rate of fat emulsion particles from plasma in Japanese subjects as determined by a triglyceride clamp technique. Nutrition 1996;12:79-82. Article PubMed
22. Klein S, Miles JM. Metabolic effects of long-chain and medium-chain triglyceride emulsions in humans. JPEN J Parenter Enteral Nutr 1994;18:396-7. Article PubMed
23. Wichmann MW, Thul P, Czarnetzki HD, Morlion BJ, Kemen M, Jauch KW. Evaluation of clinical safety and beneficial effects of a fish oil containing lipid emulsion (Lipoplus, MLF541): data from a prospective, randomized, multicenter trial. Crit Care Med 2007;35:700-6. Article PubMed
24. Ali AB, Chapman-Kiddell C, Reeves MM. Current practices in the delivery of parenteral nutrition in Australia. Eur J Clin Nutr 2007;61:554-60. Article PubMed PDF
25. Carpentier YA, Hacquebard M. Intravenous lipid emulsions to deliver omega 3 fatty acids. Prostaglandins Leukot Essent Fatty Acids 2006;75:145-8. Article PubMed
26. Fukushima K, Omura K, Koshi S, Niki A, Tanaka M, Tsujimoto T, et al. A new normal for lipid emulsion infusion rates: an empirical study on individualized rate design. J Acad Soc JSPEN 2022;4(Suppl 1):126.Article
27. Japanese Society for Parenteral and Enteral Nutrition. Parenteral and enteral nutrition guidelines. 3rd ed. Shorin-sha; 2013.
28. Inoue Y, Katsura T, Kokuba K, Fujimaki M, Kajiwara K. Safety of side-port administration of intravenous fat emulsions: an evaluation based on fat particle size. J Parenter Enteral Nutr 2014;29:863-70.
29. Myotoku T. Lipid emulsions and compatibility changes. Jpn J Surg Metab Nutr 2017;51:103-10. Article
30. Myotoku T. Precautions for mixing parenteral infusion solutions. Jpn J Pediatr Med 2021;53:2021-4.
31. Ishikawa T, Endo A, Asakawa D, Kim Y, Wakatsuki J, Koshiishi M, et al. Incompatibility in 13 cases in the NICU: effects of increased amino acid intake. Jpn Soc Pediatr Clin Pharmacol 2020;32:138-42.PDF
32. Omotani S, Hatsuda Y, Katsui Y, Asao A, Toujou H, Ihara K, et al. Microbial growth and importance of flushing inside closed-type infusion devices during administration of lipid emulsion in vitro setting. Int J Med Sci 2021;18:3106-11. Article PubMed PMC
33. McClave SA, Martindale RG, Vanek VW, McCarthy M, Roberts P, Taylor B, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr 2009;33:277-316. Article PubMed
34. Battistella FD, Widergren JT, Anderson JT, Siepler JK, Weber JC, MacColl K. A prospective, randomized trial of intravenous fat emulsion administration in trauma victims requiring total parenteral nutrition. J Trauma 1997;43:52-60. Article PubMed
35. Wanten GJ, Calder PC. Immune modulation by parenteral lipid emulsions. Am J Clin Nutr 2007;85:1171-84. Article PubMed
36. Wirtitsch M, Wessner B, Spittler A, Roth E, Volk T, Bachmann L, et al. Effect of different lipid emulsions on the immunological function in humans: a systematic review with meta-analysis. Clin Nutr 2007;26:302-13. Article PubMed
37. Ota DM, Jessup JM, Babcock GF, Kirschbaum L, Mountain CF, McMurtrey MJ, et al. Immune function during intravenous administration of a soybean oil emulsion. JPEN J Parenter Enteral Nutr 1985;9:23-7. Article PubMed
38. Da Pont MC, Pezzana A, Demagistris A, Balzola F, Cassader M, Boggio Bertinet D, et al. Total parenteral nutrition in critical patients: the metabolic-nutritional aspects and effects on immune function of 2 different isocaloric-isonitrogenous regimens. Minerva Gastroenterol Dietol 1994;40:17-26. PubMed
39. Gelas P, Cotte L, Poitevin-Later F, Pichard C, Leverve X, Barnoud D, et al. Effect of parenteral medium- and long-chain triglycerides on lymphocytes subpopulations and functions in patients with acquired immunodeficiency syndrome: a prospective study. JPEN J Parenter Enteral Nutr 1998;22:67-71. Article PubMed
40. Garnacho-Montero J, Ortiz-Leyba C, Jimenez-Jimenez FJ, Garcia-Garmendia JL, Jimenez-Jimenez LM, Garnacho-Montero MC, et al. Clinical and metabolic effects of two lipid emulsions on the parenteral nutrition of septic patients. Nutrition 2002;18:134-8. Article PubMed
41. Versleijen MW, Oyen WJ, Roelofs HM, van Emst-de Vries SE, Willems PH, Jansen JB, et al. Immune function and leukocyte sequestration under the influence of parenteral lipid emulsions in healthy humans: a placebo-controlled crossover study. Am J Clin Nutr 2008;87:539-47. Article PubMed
42. Usami M, Miyoshi M, Kawakami S, Aoyama M, Iizuka N, Watanabe M, et al. Lipid emulsion administration—what are the indications and limitations? J Parenter Enteral Nutr 2010;25:591-6.
43. Heyland DK, Dhaliwal R, Drover JW, Gramlich L, Dodek P; Canadian Critical Care Clinical Practice Guidelines Committee. Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. JPEN J Parenter Enteral Nutr 2003;27:355-73. Article PubMed
44. McCowen KC, Friel C, Sternberg J, Chan S, Forse RA, Burke PA, et al. Hypocaloric total parenteral nutrition: effectiveness in prevention of hyperglycemia and infectious complications: a randomized clinical trial. Crit Care Med 2000;28:3606-11. Article PubMed
45. Tateishi W. Reevaluating the indications for lipid emulsions in the field of intensive care. J Acad Soc JSPEN 2022;4(Suppl 1):128.Article
46. Faucher M, Bregeon F, Gainnier M, Thirion X, Auffray JP, Papazian L. Cardiopulmonary effects of lipid emulsions in patients with ARDS. Chest 2003;124:285-91. Article PubMed
47. Doig GS, Simpson F, Sweetman EA, Finfer SR, Cooper DJ, Heighes PT, et al. Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: a randomized controlled trial. JAMA 2013;309:2130-8. Article PubMed
48. Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med 2011;365:506-17. Article PubMed
49. Heidegger CP, Berger MM, Graf S, Zingg W, Darmon P, Costanza MC, et al. Optimisation of energy provision with supplemental parenteral nutrition in critically ill patients: a randomised controlled clinical trial. Lancet 2013;381:385-93. Article PubMed
50. Cha SW, Kim SH, Baek SE, Kim KS. Development of a nutritional index to evaluate the effectiveness of total parenteral nutrition during the early postoperative period after pancreaticoduodenectomy. Gland Surg 2021;10:2622-30. Article PubMed PMC
51. De Waele E, Malbrain ML, Spapen H. Nutrition in sepsis: a bench-to-bedside review. Nutrients 2020;12:395.Article PubMed PMC
52. Gao X, Liu Y, Zhang L, Zhou D, Tian F, Gao T, et al. Effect of early vs late supplemental parenteral nutrition in patients undergoing abdominal surgery: a randomized clinical trial. JAMA Surg 2022;157:384-93. Article PubMed PMC
53. Niihara M, Hiki N. The pros and cons of perioperative peripheral parenteral nutrition (PPN). Jpn J Surg Metab Nutr 2020;54:31-35. Article

Figure & Data

REFERENCES

Citations

Citations to this article as recorded by

Cite

CITE: export Copy Download Format; Close

Download Citation

Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

Format:

RIS — For EndNote, ProCite, RefWorks, and most other reference management software
BibTeX — For JabRef, BibDesk, and other BibTeX-specific software

Include:

Citation for the content below
Citation and abstract for the content below

Improving the usability of lipid emulsions and optimizing their user-friendliness: a narrative review

Ann Clin Nutr Metab. 2025;17(2):104-113. Published online August 1, 2025

DOI: https://doi.org/10.15747/ACNM.25.0015

XML Download

Improving the usability of lipid emulsions and optimizing their user-friendliness: a narrative review

Item	Precise use
Dosage and administration	250 mL (20% solution) per day by intravenous drip infusion over at least 3 hours
Contraindications	Thrombosis, severe hepatic dysfunction, severe coagulation disorders, hyperlipidemia, diabetes mellitus with acidosis
Use with caution	Hepatic dysfunction, coagulation disorders, respiratory disorders, low birth weight infants, severe sepsis
General precautions	Mixing with other drugs, “Avoid administration within 96 hours after administration of plasma expanders (such as dextran, gelatin preparations, etc.)”
Cautions for concomitant use	Warfarin

Process	Details
1. Consider increasing nutritional administration	Especially in the following special conditions: essential fatty acid deficiency; fatty liver or hepatic dysfunction due to excessive glucose administration; impaired glucose tolerance; congestive heart failure; chronic obstructive pulmonary disease, etc.
1. Consider increasing nutritional administration	→ Consider using a lipid emulsion
2. Confirm patient status	1) Under significant stress (invasive phase)
	→ Apply as appropriate for each case; observe carefully
	2) Early postoperative period
	→ Although administration is technically possible immediately postoperative, necessity is low; begin from postoperative days 3–4
3. For all other situations, start administration per guidelines	Begin infusion via a dedicated line at a rate of 0.1 g/kg/hr.
4. If clinical complications arise	In situations such as difficulty securing a line or decreased activities of daily living:
	→ If the primary infusion is standard intravenous fluids, the lipid emulsion can be given via a side port
	→ Gradually increase infusion rate while monitoring overall patient condition and triglyceride levels

Table 1. Excerpt from the package insert of a lipid emulsion (Intralipos)

Table 2. Proposed methods and precautions for the use of lipid emulsions