Lipid Management- Current thinking

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Philip C. CalderGordon L. JensenBerthold V. KoletzkoPierre Singer

Geert J. A. Wanten

Lipid emulsions in parenteral nutrition

of intensive care patients: current thinking

and future directions

Received: 3 August 2009Accepted: 28 December 2009

Published online: 14 January 2010 The Author(s) 2010. This article ispublished with open access atSpringerlink.com

P. C. CalderInstitute of Human Nutrition,University of Southampton,Southampton, UK

G. L. JensenDepartment of Nutritional Sciences,The Pennsylvania State University,

University Park, PA, USA

B. V. KoletzkoDivision of Metabolic Disease andNutritional Medicine, Dr. von HaunerChildrens Hospital, University of MunichMedical Centre, Munich, Germany

P. SingerDepartment of General Intensive Care,Rabin Medical Center, Sackler Schoolof Medicine, Tel Aviv University,Tel Aviv, Israel

G. J. A. Wanten

Department of Gastroenterology andHepatology, Radboud University NijmegenMedical Centre, Nijmegen, The Netherlands

P. C. Calder ())School of Medicine, Universityof Southampton, IDS Building,

MP887 Southampton General Hospital,Tremona Road,Southampton SO16 6YD, UKe-mail: [email protected].: ?44-2380-795250Fax: ?44-2380-795255

Abstract Background: Energydeficit is a common and seriousproblem in intensive care units and isassociated with increased rates ofcomplications, length of stay, andmortality. Parenteral nutrition (PN),

either alone or in combination withenteral nutrition, can improve nutrientdelivery to critically ill patients. Lip-ids provide a key source of calorieswithin PN formulations, preventing orcorrecting energy deficits andimproving outcomes. Discus-sion: In this article, we review therole of parenteral lipid emulsions(LEs) in the management of criticallyill patients and highlight importantbiologic activities associated withlipids. Soybean-oil-based LEs with

high contents of polyunsaturated fattyacids (PUFA) were the first widelyused formulations in the intensive

care setting. However, they may beassociated with increased rates of

infection and lipid peroxidation,which can exacerbate oxidativestress. More recently developedparenteral LEs employ partial substi-tution of soybean oil with oilsproviding medium-chain triglycer-ides,x-9 monounsaturated fatty acidsor x-3 PUFA. Many of these LEshave demonstrated reduced effects onoxidative stress, immune responses,and inflammation. However, theeffects of these LEs on clinicaloutcomes have not been extensively

evaluated.Conclusions: Ongoingresearch using adequately designedand well-controlled studies that char-acterize the biologic properties ofLEs should assist clinicians inselecting LEs within the critical caresetting. Prescription of PN containingLEs should be based on availableclinical data, while considering theindividual patients physiologicprofile and therapeutic requirements.

Keywords Energy deficit Fatty acid Intensive care Lipid emulsion

Parenteral nutrition

Introduction

Many critically ill patients admitted to the intensive careunit (ICU) enter a state of negative energy balance during

the first 34 days following admission [1,2]. This energydeficit often progresses during their ICU stay and mayresult in malnutrition and adverse outcomes [1]. Multiplefactors contribute to energy deficit, including increased

Intensive Care Med (2010) 36:735749DOI 10.1007/s00134-009-1744-5 RE VIE W


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metabolism [3,4], delays in the initiation of feeding, andinadequate caloric provision [1]. Indeed, a number ofstudies have demonstrated that target caloric intake isachieved in only 5075% of ICU patients and that asmany as 25% of patients receive only 1,0001,500 kcal/day [5].

Prolonged negative energy balance within the ICU isassociated with serious complications [1, 2]. In two sep-arate studies, progressive negative energy balance wasstrongly correlated with increased numbers of infectiouscomplications, particularly sepsis [1, 2]. In addition,cumulative total energy deficit has been correlated withincreased length of mechanical ventilation, length of ICUstay, total number of complications, and duration ofantibiotic use [1]. Delayed initiation of feeding and/ornegative energy balance in critical care patients may alsobe associated with higher ICU and in-hospital mortalityrates [5, 6], while early initiation of feeding results inimproved caloric intake [7].

This article aims to review well-known papers thatevaluate potential biologic effects of lipids when providedas a parenteral energy source and to provide future per-spectives on the use of parenteral lipid emulsions (LEs) incritically ill patients.

Role of parenteral nutrition in the intensive caresetting

Given the association between negative energy balance/malnutrition and both morbidity and mortality, ensuringthat critically ill patients receive adequate caloric andnutrient intake should be a high priority for intensivecare clinicians. Current guidelines recommend that allICU patients who tolerate enteral nutrition (EN) shouldreceive EN (approximately 2530 kcal/kg per day) ifthey are not expected to be on a full oral diet within3 days [8]. However, within the ICU setting EN maynot be feasible or cannot be established at rates thatprovide adequate nutrition for a number of reasons. Forexample, EN may be frequently interrupted because ofdiagnostic investigations, surgery, diarrhea, vomiting,mechanical problems (e.g., tube displacement) or patienttransfers [9]. EN may be contraindicated in patients with

anatomic gastrointestinal disorders, severe diarrhea, andreduced intestinal blood flow [10]. Parenteral nutrition(PN) is therefore recommended under certain circum-stances (Table1) [11].

Despite these recommendations, PN is often underused.Although PN was once a popular means of administering

nutrients, utilization has decreased in recent years becauseof concerns regarding metabolic complications associatedwith overfeeding [12,13] and an increased risk of septiccomplications [8]. It has been suggested that EN is requiredin order to maintain gut function and is less likely to causebacterial translocation than PN, although other perspec-tives exist [12,14]. However, available literature suggeststhat supplementation of EN with PN enhances caloricintake and nutritional status [1, 15] andthat PN isas safe asEN in critically ill patients [16,17].

Individualizing nutrition in critically ill patients

The systemic inflammatory response is associated withmetabolic stress in critically ill patients, including anoverall increase in metabolic rate, production of reactivespecies, insulin resistance, and alterations in substrate uti-lization that result in hyperglycemia (partly because ofincreased gluconeogenesis), lipolysis, and increased pro-teolysis relative to protein synthesis, potentially resultingin negative nitrogen balance [3, 4, 11, 18, 19]. The nutritionprovided to patients within the ICU setting should thereforeaim to blunt this catabolic state and enhance anabolicactivity during recovery while avoiding overfeeding.Administration of dextrose must often be balanced withinfusion of insulin to maintain euglycemia and minimizeincreases in carbon dioxide (CO2) production. Amino acidsare required to promote nitrogen retention and supportprotein synthesis [10]. Lipids are generally administered toprovide 30% of total calories, but dosage reduction shouldbe considered when triglyceride concentrations are[400 mg/dL [15]. Nutritional requirements vary depend-ing upon the level of metabolic stress; therefore, energyrequirements, as well as blood glucose and electrolyteconcentrations, should be monitored on a daily basis, andthe composition of artificial nutrition adjusted as required[15].

Table 1 Potential indicationsfor parenteral nutrition inintensive care patients [810]

Parenteral nutrition as asupplement to enteral nutrition

Parenteralnutrition alone

Enteral nutrition is insufficient to meettarget caloric intake

Intolerance to enteral nutrition

Suppression of gastrointestinal activity(e.g., immediately following injury orsurgery)

Major gut failure (e.g., extensive intestinalresection)

Conditions preventing adequate nutrientabsorption (e.g., inflammatory bowel disease,gastric outlet obstruction, intractable vomiting,severe diarrhea, paralytic ileus)

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The role of lipid emulsions in parenteral nutrition

Early PN formulations consisted primarily of high con-centrations of glucose and amino acids in order to provideadequate calories [20] and were often associated with anumber of complications. Prolonged use of these formu-

lations was associated with essential fatty acid (EFA)deficiency because they did not provide linoleic acid (LA;18:2x-6) or a-linolenic acid (ALA; 18:3x-3), which arenot synthesized by the body and must be obtained fromthe diet [2022]. Furthermore, the high dextrose loadsprovided by early PN solutions were associated with avariety of other complications, such as excessive CO2production, metabolic stress (increased concentrations ofcortisol, epinephrine, and glucagon), fever, and hepaticsteatosis [20]. As critical illnesses can be associated withimpaired glucose tolerance, overzealous infusion ofhypertonic dextrose solutions was often also associatedwith hyperglycemia, which, if undetected and untreated,

can progress to hyperosmolar nonketotic coma [23].Hyperglycemia can also be associated with an increasedincidence of complications in critically ill patients, suchas severe infections, multiple organ failure, and increasedmortality rates [24].

The incorporation of lipids into PN formulations hasaddressed many of these issues. Lipids provide a moreenergy-dense source of calories (approximately 9 kcal/g) than either amino acids (4 kcal/g) or dextrosemonohydrate (3.4 kcal/g) [22]. Therefore, the fluidvolume of PN required to achieve adequate caloricintake can be substantially reduced. The reduced fluidvolume and increase in osmolarity of formulationsincorporating LEs permit the safe administration of PNvia the peripheral and central routes. Formulations withosmolarities B900 mOsm/L can be administeredperipherally, while highly osmolar formulations can beadministered via central veins, which may be ofimportance in critically ill patients requiring fluidrestriction [10, 25]. Currently available parenteral LEsalso contain sufficient LA and ALA to prevent EFAdeficiency [21]. Perhaps most importantly, the use ofLEs in PN is associated with a reduction in the meta-bolic complications related to excessive hypertonicglucose infusion because the dextrose load is corre-spondingly reduced. Results of a study involvingcritically ill patients with gastric carcinoma, sepsis,colitis or pancreatitis demonstrated that replacement ofone-third of the total calories contained in a conven-tional glucose-amino acid PN formulation with a LEmaintained or increased patients body weight [26].Plasma glucose concentrations were maintained orreduced, and no cases of hyperglycemia, hyperosmolarnonketotic coma or hypertriglyceridemia were observed[26]. Another study found that ICU patients receiving

parenteral fluids unintentionally received 150600 kcal/day dextrose as a constituent of various fluids and drugs[1]. Therefore, the administration of PN containingLEs may help to prevent hyperglycemia and itscomplications.

It should be noted that, despite the potential benefits of

parenteral lipids, the use of LEs may be limited in somepatients. Triglycerides and other components of LEs formartificial chylomicrons, which are hydrolyzed in the bodyinto free fatty acids (FA) and small remnant particlestaken up by the liver [22,27,28]; the presence of excessphospholipids can also form liposomes, which interferewith lipid metabolism and may result in hypercholester-olemia [21, 22, 28]. When parenteral lipids are given inexcess of the livers ability to process them, hyperlipid-emia and hepatic steatosis may occur [21, 22, 28].Parenteral LEs also commonly contain phytosterols,which may be present in the circulation in quantities largeenough to induce cholestasis [28]. Although hepaticimpairment is most common among patients on long-termPN [28,29], critically ill patients are also at increased riskbecause plasma levels of FA increase with metabolicstress [27,30]. Therefore, parenteral LEs should be usedwith caution in septic patients [27, 28, 30] and patientswith other conditions known to impair hepatic clearanceof FA [28, 30]. In addition to the duration and dose ofparenteral LEs and the patients level of metabolic stress,the oil source of the LE may also affect the relative risk ofdeveloping abnormal liver function [21,22,28,31].

Evolution of parenteral lipid emulsions

Fatty acids

Although LEs contain numerous biologically activecompounds, triacylglycerols providing FA are their pri-mary component. Fatty acids are classified according totheir structure, in terms of their hydrocarbon chain length(short, medium or long), degree of saturation (number ofdouble bonds), and location of double bonds (countedfrom the methyl carbon of the hydrocarbon chain)(Table2) [21, 22, 32]. Fatty acids play key roles indetermining the structural integrity and fluidity of cellmembranes and can give rise to several important bio-active mediators [21,22,33]. They can also regulate theexpression of a variety of genes and modulate cell sig-naling pathways, such as those involved in apoptosis,inflammation, and cell-mediated immune responses. Forexample, longer-chain FA, such as arachidonic acid (AA;20:4x-6), eicosapentaenoic acid (EPA; 20:5x-3), anddocosahexaenoic acid (DHA; 22:6x-3), are involved inthe generation of pro- and anti-inflammatory lipid medi-ators [22].

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Early parenteral lipid emulsions

The majority of early LEs, which were first included inPN during the 1960s, were derived from soybean oil,which contains a high concentration of both LA andALA [21,22,33]. These early LEs were demonstrated toefficiently deliver nonglucose energy, thereby reducingthe adverse effects associated with intake of high dex-trose concentrations [21]. Furthermore, they providedEFA and the fat-soluble vitamins E and K [ 33]. How-ever, studies published during the 1970s and 1980sfound that soybean-oil- and cottonseed-oil-based LEswere associated with a number of adverse immunolog-ical effects, such as reduced migration and phagocytosisof granulocytes, which resulted in increased rates ofinfections, including sepsis [3437]. The cottonseed-oil-based LE (Lipomul) had such adverse clinical effects(e.g., hemolytic anemia) that it has since been removedfrom the market.

Minimization of risks associated with parenteral lipidsin critical care patients

In an effort to address concerns associated with the soy-

bean-oil-based LEs, alternative sources of FA wereinvestigated [21]. Much of this research focused onminimizing complications to which critically ill patientsare particularly susceptible, including oxidative stress,alterations in cell-mediated immunity, inflammation, andthrombosis. Although these are important issues to con-sider, well-controlled clinical data in critically ill patientsare limited, and discrepancies may be observed betweenstudies because of the heterogeneity of the study designs,patient populations, and specific LEs used.

Oxidative stress

Reactive oxygen species (ROS) can react with and dam-age cell membranes, lipids, proteins, and DNA throughoxidation. Under normal circumstances, ROS may beproduced in increased amounts by cells such as neutro-phils and macrophages as part of a natural immuneresponse. Levels of ROS are balanced by the neutralizingactivity of antioxidant molecules and enzymes, therebypreventing excessive damage to the host [38,39].

Oxidative stress occurs when an imbalance developsbecause of high ROS levels and/or low antioxidant levels.During critical illness, increased ROS and inflammatorymediator production occurs against a background ofcompromised antioxidant activity, which is partly due topreexisting nutritional deficiencies and/or suboptimalprovision of artificial nutrition. Depletion of the antioxi-dants selenium and zinc has been observed in trauma andburn patients, while surgery is associated with reductionsin vitamins A, C, and E. This state of imbalance can causetissue damage and may play an important role in thedevelopment of sepsis and multiple organ failure, amongother complications (Table3)[38,39].

A key consequence of oxidative stress is lipid perox-idation, where ROS react with the double bond of

unsaturated lipids, producing unstable lipid peroxides thatmay cause cell death [38,39]. The high number of doublebonds present inx-6 andx-3 polyunsaturated fatty acids(PUFA) provide targets for lipid peroxidation, and theseFA may therefore be associated with an increased risk ofoxidative stress [40]. For this reason, the antioxidanta-tocopherol (vitamin E) is sometimes added to PUFA-rich LEs in clinical practice.

Another approach to minimize oxidative stress is thepartial replacement of PUFA-rich oils with alternative FA

Table 2 Fatty acid nomenclature and key dietary sources [22,32]

Common name Chemical name Chemical structure[length of hydrocarbonchain (C atoms): numberof double bonds and positionof first double bond]

Dietary sources

Capric Decanoic 10:0 Coconut oilLauric Dodecanoic 12:0 Coconut oilMyristic Tetradecanoic 14:0 Milk Palmitic Hexadecanoic 16:0 Milk, eggs, animal fats, meat, cocoa butter,

palm oil, fish and fish oilsPalmitoleic 9-Hexadecenoic 16:1x-7 Fish and fish oilsStearic Octadecanoic 18:0 Milk, eggs, animal fats, meat, cocoa butterOleic 9-Octadecenoic 18:1x-9 Milk, eggs, animal fats, meat, cocoa butter, olive oilLinoleic 9,12-Octadecadienoic 18:2x-6 Seeds, seed oils, eggs, animal fats, meatArachidonic 5,8,11,14-Eicosatetraenoic 20:4x-6 Meat, egg lipids, algal oilsa-Linolenic 9,12,15-Octadecatrienoic 18:3x-3 Seeds, seed oils, green leaves, nutsEicosapentaenoic 5,8,11,14,17-Eicosapentaenoic 20:5x-3 Fish and fish oilsDocosapentaenoic 7,10,13,16,19-Docosapentaenoic 22:5x-3 Fish and fish oilsDocosahexaenoic 4,7,10,13,16,19-

Docosahexaenoic22:6x-3 Fish and fish oils, algal oils

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sources, such as oils rich in medium-chain triglycerides(MCT; derived from coconut oil containing medium-chain FA such as capric acid), which are more resistant tooxidative damage [41]. In one study of adults requiringPN, a 1:1 mixture of MCT (derived from coconut oil) andsoybean oil (MCT/soybean oil LE) supplemented with a-tocopherol demonstrated a reduced propensity to lipidperoxidation when compared with a conventional soy-bean-oil-based LE (Table4) [42]. However, a separatestudy comparing a soybean-oil-based LE with a MCT/soybean oil LE supplemented with a-tocopherol inpatients undergoing abdominal surgery found no differ-ence in lipid peroxidation between the two LEs [43].

Metabolism of MCT differs from that of long-chaintriglycerides (LCT). Unlike longer-chain FA, MCTrequire little carnitine for mitochondrial entry, and it hasbeen suggested that their more rapid breakdown mayimpart an increased production of ketones in critically illpatients [44]. However, this is thought to be a transientphenomenon that is reversible upon discontinuation ofMCT infusion and rarely causes clinical problems.However, formulations containing MCT should not beused in patients who develop ketosis or acidosis in theICU setting [41].

It has been suggested that monounsaturated FA(MUFA; often derived from olive oil, which also providesantioxidants) with only one double bond, such as oleicacid (OA; 18:1x-9), may be less susceptible to lipidperoxidation thanx-6 andx-3 PUFA with several doublebonds. In vitro studies indicated that cells treated withOA or olive oil were associated with less mitochondrialROS production than cells treated with certain PUFA

(e.g., DHA) or a soybean-oil-based LE [45, 46]. In apreclinical rodent study, lipid peroxidation was loweramong mice administered OA or olive oil by gavage thanamong mice administered PUFA (i.e., LA or DHA) or fishoil [47]. In children requiring PN, a LE containing 80%olive oil led to lower concentrations of certain lipid per-oxides than a soybean-oil-based LE (Table4) [48]. In aseparate study involving preterm infants, peroxidationmarkers were similar between an olive-oil-rich LEsupplemented with a-tocopherol and a conventional

soybean-oil-based LE, whereas vitamin E status wasenhanced with olive-oil-rich LE [49].

Cell-mediated immunity

Fatty acids have been shown to modulate the immunesystem in a number of ways, influencing cell signaling,gene expression, and apoptosis. In particular, x-6 PUFAhave been associated with reduced migration and phag-ocytic activity of neutrophils and macrophages,decreased lymphocyte reactivity to microbial antigens,and inhibition of antibody-dependent cellular cytotoxic-ity [34, 35, 5052]. The consequences of theseimmunosuppressive actions have been demonstrated

within the ICU setting. When compared with PN con-taining no lipids administered to trauma patients, PNcontaining a soybean-oil-based LE was associated withhigher rates of infection and significantly longer durationsof mechanical ventilation, longer ICU stays, and longerhospital stays (Table4) [53]. In patients with septicshock, those receiving a soybean-oil-based LE showedincreased leukocyte counts and reduced neutrophil cyto-toxic activity, while those receiving a fish-oil-based LEexperienced opposite effects [54]. However, excessive(hypercaloric) feeding may also have contributed toimmunosuppression observed in some older studies.

Among surgical patients receiving PN, a soybean-oil-based LE supplemented with fish oil was associated witha shorter ICU and overall hospital stay when comparedwith a LE that did not contain fish oil; however, the ratesof infection were similar between groups (Table 4) [55].When a soybean-oil-based LE was supplemented withfish oil, higher doses were associated with a reduction inthe length of ICU and overall hospital stay, significantlyreduced antibiotic requirement, and significantlyincreased survival [56].

In comparison with soybean oil, MCT are generallydescribed as immune neutral; however, effects upon cer-tain components of the immune system have beendescribed. In two ex vivo studies, MCT and MCT/soy-bean oil LEs increased monocyte activation andneutrophil adhesion and degranulation [57, 58]. In con-trast, another ex vivo study reported that MCT and MCT/soybean oil LEs were both associated with impairedneutrophil killing of Candida albicans [59]. An in vitro

study showed that a MCT/soybean oil LE inhibited theproliferation of T-lymphocytes but not lymphokine-acti-vated killer cells [60].

There are few clinical data evaluating the effect ofMCT on immune function. In a study involving healthyvolunteers, administration of an MCT/soybean oil LE wasassociated with increased total leukocyte and neutrophilcounts and significantly decreased lymphocyte counts[61]. A second study of healthy subjects found that, incontrast to intermittent infusion of soybean-oil-based LE,

Table 3 Diseases and intensive care unit states associated withreactive oxygen species-mediated tissue damage [39]

Septic shockAcute respiratory distress syndromeSystemic inflammatory response syndromeDisseminated intravascular coagulationMultiple organ dysfunction

BurnsCardiovascular diseaseDiabetes mellitusTraumaReperfusion injuryCancer

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Table4

continued

Clinicalstudy

Population

Design

Treatmentgroups

Keyfindings

Huschaketal.[88]

Ad

ultmultipletrauma

patients(N=

33)

Prospectiv

e,randomized,

open-labelstudy

ClinOleic(lipid-to-

glucoseratio=3:1)vs.

Lipofundin-MCT

(lipid-to-glucose

ratio=

1:3)for6

days

Meandurationofmechanicalv

entilation:13

(ClinOleic/lowglucose)vs.24days(Lipofundin-

MCT/highglucose;P=

0.01)

MeanICUstay:18(ClinOleic/lowglucose)vs.

25days(Lipofundin-MCT/highglucose;

P=

0.04)

Meanhospitalstay:80(ClinOleic/lowglucose)vs.

85days(Lipofundin-MCT/highglucose;NS)

Meansepsisscoresignificantly

lowerforClinOleic/

lowglucosevs.Lipofundin-M

CT/highglucoseon

days514(P\

0.05)

Wichmannetal.[70]

Ad

ultsundergoingabdominal

surgery(N=

256)

Prospectiv

e,randomized

study

Intralipidvs.Lipoplusfor

5days

MeanICUstay:6.3(Intralipid)vs.4.1days

(Lipoplus;NS)

Meanhospitalstay:21.9(Intralipid)vs.17.2days

(Lipoplus;P=

0.0061)

Incidenceofpyrexia:24.0%(Intralipid)vs.17.3%

(Lipoplus;NS)

Incidenceofcatheter-relatedsepsis:3.9%(Intralipid)

vs.3.1%(Lipoplus;NS)

Incidenceofpneumonia:3.9%

(Intralipid)vs.0.8%

(Lipoplus;NS)

Incidenceofmortality:1.6%(Intralipid)vs.4.7%

(Lipoplus;NS)

Mateu-deAntonio

etal.[74]

Ad

ultsrequiringPN

(N=

42)

Retrospective,

observationalstudy

Intralipidvs.ClinOleic

MeanICUstay:31.3(Intralipid)vs.25.2days

(ClinOleic;NS)

Meanhospitalstay:46.5(Intralipid)vs45.4days

(ClinOleic;NS)

Incidenceofsepsis:50%(Intra

lipid)vs.43.5%

(ClinOleic;NS)

Incidenceofmortality:44%(Intralipid)vs.47.8%

(ClinOleic;NS)

Helleretal.[56]

Ad

ultsrequiringtotalPN

(N=

661)

Prospectiv

e,open-label

study

Intralipid?

Omegav

en

forC3days

MeanICUstay:significantlyde

creasedatOmegaven

doses[0.05g/kgperday(P

\

0.001)

Meanhospitalstay:significantlydecreasedat

Omegavendoses[0.05g/kg

perday(P\

0.001)

Requirementforantibiotics:significantlyhigherat

Omegavendoses\0.05vs.0

.150.2g/kgperday

(P\

0.001)

Survivalrate:significantlyloweratOmegavendoses

\0.05vs.0.10.2g/kgperd

ay(P\

0.001)

Inflammation

Gogosetal.[68]

Severelyilladults(N=

20)

Prospectiv

e,randomized

study

Lipofundin-Svs.

Lipofundin-MCTfor

30days

CirculatingTNF-aconcentratio

ns:nodifferences

betweengroups

Endotoxin-inducedTNF-areleaseatday30vs.

baseline:185.4vs.95.3pg/m

L(Lipofundin-S;

P\

0.01);90.7vs.103.8pg

/mL(Lipofundin-

MCT;NS)

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Table4

continued

Clinicalstudy

Pop

ulation

Design

Treatmentgroups

Keyfindings

Kolleretal.[71]

Adultsundergoingabdominal

surgery(N=

30)

Prospective,randomized,

double-b

lindstudy

Intralipidvs.Lipoplu

sfor

5days

Day6:significantincreaseinL

TB5

releasevs.

baselinewithLipoplusbutno

tIntralipid

(P=

0.0104)

Nodifferencebetweengroupsf

orLTC5

release

Day6LTB5/LTB4

ratio:significantincreasevs.

baselinewithLipoplusbutno

tIntralipid

(P\

0.02)

Wichmannetal.[70]

Adultsundergoingabdominal

surgery(N=

256)

Prospective,randomized

study

Intralipidvs.Lipoplu

sfor

5days

Day6:significantincreaseinLT

B5

releasevs.day1

inbothgroups(P\

0.01)

Day6LTB5/LTB4

ratio:significantincreasevs.

day1withLipoplus(P=

0.002)butnotIntralipid

Mayeretal.[73]

Adultswithsepsis(N=

21)


study

Lipovenvs.Omegaven

for5days

Endotoxin-inducedTNF-a,IL-1

b,IL-6,IL-8release

(days1-18):significantincreasefrombaseline

withLipoven;significantdecreasefrombaseline

withOmegaven

Mateu-deAntonio

etal.[74]

AdultsrequiringPN

(N=

42)

Retrospective,

observationalstudy

Intralipidvs.ClinOle

ic

MeanconcentrationsofC-reactiveproteinatendof

PN:8.4(Intralipid)vs.11.0m

g/L(ClinOleic;NS)

Thrombosis

Portaetal.[78]

Adultcriticallyillpatients

(N=

23)

Prospective,randomized,

open-lab

elstudy

Intralipidvs.Lipofun

din-

MCTfor7days

Nosignificantchangesinplatel

etaggregationin

eithertreatmentgroup

Rouletetal.[78]

Adultsundergoingtotal

esophagectomy(N=

19)


study

Lipovenvs.

Lipoven?

Omegaven

for7days

Meanbleedingtime:3.1(Lipov

en)vs.3.3min

(Lipoven?

Omegaven;NS)

Meanmaximalcollagen-inducedplatelet

aggregation:91%(Lipoven)vs.87%

(Lipoven?

Omegaven;NS)

Meanmaximaladenosinedipho

sphate-induced

plateletaggregation:78%(Li

poven)vs.77%

(Lipoven?

Omegaven;NS)

Alllipidemulsionsadminister

edaspartoftotalparenteralnutritionwithintheICUsetting,unlessotherwisestated

LDLlow-densitylipoprotein,N

Snotsignificant,VLDLverylow-densitylipoprotein,PNparenteralnutrition,ICUintensivecareunit,MCTmedium-chaintriglycerides,TNF

tumornecrosisfactor,LTleuk

otriene,ILinterleukin

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infusion of PN containing MCT/soybean oil LE did notimpair the clearance of 99Tc-sulfur colloid by the retic-uloendothelial system [62]. In pediatric surgical patientsreceiving PN, an MCT/soybean oil LE was associatedwith a significantly increased lymphocyte count whencompared with a soybean-oil-based LE [63]. Another

study compared an MCT/soybean oil LE with a soybean-oil-based LE in severely undernourished patients under-going laparotomy [64]. In that study, the incidence ofintra-abdominal abscesses was significantly lower in theMCT/soybean oil group than the soybean oil group, butthere were no significant differences between the groupsfor other infections (Table4)[64].

Lipid emulsions containing high concentrations ofolive oil may have less impact on the host immuneresponse than soybean-oil-based or MCT/soybean oilLEs, with little effect on lymphocytes, natural killer cells,and neutrophils. In an in vitro study, the percentage oflymphocytes undergoing apoptosis or necrosis was higherfollowing incubation with 200 lM LA (77%) than with200 lM OA (23%); both were higher than the controlgroup (3%) [65]. Another study showed that lymphocyteactivation was dose-dependently inhibited by soybean-oil-based LEs but not an olive-oil-rich LE [66]. In con-trast to a MCT/soybean oil LE, an olive-oil-rich LEhad little effect on neutrophil activation, phagocytosis,generation of ROS or chemotaxis [67]. The immunosup-portive effects of an olive-oil-rich emulsion may bereflected clinically by the low incidence of infectiouscomplications reported in severely burned patientsreceiving PN in the ICU: in a study evaluating this patientpopulation, the incidences of sepsis and multiple organfailure and the duration of mechanical ventilation, ICUstay, and hospital stay were comparable for patientsreceiving olive-oil-rich and MCT/soybean oil LEs(Table4)[31].

Inflammation

Administration of soybean-oil-based LEs is associatedwith high blood levels of the x-6 PUFA LA and itsmetabolite AA, the further metabolism of which mayproduce proinflammatory eicosanoids [e.g., prostaglan-dins, thromboxanes, and leukotrienes (LT)] that canregulate additional inflammatory mediators [e.g., tumor

necrosis factor (TNF)-a] [32]. This hypothesis is sup-ported by a study reporting that malnourished, severely illpatients experienced significantly increased total produc-tion of TNF-a when receiving PN with a soybean-oil-based LE but not an MCT/soybean oil LE [68]. Althoughthere has been much focus on the proinflammatory effectsof AA-derived eicosanoids, lipoxins derived from AAhave potent inflammation-resolving effects [69].

Conversely, the long-chainx-3 PUFAs EPA and DHAfound in fish oils are thought to possess anti-inflammatory

properties because they are readily incorporated into cellmembranes and thereby impact AA metabolism [18,32],because the metabolism of EPA is associated with pro-duction of less biologically potent eicosanoids than thoseproduced from AA [18,32], and because EPA and DHAare precursors of resolvins with powerful inflammation-

resolving properties [18, 69]. Indeed, when soybean oilwas partially replaced with fish oil (3:1 ratio) in surgicalpatients receiving PN, LT synthesis was shifted from theproinflammatory LTB4 (produced from AA) to the lesspotent LTB5 (produced from EPA) (Table4) [70, 71].This change was associated with significantly reducedconcentrations of the inflammatory mediators interleukin(IL)-6 and TNF-a [72]. In patients with sepsis, concen-trations of IL-1b, IL-6, IL-8, and TNF-a released frommononuclear leukocytes were significantly increasedfollowing administration of a soybean-oil-based LEcompared with a decrease of approximately 30% fol-lowing administration of a fish-oil-based LE [73].

Lipid emulsions rich in olive oil have not been wellstudied with regard to their effect on inflammation;however, a few studies have demonstrated that OA hasrelatively few effects on the production of inflammatorymediators. In a preclinical study, lipopolysaccharide-induced production of IL-1b, IL-6, IL-8, and TNF-a byneutrophils was not altered by an olive-oil-rich LE,compared with significant reductions in IL-1b with soy-bean-oil-based and MCT/soybean oil LEs [67]. In anotherstudy, infectious complication rates, mortality rates, andlength of ICU stay were similar among critically illpatients receiving PN containing soybean-oil-based andolive-oil-rich LEs [74].

Thrombosis

Thrombosis is a common and serious complication formany critically ill, surgical, and trauma patients, as thesestates may be associated with changes in the availabilityof clotting factors and alterations in the fibrinolyticpathway, resulting in intravascular coagulation [75].However, the effects of LEs on coagulation have not beenextensively assessed. In one study, platelet aggregationwas inhibited immediately following intravenous infusionof a fish-oil-based LE to healthy volunteers, but hadreturned to normal at 24 h [76]. In surgical patients

receiving PN, the latency to collagen-induced plateletaggregation and time to maximal platelet aggregationwere significantly longer for a soybean-oil-based LE thanfor a fish-oil-enriched LE; however, adenosine-dipho-sphate-induced platelet aggregation and bleeding timewere unchanged [77]. Another study found no change inplatelet aggregation for critically ill patients receivingeither soybean-oil-based or MCT/soybean oil LEs [78].

The effects of parenteral olive-oil-rich LEs onthrombosis have not been systematically evaluated.

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Table5

Keycharacteristicso

fwidelyavailableparenterallipidemuls

ions[22,43,73,89]

Intralipid

Lipoven

Lipofundin-M

CT

Structolipid

Omegaven

Lipoplus

ClinOleic

SMOFLipid

Manufacturer

Freseniu

s-Kabi,

Germany

Fresenius-Kabi,

Germany

B.Braun,Germany

Fresenius-Kabi,

Germany

Fresenius-Kabi,

Germany

B.Braun,

Germany

Baxter,France

Fresenius-Kabi,

Germany

Oilsource(%by

weight)

Soybean

Soybean

Coconut(50%),

soybean(5

0%)

Coconut(36%),

soybean(64%)

Fish(100%)

Coconut(50%),

soybean

(40%),fish

(10%)

Olive(80%),

soybean

(20%)

Coconut(30%),

soybean(30%),

olive(25%),

fish(15%)

TypicalFAcomposition(%oftotalFA)

Caproic

0.5

Trace

Trace

Caprylic

28.5

26

30

10

Capric

20

10

19.5

11

Lauric

1

Trace

Trace

Myristic

5

0.5

Trace

1

Palmitic

11

12

7.5

7

12

6

12

10

Stearic

4

5

2

3

4.5

2.5

2

3.5

Palmitoleic

9

0.5

1.5

1.5

Oleic

24

24

11

14

15

8

62

31

Linoleic

53

53

29

35

4.5

24.5

19

20

a-Linolenic

8

8

4.5

4

1.8

3.5

2.5

2

Arachidonic

2

Eicosapentaenoic

20

3.5

3

Docosapentaenoic

2

3

Trace

Docosahexaenoic

12

2.5

2

a-Tocopherol

(lmol/L)

87

132

502

16

505

562

75

500

FAfattyacids

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However, in one study of patients undergoing hemodial-ysis, the need to change hemofilters due to bloodcoagulation was significantly reduced among patientsreceiving PN containing an olive-oil-rich LE comparedwith a soybean-oil-based LE [79].

Choosing a parenteral lipid emulsion for the criticallyill patient

Components of commercially available lipidemulsions

A summary of the key characteristics of available par-enteral LEs is presented in Table5; in some countries(i.e., the USA) only soybean-oil-based LEs are available[8]. The choice of parenteral LE should be based uponseveral considerations. It has been suggested that the ratioof LA to ALA is important because of competitionbetween these FA for a number of enzymes, therebypotentially influencing the production of eicosanoid andeicosanoid-like inflammatory mediators [80]. However, anumber of studies have suggested that the absolute con-centrations of certain PUFA are more important than theirratio in determining their biologic effects [80, 81]. Inaddition, the FA content of LEs can vary depending uponthe specific source of oil (e.g., EPA and DHA withindifferent fish oils) [80].

The stability of LEs, with respect to phase separationand presence of large globules, is also an important issuein clinical settings in which the final concentrations oflipid components and emulsifiers are of key importance.All LEs eventually become unstable when diluted above acertain threshold within the PN formulation. Currentregulations in the USA require that globules[5 lm donot exceed 0.05% (weight/volume) of the emulsion [82].In general, MCT/soybean oil and olive-oil-rich LEs havedemonstrated greater stability when compared with soy-bean-oil- and safflower-oil-based LEs, although stabilitymay vary between manufacturers [82,83]. The stability ofMCT/soybean oil LEs may be due to the inclusion ofshorter-chain lipids, which exhibit a lower free energywhen dispersed in water, resulting in greater miscibility

between phases and reduced physicochemical stress onemulsifying agents compared with LEs containing pre-dominantly longer-chain triglycerides [83]. Olive-oil-richLEs contain sodium oleate, which acts as an additionalemulsifying agent and thereby augments stability [83]. Inaddition, the stability of PN formulations that contain LEs

may be affected by interactions between FA and othercommonly administered compounds, such as carnitine,heparin, and some vitamins [8486].

Potential therapeutic roles for lipid emulsions

Lipid emulsions demonstrate different biologic effectsdepending upon their specific FA content, which maytranslate into beneficial effects for selected patients(Table6). The biologic effects associated with LEs arelikely to benefit a majority of patients receiving parenteralLEs, including those on long-term total PN, but may havethe greatest importance for patients under metabolicstress. Therefore, physicians need to consider severalissues when selecting an LE as part of a PN regimen.

All currently available LEs provide sufficient x-6 andx-3 EFA, with the exception of 100% fish oil LE, whichshould generally only be used as a pharmacological agentor as a supplement to other LEs [21,22]. Although thereare conflicting views regarding the comparative utility ofdifferent LE formulations in critically ill patients, there isgrowing consensus that LEs based entirely on soybean oilshould be avoided in favor of emulsions in which the LAand ALA content is partially replaced by MCT, olive oilproviding MUFA or fish oil providing EPA and DHA.This is particularly true for patients with highly proin-flammatory states, such as surgical, trauma, burn, andseptic patients [8,87]. In addition, the clinical use of LEsshould not exacerbate oxidative stress in critically illpatients. Unfortunately, evidence on the differentialeffects of LEs in critically ill patients remains limited.Furthermore, inconsistencies of findings between studieshave suggested that the biologic effects of FA may varywith the medical condition and level of metabolic stress;therefore, further clinical trials exploring the effects of FAin different subpopulations of critically ill patients arehighly desirable.

Table 6 Potential therapeuticapplications of lipid emulsions Cell function and proliferation

Provide sufficient fatty acidsImprove metabolism and limit/reverse energy deficit

Oxidative stressLimit the contribution of lipid peroxidation to oxidative stressMaintain or increase antioxidant concentrations

Intrinsic immune functionSupport the immune system and limit immunosuppressionReduce the incidence of infectious complications

InflammationPrevent/regulate hyperinflammation, especially important for patients with pre-existing

inflammation (e.g., surgery, sepsis, chronic inflammatory diseases)

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Conclusions

Energy deficit is a major problem among ICU patientsand is associated with an increased incidence of compli-cations, length of stay, and mortality. PN, either alone orin combination with EN, can improve caloric delivery to

critically ill patients, preventing or correcting energydeficits and improving outcomes. Lipids are an importantsource of calories in artificial nutrition, and they havedemonstrated a wide range of biologic activities that maybenefit a variety of patients receiving PN, as well as thosereceiving EN with or without PN supplementation.

Parenteral lipid emulsions derived from soybean oilare the most extensively evaluated formulations in pre-clinical and clinical studies and have demonstratedefficacy and safety in delivering vital nutrition to criti-cally ill patients. Newer LEs that utilize partialsubstitution of soybean oil with MCT, olive oil or fish oileither alone or in combination have demonstrated poten-

tial benefits in terms of reduced impacts on oxidativestress and differential effects on cell-mediated immunityand inflammation. However, few published studies haveevaluated the biologic effects of newer parenteral LEs,and data assessing the clinical benefits of these newerformulations are limited and sometimes inconsistentbecause of the heterogeneity of the study designs andpatient populations. Ongoing research to further charac-terize and compare the biologic properties of lipids givenparenterally, as well as enterally, will be an importantresource for physicians, especially those managing

critically ill patients, who are often under metabolicstress. These studies must be adequately designed andwell controlled. Until then, the prescription of LEs shouldbe based upon the limited clinical data available, therange of available LEs, cost implications, and an under-standing of the potential biologic effects of their

components, bearing in mind the situation and therapeuticgoals of the individual patient.

Acknowledgments Editorial assistance was provided by KimberlyBrooks, PhD, of MedErgy (Yardley, PA).

Conflict of interest statement The writing of this manuscriptwas financially supported by a grant from Baxter Healthcare,Deerfield, IL, USA to MedErgy, Yardley, PA. All authors werefinancially supported by Baxter Healthcare to attend a workshop onlipid emulsions held in May 2008 in Rome, Italy. P.C.C. hasreceived speaking honoraria from B. Braun, Baxter Healthcare,Fresenius-Kabi, and Abbott Nutrition and has received researchfunding from B. Braun. B.V.K. has received speaking honorariaand research funding from B. Braun, Baxter Healthcare, andFresenius-Kabi. P.S. has received speaking honoraria from Abbott

Nutrition, Baxter Healthcare, and Fresenius-Kabi and researchfunding from B. Braun and Fresenius-Kabi. G.J.A.W. has receivedspeaking honoraria from Baxter Healthcare and Fresenius-Kabi.G.L.J. has received speaking honoraria and/or consulting fees fromBaxter Healthcare, Nestle Nutrition, and Abbott Nutrition.

Open Access This article is distributed under the terms of the Cre-

ative Commons Attribution Noncommercial License which permits any

noncommercial use, distribution, and reproduction in any medium,

provided the original author(s) and source are credited.

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Lipid Management- Current thinking