Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ictx20 Download by: [University of Sydney Library] Date: 16 August 2017, At: 17:44 Clinical Toxicology ISSN: 1556-3650 (Print) 1556-9519 (Online) Journal homepage: http://www.tandfonline.com/loi/ictx20 Systematic review of clinical adverse events reported after acute intravenous lipid emulsion administration Bryan D. Hayes, Sophie Gosselin, Diane P. Calello, Nicholas Nacca, Carol J. Rollins, Daniel Abourbih, Martin Morris, Andrea Nesbitt-Miller, José A. Morais, Valéry Lavergne & Lipid Emulsion Workgroup To cite this article: Bryan D. Hayes, Sophie Gosselin, Diane P. Calello, Nicholas Nacca, Carol J. Rollins, Daniel Abourbih, Martin Morris, Andrea Nesbitt-Miller, José A. Morais, Valéry Lavergne & Lipid Emulsion Workgroup (2016) Systematic review of clinical adverse events reported after acute intravenous lipid emulsion administration, Clinical Toxicology, 54:5, 365-404, DOI: 10.3109/15563650.2016.1151528 To link to this article: http://dx.doi.org/10.3109/15563650.2016.1151528 Published online: 01 Apr 2016. Submit your article to this journal Article views: 1220 View related articles View Crossmark data Citing articles: 20 View citing articles
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Full Terms & Conditions of access and use can be found athttp://www.tandfonline.com/action/journalInformation?journalCode=ictx20
Download by: [University of Sydney Library] Date: 16 August 2017, At: 17:44
Systematic review of clinical adverse eventsreported after acute intravenous lipid emulsionadministration
Bryan D. Hayes, Sophie Gosselin, Diane P. Calello, Nicholas Nacca, CarolJ. Rollins, Daniel Abourbih, Martin Morris, Andrea Nesbitt-Miller, José A.Morais, Valéry Lavergne & Lipid Emulsion Workgroup
To cite this article: Bryan D. Hayes, Sophie Gosselin, Diane P. Calello, Nicholas Nacca, CarolJ. Rollins, Daniel Abourbih, Martin Morris, Andrea Nesbitt-Miller, José A. Morais, Valéry Lavergne& Lipid Emulsion Workgroup (2016) Systematic review of clinical adverse events reportedafter acute intravenous lipid emulsion administration, Clinical Toxicology, 54:5, 365-404, DOI:10.3109/15563650.2016.1151528
To link to this article: http://dx.doi.org/10.3109/15563650.2016.1151528
Published online: 01 Apr 2016. Submit your article to this journal
Article views: 1220 View related articles
View Crossmark data Citing articles: 20 View citing articles
Systematic review of clinical adverse events reported after acute intravenouslipid emulsion administration
Bryan D. Hayesa, Sophie Gosselinb,c,d, Diane P. Calelloe, Nicholas Naccaf, Carol J. Rollinsg, Daniel Abourbihh,Martin Morrisi, Andrea Nesbitt-Milleri, Jos�e A. Moraisj, and Val�ery Lavergnek, Lipid Emulsion Workgroup*aDepartment of Pharmacy, University of Maryland Medical Center and Department of Emergency Medicine, University of Maryland School ofMedicine, Baltimore, MD, USA; bDepartment of Medicine, McGill Faculty of Medicine, Emergency Medicine, McGill University Health Centre,Montr�eal, Canada; cProvince of Alberta Drug Information Services, Alberta, Canada; dCentre antipoison du Qu�ebec, Qu�ebec, Canada; eMedicalToxicology, Department of Emergency Medicine, Morristown Medical Center, Emergency Medical Associates, Morristown, NJ, USA;fDepartment of Surgery, Division of Emergency Medicine, University of Vermont, Burlington, VT, USA; gBanner-University Medical CenterTucson, University of Arizona College of Pharmacy, Tucson, AZ, USA; hDepartment of Medicine, Division of Emergency Medicine, University ofToronto, Toronto, Canada; iLife Sciences Library, McGill University, Montr�eal, Canada; jDivision of Geriatric Medicine, McGill University,Montr�eal, Qu�ebec, Canada; kDepartment of Medical Biology, Sacr�e-Coeur Hospital, University of Montr�eal, Montr�eal, Canada
ABSTRACTBackground: Intravenous lipid emulsions (ILEs) were initially developed to provide parenteral nutrition.In recent years, ILE has emerged as a treatment for poisoning by local anesthetics and various otherdrugs. The dosing regimen for the clinical toxicology indications differs significantly from those used forparenteral nutrition. The evidence on the efficacy of ILE to reverse acute toxicity of diverse substancesconsists mainly of case reports and animal experiments. Adverse events to ILE are important to considerwhen clinicians need to make a risk/benefit analysis for this therapy. Methods: Multiple publicationdatabases were searched to identify reports of adverse effects associated with acute ILE administrationfor either treatment of acute poisoning or parenteral nutrition. Articles were selected based onpre-defined criteria to reflect acute use of ILE. Experimental studies and reports of adverse effects as acomplication of long-term therapy exceeding 14 days were excluded. Results: The search identified 789full-text articles, of which 114 met the study criteria. 27 were animal studies, and 87 were human stud-ies. The adverse effects associated with acute ILE administration included acute kidney injury, cardiacarrest, ventilation perfusion mismatch, acute lung injury, venous thromboembolism, hypersensitivity, fatembolism, fat overload syndrome, pancreatitis, extracorporeal circulation machine circuit obstruction,allergic reaction, and increased susceptibility to infection. Conclusion: The emerging use of ILE adminis-tration in clinical toxicology warrants careful attention to its potential adverse effects. The dosing regi-men and context of administration leading to the adverse events documented in this review are notgeneralizable to all clinical toxicology scenarios. Adverse effects seem to be proportional to the rate ofinfusion as well as total dose received. Further safety studies in humans and reporting of adverseevents associated with ILE administration at the doses advocated in current clinical toxicology literatureare needed.
ARTICLE HISTORYReceived 18 August 2015Revised 26 January 2016Accepted 2 February 2016Published online 31 March2016
KEYWORDSGut and hepatotoxicity;liver; metabolic
Introduction
Intravenous lipid emulsion (ILE) has recently received muchattention in the treatment of acute local anesthetic toxicityand a variety of other non-local anesthetic poisonings. Manyclinicians may be unfamiliar with the likely adverse effects ofILE, particularly regarding its use in toxicological cases. Whileat least 90 published cases describe adverse effects associ-ated with antidotal use of ILE for various toxins, reportingbias (whether bias favoring publication of a novel event orbias favoring not publishing the complications of therapy)may result in inconsistent or disproportionate representationof the clinical effects of ILE as represented by these cases.The use of ILE in various forms has occurred for decades in
total parenteral nutrition (TPN), and this longer and broaderclinical experience may indicate likely events that may alsooccur with acute antidotal use of ILE.[1]
After IntralipidVR became readily available, reports ofadverse reactions associated with its use began to surface,despite assumptions about its safety compared with previousILE preparations. These adverse effects tended to be infre-quent and non-life-threatening, but they complicated therapy.Reactions related directly to ILE can occur within minutes tohours after infusion, or they can be delayed for weeks toyears with ongoing exposure to ILE, as is necessary with long-term parenteral nutrition.
Both the rate of infusion and the total dose infused areassociated with reactions to ILE. Guidelines for maximum
CONTACT Bryan D. Hayes [email protected] Department of Pharmacy, University of Maryland Medical Center, 22 South Greene St, Baltimore, MD21230, USA*The Lipid emulsion workgroup also includes: Benoit Bailey, Theodore C. Bania, Ashish Bhalla, Ryan Chuang, Brian M. Gilfix, Andis Graudins, Ami M. Grunbaum,Lotte C. G. Hoegberg, Robert S. Hoffman, Michael Levine, Sheldon Magder, Bruno M�egarbane, Samuel J. Stellpflug, Christine Stork and Alexis F. Turgeon.� 2016 Informa UK Limited, trading as Taylor & Francis Group
doses and rates of infusion have been established for nutri-tion support and are based on reported adverse eventssuch as dyspnea, cyanosis, flushing, hypercoagulability,hypertriglyceridemia and chest pain.[2] In adults, infusionfaster than the estimated maximum oxidation rate of1.2–1.7 mg/kg/min (for ILE 20%, this is 0.35–0.51 mL/kg/h or8.6–12.24 mL/kg/day) likely increases the risk of significantadverse events and is not recommended.[3–5]
Rapid reactions to ILE can transpire with any of the indica-tion for its use (i.e., nutrition, drug carrier, or treatment of poi-soning). ILE as an antidote was used initially to countercardiac arrest induced by a local anesthetic. An increasingnumber of case reports have documented the use of ILE forless or non-life-threatening indications. Under emergencyconditions, the amount of ILE given in a short period of timemay exceed, by many fold, the daily limit usually given forTPN. If ILE is being considered for a non-life-threatening con-dition, the risk/benefit profile should be part of thatconsideration.
The purpose of this literature review is to characterize theadverse effects that have been reported after administrationof ILE, irrespective of the purpose for ILE (i.e., nutrition, drugcarrier, or treatment of poisoning), to assist clinicians in arisk/benefit assessment when ILE treatment for poisoning isconsidered.
Methods
The American Academy of Clinical Toxicology initiated a col-laboration among the European Association of Poison Centersand Clinical Toxicologists, the Asia Pacific Association ofMedical Toxicologist, the Canadian Association of PoisonControl Centers, the American College of Medical Toxicology,and the American Association of Poison Control Centers toreview the evidence and produce recommendations on theuse of this novel therapy for drug toxicity. A working sub-group (the authors) formed to gather and review the evidenceregarding clinical adverse events associated with short-termuse of ILE. This subgroup comprised clinical experts and vari-ous stakeholders involved in the workgroup. It also includedtwo medical librarians who assisted in conducting the system-atic searches and the retrieval of potentially eligible publica-tions, as well as an epidemiologist with specificmethodological expertise in conducting systematic reviews.Subgroup members divulged all potential conflicts of interestsprior to inclusion in the workgroup. All communicationoccurred by email exchanges and by telephone conferences.
Two medical librarians created a systematic search strategyfor Medline (Ovid), which appears in the Appendix. The strat-egy comprised a combination of Medical Subject Headings,title/abstract key words, truncations, and Boolean operators,and included the concepts of ILE. The same search strategywas used for Embase (via Ovid), CINAHL (via EBSCO), BIOSISPreviews (via Ovid), Web of Science, Scopus, and theCochrane Library/DARE. All databases searches ran frominception to 15 December 2014.
In addition, conference abstracts from the EuropeanAssociation for Poison Centers and Clinical Toxicologists, and
the North American Congress of Clinical Toxicology (bothfrom 2000 to 2014) and abstracts from the Asia PacificAssociation of Medical Toxicology from 2007 to 2014 weresearched. Group members hand-searched previous reviewarticles. Group members also performed cross-referencing offull-text articles. No limits were applied for language, and can-didate studies in languages not known to any of the authorswere translated.
In summary, the criteria for publication inclusion in theevaluation of the effect of ILE include studies in humans andanimals who received ILE for any indication. Rapidly occurringreactions to ILE from the parenteral nutrition literature wereincluded. These cases are applicable to the evaluation of thesafety profile for ILE used for acute poisonings and are appro-priate to include in this review. Articles describing adverseevents associated with long-term use (defined as >14 days)of ILEs for TPN were excluded. Other exclusion criteria werenon-original data or animal studies with methods and resultsthat cannot be extrapolated or are uninterpretable. A com-plete methodology of the larger project of which this system-atic review is one part has been previously published anddescribes in detail all relevant methodological aspects such asclinical questions, search strategies, eligibility of publications,data extraction and summary, and assessment of the risk ofbias.[151] The Grading of Recommendations Assessment,Development and Evaluation (GRADE) methodology was usedto appraise the quality of the evidence.
Results
The initial search identified 36,903 citations. A total of 36,933citations were screened for relevance. Full text copies unavail-able for five citations. This selection yielded 789 full textarticles, of which 675 full text articles were excluded fromanalysis. Figure 1 lists the reasons for exclusion.
One hundred fourteen articles were analyzed for theirreport of acute adverse events that followed the thera-peutic use of ILE for TPN or for the treatment of poisoning.The articles were divided into human (87 articles) and ani-mal (27 articles) studies. We assigned each publication toan adverse event category to facilitate analysis. The finallevel of evidence was reported as per the GRADE sys-tem.[6–9] Table 1 summarizes the quality of the evidence.Most studies received low grades because they use animalmodels or are case reports of human patients. However,given the amount of animal data available and the ten-dency to rely on animal data for guidance in managingrare events that are difficult to randomize in humans, theywere also included for analysis.
Human studies
The human studies were categorized according to the pre-dominant effect of ILE administration: organ dysfunction(including cardiovascular, hematological, acute kidney injury[AKI], and metabolic acidosis); pulmonary effects (includingacute respiratory distress syndrome [ARDS], acute lunginjury [ALI], hypoxia, and ventilation/perfusion [V/Q]
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mismatch); hypersensitivity and allergic effects; vascularocclusion including priapism, deep vein thrombosis [DVT],phlebitis, coagulopathy, fat embolism, continuous veno-ven-ous hemodiafiltration [CVVHF], and extracorporeal mem-brane oxygenation [ECMO] line interference; infectionsusceptibility and inflammatory effects; and fat overloadsyndrome, hypertriglyceridemia, lipemia, hyperamylasemia,pancreatitis, and cholestasis.
Organ failure
Cardiovascular effectsTen articles describing adverse effects were categorized ascardiovascular (Table 2).[10–19] Fatal cardiac arrest and deathwere reported in neonates receiving IntralipidVR at 0.08–0.15 g/kg/h (0.4–0.75 mL/kg/h for ILE 20%) as part of TPN ther-apy.[13,20] It is unclear if the ILE administration caused thecardiac events or was simply associated with them.Pulmonary fat microemboli were found in the lung of oneinfant at autopsy.[13] One report described two adult patientswho received IntralipidVR for drug-induced shock in whichasystole immediately followed the ILE bolus in both cases.[11]Both patients had refractory hypotension and bradycardia
prior to ILE administration and the only conclusion that canbe drawn is that there was a temporal relationship betweenILE administration and onset of asystole. Kidney failure andcardiac arrest were reported in a TPN patient following theadministration of 2580 mL of ILE (10 and 20%) over 24 h.[12]
Abel et al. studied 19 adult patients divided into twogroups following uncomplicated isolated coronary arterybypass surgery.[10] One treatment group received a constant60-min infusion of 2 mL/min of soy oil emulsion (20%IntralipidVR ) while the second group received 20% Intralipid at1 mL/min for 1 h followed by an increase to 2 mL/min for anadditional hour. Patients receiving the constant 2 mL/mininfusion (averaging 5.25 mg/kg/min) had lower cardiac outputand higher pulmonary wedge pressure than patients startingat 1 mL/min. No significant hemodynamic changes or adverseside effects occurred in the 1 mL/min group.[10] The authorsconcluded that the rate should not exceed the maximumclearance rate of 1 mL/min averaging 2.67 mg/kg/min in thestudy population. Marfella et al. studied the effect of 10% ILEplus heparin (to stimulate lipoprotein lipase activity) on car-diac repolarization in a controlled, crossover study with 32healthy non-obese subjects.[15] Compared with saline, ILEplus heparin increased blood pressure, heart rate, QTc disper-sion, and plasma concentrations of epinephrine and free fatty
Records identified through databasesearching (n = 36,903)
Additional records identified throughother sources (n = 30)
Adverse effect not applicableto ILE in poisoning (n=39)
Duplicate data (n=14)
Experimental (n = 38)
Interferences (n = 12)
No adverse effect reported (n= 100)
No relevant data (n = 227)
Opinion: no new data (n = 50)
Review: no new data (n = 137)
Studies included in qualitativesynthesis (n = 114; Human = 87,
Animal =27)
Figure 1. Selection of article flow diagram.
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Tabl
e1.
Sum
mar
yes
timat
esw
ithas
soci
ated
GRA
DE
ratin
gsfo
rco
ntro
lled
stud
ies
repo
rtin
gad
vers
eev
ents
.
Com
paris
onSu
mm
ary
offin
ding
Qua
lity
ofev
iden
ce
No.
ofst
udie
sPo
pula
tion
Inte
rven
tion
(No.
ofpa
tient
s)Co
mpa
rato
r(N
o.of
patie
nts)
Sum
mar
yes
timat
eaIn
terp
reta
tion
Qua
lity
asse
ssm
entb
GRA
DE
ratin
g
Orga
ndy
sfunc
tion
Card
iova
scul
arev
ents
N=
1[1
0]Po
stco
rona
ryar
tery
bypa
ssH
ighe
rin
fusi
onra
te(n
=12
)Sl
ower
infu
sion
rate
(n=
7)RD
(95%
CI)
inca
rdia
cis
chem
ia=þ
0.08
(NA)
No
diffe
renc
ein
card
iac
isch
e-m
iaev
ents
betw
een
grou
ps.
Obs
erva
tiona
lstu
dy;D
owng
rade
:Im
prec
isio
ndu
eto
smal
lsam
ple
size
(�1)
Very
low
N=
1[1
9]Po
stm
ajor
GI
surg
ery
Lipo
synTM
II(n
=10
)In
tral
ipid
VR
(n=
10)
No
card
iova
scul
arev
ents
repo
rted
No
diffe
renc
ein
card
iova
scu-
lar
even
tsbe
twee
ngr
oups
.RC
T;D
owng
rade
:Im
prec
isio
ndu
eto
smal
lsam
ple
size
(�1)
and
abse
nce
ofev
ents
repo
rted
(�1)
Low
Card
iac
outp
utN
=1
[10]
Post
coro
nary
arte
ryby
pass
ILE
(n=
12)
No
ILE
(sal
ine)
(n=
7)M
D(9
5%CI
)in
card
iac
outp
ut(L
/min
)=�
1.79
(�3.
10;�
0.48
)IL
Ew
assi
gnifi
cant
lyas
soci
-at
edw
ithlo
wer
card
iac
inde
xas
com
pare
dto
salin
e.
Obs
erva
tiona
lstu
dy;D
owng
rade
:Li
mita
tion
due
topo
tent
ials
elec
-tio
nbi
as(lo
wer
card
iac
outp
utat
base
line
inth
eIL
Egr
oup)
(�1)
;In
dire
ctne
ssdu
eto
surr
ogat
em
arke
r(�
1),I
mpr
ecis
ion
due
tosm
alls
ampl
esi
ze(�
1)
Very
low
N=
2[1
0,17
]Po
stco
rona
ryar
tery
bypa
ssor
criti
cally
illH
ighe
rin
fusi
onra
te(n
=30
)Sl
ower
infu
sion
rate
(n=
25)
MD
(95%
CI)
inca
rdia
cou
tput
(L/m
in)=�
1.57
(�2.
79;�
0.35
)[1
0];
Repo
rted
com
para
tive
card
iac
inde
x-=
low
erin
seps
isan
dhi
gher
inAR
DS
whe
nco
mpa
ring
high
erin
fusi
onra
tegr
oups
toco
ntro
ls.(
P=
NR)
[17]
Hig
her
infu
sion
rate
was
sig-
nific
antly
asso
ciat
edw
ithlo
wer
card
iac
inde
xin
coro
n-ar
yar
tery
bypa
ss.
Hig
her
infu
sion
rate
was
pos-
sibl
yas
soci
ated
with
low
erca
rdia
cin
dex
inse
psis
and
with
high
erca
rdia
cin
dex
inAR
DS.
RCT
cros
sove
ran
dO
bser
vatio
nal
stud
y;D
owng
rade
:Lim
itatio
ndu
eto
pote
ntia
lsel
ectio
nbi
as(lo
wer
card
iac
outp
utat
base
line
inth
ehi
gher
infu
sion
rate
inon
est
udy)
(�1)
;Ind
irect
ness
due
tosu
rro-
gate
mar
ker
(�1)
,Im
prec
isio
ndu
eto
smal
lsam
ple
size
inon
est
udy
and
indi
rect
com
paris
onbe
twee
ngr
oups
inth
eot
her
(�1)
;Upg
rade
:Dos
egr
adie
ntre
spon
sein
one
stud
y(þ
1)
Very
low
N=
1[1
6]Pa
ncre
atiti
sw
ithAR
DS
LCT/
MCT
(n=
9)LC
T(n
=9)
MD
(95%
CI)
inca
rdia
cou
tput
(L/
min
)=þ
0.5
(þ0.
12;þ
0.88
)LC
T/M
CTw
assi
gnifi
cant
lyas
soci
ated
with
high
erca
rdia
cou
tput
asco
mpa
red
toLC
T.
RCT
cros
sove
r;D
owng
rade
:In
dire
ctne
ssdu
eto
surr
ogat
em
arke
r(�
1),I
mpr
ecis
ion
due
tosm
alls
ampl
esi
ze(�
1)
Low
QT-
cN
=1
[15]
Hea
lthy
volu
ntee
rsIL
E(n
=32
)N
oIL
E(s
alin
e)(n
=32
)Es
timat
edM
D(9
5%CI
)in
Q-T
c(m
s)=þ
40(N
R)(p<
0.01
)IL
Ew
assi
gnifi
cant
lyas
soci
-at
edw
ithlo
nger
Q-T
can
dQ
-Tc
disp
ersi
onas
com
pare
dto
salin
e.
RCT
cros
sove
r;D
owng
rade
:In
dire
ctne
ssdu
eto
surr
ogat
em
arke
r(�
1)
Mod
erat
e
Estim
ated
MD
(95%
CI)i
nQ
-Tc
disp
ersio
n(m
s)=þ
27(N
R)(p<
0.01
)(c
ontin
ued)
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Tabl
e1.
Cont
inue
d
Com
paris
onSu
mm
ary
offin
ding
Qua
lity
ofev
iden
ce
No.
ofst
udie
sPo
pula
tion
Inte
rven
tion
(No.
ofpa
tient
s)Co
mpa
rato
r(N
o.of
patie
nts)
Sum
mar
yes
timat
eaIn
terp
reta
tion
Qua
lity
asse
ssm
entb
GRA
DE
ratin
g
Acut
eki
dney
inju
ryN
=1
[29]
Prem
atur
ein
fant
sne
edin
gar
tific
ial
nutr
ition
ILE
(n=
50)
No
ILE
(ent
eral
nutr
i-tio
n)(n
=54
)M
D(9
5%CI
)in
seru
mcy
stat
inC
(mg/
L)=þ
0.3
(þ0.
20;þ
0.40
)
ILE
was
sign
ifica
ntly
asso
ci-
ated
with
high
erle
vels
ofgl
omer
ular
and
tubu
lar
func
-tio
nbi
omar
kers
asco
mpa
red
toco
ntro
ls.
No
diffe
renc
ein
rena
lfun
c-tio
nbe
twee
ngr
oups
.
Obs
erva
tiona
lstu
dy;D
owng
rade
:Li
mita
tion
due
topo
tent
ials
elec
-tio
nbi
as(c
onfo
undi
ng-b
y-in
dica
-tio
n)(�
1)an
dab
senc
eof
adju
stm
ent
for
pote
ntia
lcon
-fo
unde
rs(�
1),I
ndire
ctne
ssdu
eto
surr
ogat
em
arke
rs(�
1)
Very
low
MD
(95%
CI)
inur
inar
yb2
mic
rogl
o-bu
lin(m
g/L)
=þ
6.5
(þ4.
35;þ
8.65
)M
D(9
5%CI
)in
glut
hatio
ne-S
-tra
nsfe
r-as
ep
(ng/
mL)
=þ
34.3
(þ16
.57;
þ52
.23)
MD
(95%
CI)
N-a
cety
l-b
-Dgl
ucos
ami-
nida
se(m
g/L)
=þ
2.5
(þ0.
31;þ
4.69
)M
D(9
5%CI
)in
BUN
(mg/
dL)=þ
2.6
(�0.
19;þ
5.39
)M
D(9
5%CI
)in
crea
tinin
e(m
g/dL
)=�
0.05
(�0.
11;þ
0.01
)
Pulm
onar
yad
vers
eef
fects
Resp
irato
ryev
ents
/pne
umon
iaN
=1
[32]
Poly
trau
ma
patie
nts
ILE
(n=
30)
No
ILE
(n=
27)
RD(9
5%CI
)of
pneu
mon
ia=þ
0.25
(þ0.
01;þ
0.50
)IL
Ew
assi
gnifi
cant
lyas
soci
-at
edw
itha
high
erris
kof
pneu
mon
iaas
com
pare
dto
cont
rols
.
RCT;
Dow
ngra
de:L
imita
tion
due
topo
tent
ialr
epor
ting
bias
(uns
peci
fied
dura
tion
tore
port
clin
ical
outc
omes
)(�
1)an
ddu
eto
inco
mpl
ete
repo
rtin
gof
pote
n-tia
lcon
foun
ding
fact
ors
(�1)
;Im
prec
isio
ndu
eto
smal
lsam
ple
size
(�1)
Very
low
N=
1[1
9]Po
stm
ajor
GI
surg
ery
Lipo
synTM
II(n
=10
)In
tral
ipid
VR
(n=
10)
No
resp
irato
ryad
vers
eev
ents
repo
rted
No
diffe
renc
ein
resp
irato
ryad
vers
eev
ents
betw
een
the
two
type
sof
ILE.
RCT;
Dow
ngra
de:I
mpr
ecis
ion
due
tosm
alls
ampl
esi
ze(�
1)an
dab
senc
eof
even
tsre
port
ed(�
1)
Low
Pulm
onar
yva
scul
arre
sista
nce
N=
3[3
5,38
,43]
Vario
us(p
rem
atur
elo
wbi
rth
wei
ght
infa
nts
toad
ults
;w
ithor
with
out
ARD
S)
ILE
(n=
25)
(32
infu
sion
s)N
oIL
E(n
=19
)(1
9in
fusi
ons)
WM
D(9
5%CI
)in
ratio
ofRV
PEP/
ET(R
ight
vent
ricul
arpr
e-ej
ectio
npe
riod
toej
ectio
ntim
e)=þ
0.07
7(þ
0.05
3;þ
0.10
1)[3
8,43
];Re
port
edco
mpa
rativ
epu
lmon
ary
vas-
cula
rre
sist
ance
inAR
DS
=gr
eate
rin
crea
sefr
omba
selin
ein
ILE
grou
pas
com
pare
dto
noIL
Egr
oup
(p=
NR)
.[3
5]
ILE
was
sign
ifica
ntly
asso
ci-
ated
with
ahi
gher
pulm
onar
yva
scul
arre
sist
ance
than
con-
trol
s.N
odi
ffere
nce
insy
stem
icva
s-cu
lar
resi
stan
cebe
twee
ngr
oups
.
Obs
erva
tiona
lstu
dies
;Dow
ngra
de:
Lim
itatio
ndu
eto
pote
ntia
lsel
ec-
tion
bias
(�1)
,Ind
irect
ness
due
tosu
rrog
ate
mar
kers
(�1)
,Im
prec
isio
ndu
eto
smal
lsam
ple
size
(�1)
Very
low
(n=
17)
(24
infu
sion
s)(n
=14
)(1
4in
fusi
ons)
MD
(95%
CI)
inra
tioof
LVPE
P/ET
(Lef
tve
ntric
ular
pre-
ejec
tion
perio
dto
ejec
tion
time)
=�
0.04
1(�
0.09
1;þ
0.00
9)[3
8];
Repo
rted
NS
[43]
(con
tinue
d)
CLINICAL TOXICOLOGY 369
Dow
nloa
ded
by [
Uni
vers
ity o
f Sy
dney
Lib
rary
] at
17:
44 1
6 A
ugus
t 201
7
Tabl
e1.
Cont
inue
d
Com
paris
onSu
mm
ary
offin
ding
Qua
lity
ofev
iden
ce
No.
ofst
udie
sPo
pula
tion
Inte
rven
tion
(No.
ofpa
tient
s)Co
mpa
rato
r(N
o.of
patie
nts)
Sum
mar
yes
timat
eaIn
terp
reta
tion
Qua
lity
asse
ssm
entb
GRA
DE
ratin
g
N=
1[4
3]Pr
eter
min
fant
sei
ther
heal
thy
orw
ithAR
DS
Hig
her
dose
(n=
11)
Low
erdo
se(n
=11
)M
D(9
5%CI
)in
ratio
ofRV
PEP/
ET=þ
0.07
9(þ
0.04
2;þ
0.11
6);
Hig
her
dose
ofIL
Ew
assi
gnifi
-ca
ntly
asso
ciat
edw
itha
high
erpu
lmon
ary
vasc
ular
resi
stan
ce.
No
diffe
renc
ein
syst
emic
vas-
cula
rre
sist
ance
betw
een
grou
ps.
Obs
erva
tiona
lstu
dy;D
owng
rade
:Li
mita
tion
due
topo
tent
ials
elec
-tio
nbi
as(�
1),I
ndire
ctne
ssdu
eto
surr
ogat
em
arke
rs(�
1),
Impr
ecis
ion
due
tosm
alls
ampl
esi
ze(�
1);U
pgra
de:D
ose
resp
onse
grad
ient
(þ1)
Very
low
MD
(95%
CI)
inra
tioof
LVPE
P/ET
=þ
0.01
1(�
0.00
3;þ
0.03
5)N
=1
[49]
Pret
erm
infa
nts
Oliv
e-ba
sed
emul
sion
(n=
5)So
y-oi
lbas
edem
ulsi
on(n
=10
)M
D(9
5%CI
)in
ratio
ofTV
P/RV
ET(r
atio
oftim
eto
peak
velo
city
torig
htve
ntric
ular
ejec
tion
time)
=þ
0.05
1(�
0.04
5;þ
0.14
7)Re
port
edco
mpa
rativ
epu
lmon
ary
arte
rialp
ress
ure
=gr
eate
rde
crea
sefr
omba
selin
ein
the
oliv
e-oi
lbas
edem
ulsi
ongr
oup
asco
mpa
red
toco
n-tr
ols
(p=
0.02
)
No
diffe
renc
ein
pulm
onar
yar
teria
lpre
ssur
ebe
twee
ngr
oups
,but
grea
ter
decr
ease
from
base
line
inol
ive-
base
dem
ulsi
onas
com
pare
dto
soy-
oilb
ased
emul
sion
.
Obs
erva
tiona
lstu
dy;D
owng
rade
:Li
mita
tion
due
pote
ntia
lsel
ectio
nbi
as(g
roup
sno
tco
mpa
rabl
eat
base
line)
and
noad
just
men
tfo
rpo
tent
ialc
onfo
unde
rs(�
1),
Indi
rect
ness
due
tosu
rrog
ate
mar
kers
(�1)
,Im
prec
isio
ndu
eto
smal
lsam
ple
size
(�1)
Very
low
Hyp
oxem
iaN
=1
[35]
Patie
nts
with
orw
ithou
tAR
DS
ILE
(n=
8)N
oIL
E(n
=5)
Repo
rted
com
para
tive
PaO
2/FI
O2
inAR
DS
=gr
eate
rde
crea
sein
ILE
grou
pas
com
pare
dto
cont
rols
(p=
NR)
ILE
was
poss
ibly
asso
ciat
edw
itha
grea
ter
decr
ease
inPa
O2/
FIO
2an
dco
mpl
ianc
eof
resp
irato
rysy
stem
asco
m-
pare
dto
cont
rols
.
Obs
erva
tiona
lstu
dy;D
owng
rade
:In
dire
ctne
ssdu
eto
surr
ogat
em
arke
rs(�
1),I
mpr
ecis
ion
due
tosm
alls
ampl
esi
ze(�
1)an
ddu
eto
indi
rect
com
paris
onbe
twee
ngr
oups
(�1)
Very
low
Repo
rted
com
para
tive
com
plia
nce
ofre
spira
tory
syst
emin
ARD
S=
grea
ter
decr
ease
from
base
line
inIL
Egr
oup
asco
mpa
red
toco
ntro
ls(p
=N
R)N
=1
[33]
Very
low
birt
hw
eigh
tne
onat
esH
ighe
rdo
se(n
=12
)Lo
wer
dose
(n=
15)
MD
(95%
CI)
inA-
aDO
2(m
mH
g)=þ
4.0
(�11
.8;þ
19.2
)N
odi
ffere
nce
inal
veol
ar-
arte
riola
rox
ygen
diffu
sion
grad
ient
orbl
ood
pHbe
twee
ngr
oups
.
RCT;
Dow
ngra
de:L
imita
tion
due
topo
tent
ials
elec
tion
bias
(impo
rtan
tlo
stto
follo
w-u
p)(�
1),
Indi
rect
ness
due
tosu
rrog
ate
mar
kers
(�1)
,Im
prec
isio
ndu
eto
smal
lsam
ple
size
(�1)
Very
low
RD(9
5%CI
)of
havi
ngpH
<7.
20=þ
0.02
(�0.
36;þ
0.39
)(c
ontin
ued)
370 B. D. HAYES ET AL.
Dow
nloa
ded
by [
Uni
vers
ity o
f Sy
dney
Lib
rary
] at
17:
44 1
6 A
ugus
t 201
7
Tabl
e1.
Cont
inue
d
Com
paris
onSu
mm
ary
offin
ding
Qua
lity
ofev
iden
ce
No.
ofst
udie
sPo
pula
tion
Inte
rven
tion
(No.
ofpa
tient
s)Co
mpa
rato
r(N
o.of
patie
nts)
Sum
mar
yes
timat
eaIn
terp
reta
tion
Qua
lity
asse
ssm
entb
GRA
DE
ratin
g
N=
2[1
7,33
]Va
rious
(ver
ylo
wbi
rth
wei
ght
neo-
nate
san
dcr
itica
llyill
adul
ts)
Hig
her
infu
sion
rate
(n=
32)
Low
erin
fusi
onra
te(n
=33
)M
D(9
5%CI
)in
A-aD
O2
(mm
Hg)
=p
=N
Sat
diffe
rent
times
(Bra
ns19
86)
Repo
rted
com
para
tive
P/T
ratio
,pul
-m
onar
ysh
unt
frac
tion
and
P(A�
a)O
2/Pa
O2
=In
ARD
Sw
ithra
pid
infu
sion
,gre
ater
incr
ease
inal
lpa
ram
eter
sas
com
pare
dto
slow
infu
-si
on;i
nse
psis
with
rapi
din
fusi
on,
grea
ter
decr
ease
inpu
lmon
ary
shun
tfr
actio
nan
dP(
A�
a)O
2/Pa
O2
only
asco
mpa
red
tosl
owin
fusi
on(p
=N
R).
Repo
rted
com
para
tive
PaO
2/Fi
O2
=in
ARD
Sw
ithra
pid
infu
sion
,gre
ater
decr
ease
asco
mpa
red
tosl
owin
fu-
sion
;in
seps
isw
ithra
pid
infu
sion
,gr
eate
rin
crea
seas
com
pare
dto
slow
infu
sion
(p=
NR)
.[17
]
No
diffe
renc
ein
pool
edox
y-ge
natio
npa
ram
eter
sbe
twee
nhi
gher
and
low
erra
tes
ofin
fusi
on,b
utpo
ssib
leop
posi
teef
fect
sw
hen
stra
tifyi
ngfo
run
derly
ing
dise
ases
(ARD
Sve
rsus
seps
is).
RCTs
(one
bein
ga
cros
sove
rst
udy)
;Dow
ngra
de:L
imita
tion
due
pote
ntia
lsel
ectio
nbi
asin
one
stud
y(im
port
ant
lost
tofo
l-lo
w-u
p)an
dla
ckof
blin
ding
inth
eot
her
stud
y(�
1),I
ndire
ctne
ssdu
eto
surr
ogat
em
arke
rsin
both
stud
ies
and
due
toin
dire
ctco
m-
paris
onbe
twee
ngr
oups
inth
eot
her
(�1)
,Im
prec
isio
ndu
eto
smal
lsam
ple
size
(�1)
Very
low
(n=
14)
(n=
15)
RD(9
5%CI
)of
havi
ngpH
<7.
20=þ
0.1
(�0.
26;þ
0.46
)[3
3]N
=2
[16,
45]
Sept
icpa
tient
sor
with
panc
reat
itis
and
ARD
S
LCT
(n=
19)
LCT/
MCT
(n=
20)
WM
D(9
5%CI
)in
PaO
2/Fi
O2
=�
36.5
(�54
.5;�
18.6
)LC
Tw
assi
gnifi
cant
lyas
soci
-at
edw
ithlo
wer
PaO
2/Fi
O2,
VO2
and
VCO
2as
wel
las
high
erpu
lmon
ary
veno
usad
mix
ture
and
DO
2as
com
-pa
red
toLC
T/M
CT.
No
diffe
renc
ein
pHbe
twee
ngr
oups
.
RCTs
(one
bein
ga
cros
sove
rst
udy)
;Dow
ngra
de:I
ndire
ctne
ssdu
eto
surr
ogat
em
arke
rs(�
1),
Impr
ecis
ion
due
tosm
alls
ampl
esi
ze(�
1)
Low
WM
D(9
5%CI
)in
VO2
(ml/m
in)-
=�
42.1
(�50
.2;�
33.9
)W
MD
(95%
CI)
ofQ
va/Q
t(%
)=þ
9.2
(þ5.
4,þ
13.0
)(n
=10
)(n
=11
)M
D(9
5%CI
)in
pH=
0(�
0.78
;0.7
8)[4
5](n
=9)
(n=
9)M
D(9
5%CI
)in
VCO
2(m
l/min
)-=�
30.0
(�43
.6;�
16.4
)[1
6]M
D(9
5%CI
)in
DO
2(m
l/min
)-=þ
140.
0(þ
43.9
;þ23
6.1)
[16]
(con
tinue
d)
CLINICAL TOXICOLOGY 371
Dow
nloa
ded
by [
Uni
vers
ity o
f Sy
dney
Lib
rary
] at
17:
44 1
6 A
ugus
t 201
7
Tabl
e1.
Cont
inue
d
Com
paris
onSu
mm
ary
offin
ding
Qua
lity
ofev
iden
ce
No.
ofst
udie
sPo
pula
tion
Inte
rven
tion
(No.
ofpa
tient
s)Co
mpa
rato
r(N
o.of
patie
nts)
Sum
mar
yes
timat
eaIn
terp
reta
tion
Qua
lity
asse
ssm
entb
GRA
DE
ratin
g
Hyp
erse
nsiti
vity
and
alle
rgic
adve
rse
effe
cts
N=
1[1
9]Po
stm
ajor
GI
surg
ery
Lipo
synTM
II(n
=10
)In
tral
ipid
VR
(n=
10)
No
alle
rgic
adve
rse
even
tsre
port
edN
odi
ffere
nce
inal
lerg
icad
vers
eev
ents
betw
een
grou
ps.
RCT;
Dow
ngra
de:I
mpr
ecis
ion
due
tosm
alls
ampl
esi
ze(�
1)an
dab
senc
eof
even
tsre
port
ed(�
1)
Low
Vasc
ular
occlu
sion
adve
rse
effe
ctsCo
agul
atio
npa
ram
eter
sN
=2
[67,
68]
Vario
us(h
ealth
ysu
b-je
cts
and
patie
nts
with
diffe
rent
dis-
ease
s;ch
ildre
nan
dad
ults
)
ILE
(n=
17)
No
ILE
(n=
17)
WM
D(9
5%CI
)in
PAI-1
(ng/
mL)
=þ
84.0
5(4
4.41
;123
.71)
[67,
68]
ILE
was
asso
ciat
edw
ithhi
gher
PAI-1
and
TAT
IIIco
mpl
exes
asco
mpa
red
toco
ntro
ls.
No
diffe
renc
esin
PFio
rPA
Pbe
twee
ngr
oups
whi
leop
pos-
iteef
fect
sar
ere
port
edfo
rTP
Abe
twee
ngr
oups
.
Obs
erva
tiona
lstu
dies
;Dow
ngra
de:
Indi
rect
ness
due
tosu
rrog
ate
mar
ker
(�1)
,Im
prec
isio
ndu
eto
smal
lsam
ple
size
(�1)
Very
low
Repo
rted
com
para
tive
tissu
epl
as-
min
ogen
activ
ator
=de
crea
sed
with
ILE
com
pare
dto
cont
rols
(P=
NR)
[67,
120]
and
incr
ease
dbu
tN
S[6
8](n
=5)
(n=
5)M
D(9
5%CI
)in
PFi(
nM)=þ
1.95
(�3.
58;þ
7.48
)[6
8]M
D(9
5%CI
)in
TAT
IIIco
mpl
exes
(mg/
L)=þ
26.0
(þ0.
25;þ
51.7
5)[6
8]Re
port
edco
mpa
rativ
ePA
P(n
mol
/L)
=N
S[6
8]EC
MO
line
inte
rfere
nce
N=
1[7
3]N
eona
tes
onEC
MO
Via
ECM
Oci
rcui
t(n
=5)
Via
ase
para
teIV
acce
ss(n
=4)
RD(9
5%CI
)of
patie
nts
need
ing
cir-
cuit
chan
ges=�
0.3
(�0.
9;þ
0.3)
No
diffe
renc
ein
patie
nts
need
ing
circ
uit
chan
ges
orcl
oths
inci
rcui
tbe
twee
ngr
oups
.
RCT;
Dow
ngra
de:L
imita
tion
due
pote
ntia
lsel
ectio
nbi
as(la
ckof
com
para
bilit
ybe
twee
ngr
oups
atba
selin
e)(�
1),I
ndire
ctne
ssdu
eto
surr
ogat
em
arke
r(�
1),
Inco
nsis
tenc
ybe
twee
ndi
ffere
ntm
easu
red
para
met
ers
(�1)
,Im
prec
isio
ndu
eto
smal
lsam
ple
size
(�1)
Very
low
RD(9
5%CI
)of
clot
sin
circ
uit=þ
0.5
(NA)
(con
tinue
d)
372 B. D. HAYES ET AL.
Dow
nloa
ded
by [
Uni
vers
ity o
f Sy
dney
Lib
rary
] at
17:
44 1
6 A
ugus
t 201
7
Tabl
e1.
Cont
inue
d
Com
paris
onSu
mm
ary
offin
ding
Qua
lity
ofev
iden
ce
No.
ofst
udie
sPo
pula
tion
Inte
rven
tion
(No.
ofpa
tient
s)Co
mpa
rato
r(N
o.of
patie
nts)
Sum
mar
yes
timat
eaIn
terp
reta
tion
Qua
lity
asse
ssm
entb
GRA
DE
ratin
g
Infe
ction
susc
eptib
ility
Infe
ctio
nsN
=1
[32]
Poly
trau
ma
patie
nts
ILE
(n=
30)
No
ILE
(for
the
first
10da
yson
ly)
(n=
27)
RD(9
5%CI
)of
pneu
mon
ia=þ
0.25
(þ0.
01;þ
0.50
)IL
Ew
asas
soci
ated
with
ahi
gher
risk
ofpn
eum
onia
and
line
infe
ctio
ns.N
odi
ffere
nce
inot
her
repo
rted
infe
ctio
nsbe
twee
ngr
oups
.
RCT;
Dow
ngra
de:L
imita
tion
due
topo
tent
ialr
epor
ting
bias
(uns
peci
fied
dura
tion
tore
port
clin
ical
outc
omes
)(�
1)an
ddu
eto
inco
mpl
ete
repo
rtin
gof
pote
n-tia
lcon
foun
ding
fact
ors
(�1)
;Im
prec
isio
ndu
eto
smal
lsam
ple
size
(�1)
Very
low
RD(9
5%CI
)of
line
infe
ctio
ns=þ
0.25
(þ0.
02;þ
0.48
)RD
(95%
CI)
ofba
cter
emia
=þ
0.04
(�0.
18;þ
0.27
)RD
(95%
CI)
ofab
dom
inal
absc
esse
s=þ
0.02
(�0.
15;þ
0.19
)RD
(95%
CI)
ofsu
perf
icia
lwou
ndin
fect
ions
=þ
0.12
(�0.
07;þ
0.31
)RD
(95%
CI)
ofot
her
infe
ctio
ns=þ
0.14
(�0.
10;þ
0.38
)
Imm
une
syst
emal
tera
tion
N=
1[3
2]Po
lytr
aum
apa
tient
sIL
E(n
=30
)N
oIL
E(fo
rth
efir
st10
days
only
)(n
=27
)Th
em
edia
nra
tioof
LAK
activ
ityda
y5/
day
0w
aslo
wer
inth
eIL
Egr
oup
than
inth
eco
ntro
lgro
up(p
=0.
03)
ILE
was
sign
ifica
ntly
asso
ci-
ated
with
alo
wer
LAK
and
NK
activ
ityas
com
pare
dto
cont
rols
.
RCT;
Dow
ngra
de:L
imita
tion
toin
com
plet
ere
port
ing
ofpo
tent
ial
conf
ound
ing
fact
ors
(�1)
,In
dire
ctne
ssdu
eto
surr
ogat
em
arke
rs(�
1),I
mpr
ecis
ion
due
tosm
alls
ampl
esi
ze(�
1)
Very
low
The
med
ian
ratio
ofN
Kac
tivity
day
5/da
y0
was
low
erin
the
ILE
grou
pth
anin
the
cont
rolg
roup
(p=
0.02
)N
=1
[78]
Vario
us(h
ealth
yor
criti
cally
illpa
tient
s)H
ighe
rin
fusi
onra
te(b
olus
)(n
=20
)Sl
ower
infu
sion
rate
(n=
8)Re
port
edco
mpa
rativ
em
onoc
yte
func
-tio
n(c
hem
otax
is)=
sim
ilar
decr
ease
inbo
thgr
oups
follo
win
gIL
E(p
=N
R).
No
diffe
renc
ein
mon
ocyt
esfu
nctio
nde
crea
seor
lym
pho-
cyte
sfu
nctio
nbe
twee
ntw
oty
pes
ofIL
Ead
min
istr
atio
n.
Obs
erva
tiona
lstu
dy;D
owng
rade
:Li
mita
tion
due
pote
ntia
lsel
ectio
nbi
as(la
ckof
com
para
bilit
ybe
twee
ngr
oups
atba
selin
e)(�
1),
Indi
rect
ness
due
tosu
rrog
ate
mar
kers
(�1)
,Im
prec
isio
ndu
eto
smal
lsam
ple
size
(�1)
Very
low
No
chan
gein
lym
phoc
ytes
func
tion.
N=
1[7
9]G
astr
icca
ncer
sLC
T(n
=10
)LC
T/M
CT(n
=10
)Re
port
edco
mpa
rativ
ene
utro
phil
bac-
teria
lkill
ing
activ
ity=
low
erin
LCT
grou
pas
com
pare
dto
LCT/
MCT
grou
p(p<
0.01
).
LCT
was
asso
ciat
edw
itha
low
erne
utro
phil
bact
eria
lkill
-in
gac
tivity
asco
mpa
red
with
LCT/
MCT
.N
odi
ffere
nce
inph
agoc
ytos
isin
dex,
chem
otax
is,s
pont
an-
eous
mig
ratio
n,or
oxid
ativ
em
etab
olis
mbe
twee
ngr
oups
.
RCT
cros
sove
r;D
owng
rade
:In
dire
ctne
ssdu
eto
surr
ogat
em
arke
rs(�
1),I
mpr
ecis
ion
due
tosm
alls
ampl
esi
ze(�
1)
Low
No
chan
gein
phag
ocyt
osis
inde
x,ch
emot
axis
,spo
ntan
eous
mig
ratio
n,or
oxid
ativ
em
etab
olis
m.
(con
tinue
d)
CLINICAL TOXICOLOGY 373
Dow
nloa
ded
by [
Uni
vers
ity o
f Sy
dney
Lib
rary
] at
17:
44 1
6 A
ugus
t 201
7
Tabl
e1.
Cont
inue
d
Com
paris
onSu
mm
ary
offin
ding
Qua
lity
ofev
iden
ce
No.
ofst
udie
sPo
pula
tion
Inte
rven
tion
(No.
ofpa
tient
s)Co
mpa
rato
r(N
o.of
patie
nts)
Sum
mar
yes
timat
eaIn
terp
reta
tion
Qua
lity
asse
ssm
entb
GRA
DE
ratin
g
Infla
mm
ator
yef
fect
sN
=1
[19]
Post
maj
orG
Isu
rger
yLi
posy
nTM
II(n
=10
)In
tral
ipid
VR
(n=
10)
MD
(95%
CI)
inCR
P(m
g/dL
)=�
1.9
(�10
.4;6
.6)
No
diffe
renc
ein
CRP
orC4
betw
een
grou
ps.
RCT;
Dow
ngra
de:I
ndire
ctne
ssdu
eto
surr
ogat
em
arke
rs(�
1),
Impr
ecis
ion
due
tosm
alls
ampl
esi
ze(�
1)
Low
MD
(95%
CI)
inC4
(mg/
dL)=þ
2.5
(�8.
8;þ
18.0
)
Fat
over
load
synd
rom
e/hy
pertr
iglyc
erid
emia
/lipe
mia
/hyp
eram
ylase
mia
/pan
crea
titis/
chol
esta
sisTr
igly
cerid
es/c
hole
ster
ol/li
pem
iaN
=1
[15]
Hea
lthy
volu
ntee
rsIL
E(n
=32
)N
oIL
E(s
alin
e)(n
=32
)M
D(9
5%CI
)in
FFA
(mm
ol/L
)=þ
261
(þ21
1;þ
311)
ILE
was
sign
ifica
ntly
asso
ci-
ated
with
ahi
gher
leve
lof
FFA
asco
mpa
red
toth
eco
n-tr
olgr
oup.
RCT
cros
sove
r;D
owng
rade
:In
dire
ctne
ssdu
eto
surr
ogat
em
arke
r(�
1)
Mod
erat
e
N=
1[3
3]Ve
rylo
wbi
rth
wei
ght
neon
ates
Hig
her
dose
(n=
12)
Low
erdo
se(n
=15
)RD
(95%
CI)
inse
vere
hype
r-lip
idem
ia=þ
0.17
(NA)
No
diffe
renc
ein
seve
rehy
per-
lipid
emia
betw
een
grou
ps.
RCT;
Dow
ngra
de:L
imita
tion
due
topo
tent
ials
elec
tion
bias
(impo
rtan
tlo
stto
follo
w-u
p)(�
1),
Indi
rect
ness
due
tosu
rrog
ate
mar
kers
(�1)
,Im
prec
isio
ndu
eto
smal
lsam
ple
size
(�1)
Very
low
N=
2[3
3,94
]Ve
rylo
wbi
rth
wei
ght
and
prem
a-tu
rein
fant
s
Hig
her
infu
sion
rate
(n=
22)
Slow
erin
fusi
onra
te(n
=22
)M
D(9
5%CI
)in
trig
lyce
rides
(mg/
dL)=þ
106.
3(þ
17.4
;þ19
5.3)
[94]
Hig
her
rate
ofin
fusi
onw
assi
gnifi
cant
lyas
soci
ated
with
high
erle
vels
oftr
igly
cerid
esan
dfr
eefa
tty
acid
sas
com
-pa
red
toa
slow
erra
teof
infu
-si
on.
No
diffe
renc
ein
leve
lsof
chol
este
rol,
HD
Lan
dLP
Lor
inoc
curr
ence
ofse
vere
hype
rlip-
idem
iabe
twee
ngr
oups
.
RCTs
(one
bein
ga
cros
sove
rst
udy)
;Dow
ngra
de:L
imita
tion
due
topo
tent
ials
elec
tion
bias
(impo
rtan
tlo
stto
follo
w-u
pin
one
stud
yan
dla
ckof
com
para
bil-
itybe
twee
ngr
oups
atba
selin
ein
the
othe
rst
udy)
(�1)
,In
dire
ctne
ssdu
eto
surr
ogat
em
arke
rs(�
1),I
mpr
ecis
ion
due
tosm
alls
ampl
esi
ze(�
1)
Very
low
MD
(95%
CI)
inFF
A(m
mol
/L)=þ
0.64
(þ0.
15;þ
1.13
)[9
4]M
D(9
5%CI
)in
chol
este
rol(
mg/
dL)=þ
13.6
(�15
.0;þ
42.2
)[9
4]M
D(9
5%CI
)in
hepa
ticlip
ase
(U/
mL)
=þ
0.21
(�0.
97;þ
1.39
)[9
4]M
D(9
5%CI
)in
LPL
(U/m
L)=þ
0.72
(�0.
22;þ
1.66
)[9
4](n
=14
)(n
=15
)RD
(95%
CI)
inse
vere
hype
r-lip
idem
ia=þ
0.07
(NA)
[33]
N=
2[1
9,84
]Va
rious
(infa
nts,
adul
tspo
stm
ajor
GI
surg
ery)
Lipo
synTM
orLy
posy
nII
(n=
28)
Intr
alip
idVR
(n=
28)
WM
D(9
5%CI
)in
trig
lyce
rides
(mg/
dL)=þ
39.0
(�21
.6;þ
99.7
)N
odi
ffere
nce
intr
igly
cerid
ele
vels
betw
een
grou
ps.
RCTs
(one
bein
ga
cros
sove
rst
udy)
;Dow
ngra
de:I
ndire
ctne
ssdu
eto
surr
ogat
em
arke
r(�
1),
Impr
ecis
ion
due
tosm
alls
ampl
esi
ze(�
1)
Low
(con
tinue
d)
374 B. D. HAYES ET AL.
Dow
nloa
ded
by [
Uni
vers
ity o
f Sy
dney
Lib
rary
] at
17:
44 1
6 A
ugus
t 201
7
Tabl
e1.
Cont
inue
d
Com
paris
onSu
mm
ary
offin
ding
Qua
lity
ofev
iden
ce
No.
ofst
udie
sPo
pula
tion
Inte
rven
tion
(No.
ofpa
tient
s)Co
mpa
rato
r(N
o.of
patie
nts)
Sum
mar
yes
timat
eaIn
terp
reta
tion
Qua
lity
asse
ssm
entb
GRA
DE
ratin
g
N=
1[8
0]Se
vere
acut
epa
ncre
atiti
sM
CT/L
CT/O
meg
a-3
(fish
base
d)(n
=22
)M
CT/L
CT(n
=22
)Re
port
edco
mpa
rativ
etr
igly
cerid
esan
dch
oles
tero
llev
els=
slig
htly
low
erin
the
MCT
/LCT
/Om
ega-
3gr
oup
(p=
NS)
No
diffe
renc
ein
leve
lsof
tri-
glyc
erid
esan
dch
oles
tero
l,or
inoc
curr
ence
ofhy
pert
rigly
-ce
ridem
iabe
twee
ngr
oups
.
RCT;
Dow
ngra
de:L
imita
tion
due
toin
com
plet
em
etho
dolo
gyre
port
ing
(�1)
,Ind
irect
ness
due
tosu
rrog
ate
mar
kers
(�1)
,Im
prec
isio
ndu
eto
smal
lsam
ple
size
(�1)
Very
low
RD(9
5%CI
)of
hype
r-tr
igly
cerid
emia
=�
0.05
(NA)
N=
1[7
3]N
eona
tes
onEC
MO
Via
ECM
Oci
rcui
t(n
=5)
Via
ase
para
teIV
acce
ss(n
=4)
Repo
rted
com
para
tive
trig
lyce
ri-de
s=si
mila
rbe
twee
ngr
oups
(PN
R)N
odi
ffere
nce
intr
igly
cerid
ele
vels
betw
een
grou
ps.
RCT;
Dow
ngra
de:L
imita
tion
due
pote
ntia
lsel
ectio
nbi
as(la
ckof
com
para
bilit
ybe
twee
ngr
oups
atba
selin
e)(�
1),I
ndire
ctne
ssdu
eto
surr
ogat
em
arke
r(�
1),
Impr
ecis
ion
due
tosm
alls
ampl
esi
ze(�
1)
Very
low
Lipi
dde
posit
sN
=1
[89]
Low
birt
hw
eigh
tin
fant
sw
hodi
edIL
E(n
=9)
No
ILE
(hum
anm
ilk)
(n=
12)
RD(9
5%CI
)in
pulm
onar
yar
tery
lipid
depo
sits
=þ
0.61
(þ0.
27;þ
0.96
)IL
Ew
assi
gnifi
cant
lyas
soci
-at
edw
ithpu
lmon
ary
arte
rylip
idde
posi
tsas
com
pare
dto
cont
rols
.N
odi
ffere
nce
inlip
idac
cum
u-la
tion
inbr
ain
capi
llarie
s,m
ac-
roph
ages
oral
veol
arce
llsbe
twee
ngr
oups
.
Obs
erva
tiona
lstu
dy;D
owng
rade
:Li
mita
tion
due
topo
tent
ialc
on-
foun
ders
(�1)
;Ind
irect
ness
due
tosu
rrog
ate
mar
kers
(�1)
,Im
prec
isio
ndu
eto
smal
lsam
ple
size
(�1)
Very
low
RD(9
5%CI
)in
lipid
depo
sits
inm
ac-
roph
ages
=þ
0.19
(�0.
19;þ
0.58
)RD
(95%
CI)
inlip
idde
posi
tin
alve
o-la
rce
lls=þ
0.28
(�0.
11;þ
0.67
)Re
port
edco
mpa
rativ
elip
idac
cum
ula-
tion
inbr
ain
capi
llarie
s=no
diffe
renc
e(p
=N
R)
Chol
este
rolc
ryst
als
N=
1[9
5]Pr
e-ch
olec
yste
ctom
yIL
E(n
=8)
No
ILE
(n=
8)RD
(95%
CI)
intw
oty
pes
ofch
oles
-te
rolc
ryst
als=þ
0.63
(þ0.
25;þ
1.00
)an
dþ
0.63
(NA)
(p=
0.01
)
ILE
was
sign
ifica
ntly
asso
ci-
ated
with
ahi
gher
risk
ofch
oles
tero
lcry
stal
sth
anth
eco
ntro
lgro
up.
RCT;
Dow
ngra
de:L
imita
tion
due
toa
lack
ofre
port
ing
inpa
tient
s’ba
selin
ech
arac
teris
tics
(�1)
,In
dire
ctne
ssdu
eto
surr
ogat
em
arke
rs(�
1),I
mpr
ecis
ion
due
tosm
alls
ampl
esi
ze(�
1)
Very
low
Live
rab
norm
aliti
esN
=1
[87]
Criti
cally
illpa
tient
sre
ceiv
ing
artif
icia
lnu
triti
on
ILE
(n=
303)
No
ILE
(ent
eral
nutr
i-tio
n)(n
=42
2)Li
ver
dysf
unct
ion
was
asso
ciat
edw
ithth
eus
eof
TPN
atth
eun
ivar
iate
(p<
0.00
1),b
utal
soat
the
mul
tivar
i-at
ean
alys
is(O
R1.
96,9
5%CI
1.3–
2.97
,p<
0.00
1),a
fter
adju
stin
gfo
rse
psis
,mul
tiple
orga
ndy
sfun
ctio
nsc
ore,
early
use
ofar
tific
ialn
utrit
ion,
and
ener
gyre
quire
men
ts>
25kc
al/
kg/d
ay.
ILE
was
sign
ifica
ntly
asso
ci-
ated
with
liver
dysf
unct
ion
asco
mpa
red
toco
ntro
ls
Obs
erva
tiona
lstu
dy:N
ose
rious
limita
tion
Low
(con
tinue
d)
CLINICAL TOXICOLOGY 375
Dow
nloa
ded
by [
Uni
vers
ity o
f Sy
dney
Lib
rary
] at
17:
44 1
6 A
ugus
t 201
7
Tabl
e1.
Cont
inue
d
Com
paris
onSu
mm
ary
offin
ding
Qua
lity
ofev
iden
ce
No.
ofst
udie
sPo
pula
tion
Inte
rven
tion
(No.
ofpa
tient
s)Co
mpa
rato
r(N
o.of
patie
nts)
Sum
mar
yes
timat
eaIn
terp
reta
tion
Qua
lity
asse
ssm
entb
GRA
DE
ratin
g
N=
2[8
1,96
]Pr
eter
min
fant
sVa
rious
dose
s(n
=52
3)TP
N-a
ssoc
iate
dch
oles
tasi
sw
asas
soci
-at
edw
ithhi
gher
calo
riein
take
,but
also
with
long
erdu
ratio
nof
TPN
,lo
wer
gest
atio
nala
ge,l
ower
birt
hw
eigh
t,la
ter
ente
ricfe
edin
gan
dco
mpl
icat
ions
ofpr
emat
urity
(p=
NR)
.[9
6]
Hig
her
dose
ofIL
Ew
assi
gnifi
-ca
ntly
asso
ciat
edw
ithhi
gher
unbo
und
bilir
ubin
and
chol
es-
tasi
sas
com
pare
dto
low
erdo
se.
Obs
erva
tiona
lstu
dies
;Dow
ngra
de:
Lim
itatio
ndu
eto
inco
mpl
ete
met
hodo
logy
repo
rtin
gin
one
stud
y(�
1)an
ddu
eto
pote
ntia
lco
nfou
nder
sin
both
stud
ies
(�1)
;U
pgra
de:D
ose
resp
onse
grad
ient
inon
est
udy
(þ1)
Very
low
Vario
usdo
ses
(n=
26)
Line
arin
crea
sein
unbo
und
bilir
ubin
of0.
62mg
/dL
for
each
incr
ease
in1
g/kg
/din
ILE
inta
ke(p
=0.
001)
.As
soci
atio
nst
illst
atis
tical
lysi
gnifi
cant
afte
rad
just
men
tfo
rge
stat
iona
lage
and
gluc
ose
infu
sion
(p=
0.00
3).[
81]
N=
1[9
4]Pr
emat
ure
infa
nts
with
ARD
SH
ighe
rin
fusi
onra
te(o
ver
15h)
(n=
22)
Low
erin
fusi
onra
te(o
ver
24h)
(n=
22)
MD
(95%
CI)
inun
boun
dbi
lirub
in(B
/R)
=þ
0.07
(�0.
20;0
.34)
No
diffe
renc
ein
unbo
und
bili-
rubi
nbe
twee
ngr
oups
.RC
Tcr
osso
ver;
Dow
ngra
de:
Lim
itatio
ndu
eto
lack
ofco
mpa
r-ab
ility
betw
een
grou
psat
base
-lin
e)(�
1),I
ndire
ctne
ssdu
eto
surr
ogat
em
arke
rs(�
1),
Impr
ecis
ion
due
tosm
alls
ampl
esi
ze(�
1)
Very
low
N=
2[9
6,98
]Pr
eter
min
fant
sor
neon
ates
who
died
Vario
usdu
ratio
n(n
=52
3)TP
N-a
ssoc
iate
dch
oles
tasi
sw
asas
soci
-at
edw
ithlo
nger
dura
tion
ofTP
N,b
utal
sow
ithhi
gher
calo
riein
take
,low
erge
stat
iona
lage
,low
erbi
rth
wei
ght,
late
ren
teric
feed
ing
and
com
plic
a-tio
nsof
prem
atur
ity.[9
6]
Long
erdu
ratio
nof
ILE
was
sign
ifica
ntly
asso
ciat
edw
ithhi
gher
risk
ofch
oles
tasi
san
dliv
erab
norm
aliti
esas
com
-pa
red
tosh
orte
rdu
ratio
n.
Obs
erva
tiona
lstu
dies
;Dow
ngra
de:
Lim
itatio
ndu
eto
inco
mpl
ete
met
hodo
logy
repo
rtin
gin
one
stud
y(�
1)an
ddu
eto
pote
ntia
lco
nfou
nder
sin
both
stud
ies
(�1)
Very
low
Vario
usdu
ratio
n(n
=24
)M
ore
seve
reliv
erab
norm
aliti
esw
asas
soci
ated
not
only
with
alo
nger
dura
tion
ofTP
N(p
=0.
0008
),bu
tal
sow
ithsm
alle
rge
stat
iona
lage
,bro
n-ch
opul
mon
ary
dysp
lasi
aan
ddi
rect
hype
rbili
rubi
nem
ia.[
98]
N=
1[9
7]Po
st-h
epat
ecto
my
Oliv
e(n
=15
)So
ya(n
=16
)M
D(9
5%CI
)in
tota
lbili
rubi
n(m
mol
/L)
=�
9.79
(�21
.30;þ
1.72
)N
odi
ffere
nce
inpo
st-o
pera
-tiv
eliv
erfu
nctio
nbe
twee
ntw
ogr
oups
.
RCT;
Dow
ngra
de:L
imita
tion
due
pote
ntia
lsel
ectio
nbi
as(la
ckof
appr
opria
teal
loca
tion)
(�1)
,In
dire
ctne
ssdu
eto
surr
ogat
em
arke
r(�
1),I
mpr
ecis
ion
due
tosm
alls
ampl
esi
ze(�
1)
Very
low
MD
(95%
CI)
indi
rect
bilir
ubin
(mm
ol/
L)=�
5.41
(�11
.53;þ
0.71
)M
D(9
5%CI
)in
ALT
(U/L
)=�
31.0
(�11
0.7;þ
48.7
)M
D(9
5%CI
)in
AST
(U/L
)=�
21.8
(�49
.5;þ
5.9)
MD
(95%
CI)
inAL
P(U
/L)=þ
28.5
(�11
.7;þ
68.8
)
Aspr
opos
edby
GRA
DE
met
hodo
logy
,al
lot
her
evid
ence
was
rate
d‘‘v
ery
low
’’qu
ality
ofev
iden
ce(t
his
incl
uded
pre/
post
inte
rven
tion
stud
ies
due
tohi
ghris
kof
conf
ound
ing,
unco
ntro
lled
stud
ies
due
toin
dire
ctne
ssof
com
paris
ons,
case
repo
rts/
serie
sdu
eto
very
high
likel
ihoo
dof
publ
icat
ion
bias
and
anim
alst
udie
sdu
eto
lack
ofge
nera
lizab
ility
tohu
man
san
dth
usve
ryse
rious
indi
rect
ness
).a Su
mm
ary
estim
ate
isex
pres
sed
indi
ffere
nce
betw
een
the
‘‘gro
upin
terv
entio
n–
grou
pco
mpa
rato
r’’.E
ither
aris
kdi
ffere
nce
(RD
),a
mea
ndi
ffere
nce
(MD
)or
wei
ghte
dm
ean
diffe
renc
e(W
MD
)w
asre
port
edw
ith95
%co
nfi-
denc
ein
terv
al(9
5%CI
).b
Qua
lity
asse
ssm
ent
acco
rdin
gto
GRA
DE
met
hodo
logy
.Of
note
,sin
cefe
wst
udie
sw
ere
pool
edto
geth
erto
answ
era
spec
ific
clin
ical
ques
tion,
inco
nsis
tenc
yan
dpu
blic
atio
nbi
asw
ere
not
eval
uabl
e.
376 B. D. HAYES ET AL.
Dow
nloa
ded
by [
Uni
vers
ity o
f Sy
dney
Lib
rary
] at
17:
44 1
6 A
ugus
t 201
7
Tabl
e2.
Org
andy
sfun
ctio
nad
vers
eef
fect
sre
port
edin
hum
anst
udie
s.
Refe
renc
esSt
udy
type
Type
ofpo
pula
tion
(num
ber)
Indi
catio
nof
ILE
Type
ofIL
ETo
tald
ose/
dura
tion
ofIL
ETi
min
gof
adve
rse
even
tsAd
vers
eev
ents
Card
iova
scul
aref
fects
[15]
Rand
omiz
edco
n-tr
olle
dcr
osso
ver
tria
l32
heal
thy
subj
ects
rand
omiz
edto
eith
erIL
E(n¼
32)
orsa
line
(n¼
32),
alte
rnat
ivel
yon
2se
p-ar
ate
occa
sion
s
TPN
LCT
10%
(Intr
alip
idVR
)U
nkno
wn
amou
ntof
infu
sion
give
nfo
r18
0m
in.
Pre-
infu
sion
and
at18
0m
inPr
e-/p
ost-
com
paris
on:I
ncre
ase
inQ
-Tc
from
359
to38
5m
sin
the
ILE/
prop
rano
lolg
roup
(p<
0.01
).N
osi
gnifi
cant
Q-T
cin
crea
sein
the
cont
rolg
roup
s(n
eith
erpr
opra
nolo
lgro
upno
rsa
line
grou
p).
Gro
upco
mpa
rison
:Tra
nsie
nthi
gher
inm
ean
bloo
dpr
essu
re(p<
0.05
),he
art
rate
(p<
0.05
),Q
-Tc
(p<
0.01
),an
dQ
-Tc
disp
ersi
on(p<
0.01
)in
the
ILE
grou
p.[1
6]Ra
ndom
ized
con-
trol
led
cros
sove
rtr
ial
Nin
epa
tient
sw
ithpa
ncre
atiti
san
dAR
DS
rand
omiz
edto
eith
erLC
T(n¼
9)or
LCT/
MCT
(n¼
9),
alte
rnat
ivel
yfo
r24
h
TPN
LCT
20%
(Intr
alip
idVR
)&
LCT/
MCT
20%
(Lip
ofun
dinVR
)
50%
ofda
ilyno
n-pr
otei
nca
loric
requ
irem
ent
give
nov
er8
h
Pre-
infu
sion
,30
min
befo
reth
een
dof
infu
sion
and
4h
fol-
low
ing
the
infu
sion
Pre-
/pos
t-co
mpa
rison
:Sig
nific
ant
and
tran
sien
tin
crea
sein
mea
npu
lmon
ary
arte
rypr
essu
re(fr
om28
to35
mm
Hg)
durin
gLC
Tin
fusi
on.S
igni
fican
tin
crea
sein
card
iac
outp
ut(fr
om8.
8to
9.5
L/m
in)
durin
gLC
T/M
CTin
fusi
on.
Gro
upco
mpa
rison
:Tra
nsie
nthi
gher
mea
npu
lmon
-ar
yar
tery
pres
sure
durin
gLC
Tin
fusi
on(p<
0.05
).Tr
ansi
ent
high
erca
rdia
cou
tput
durin
gLC
T/M
CTgr
oup
(p<
0.05
).[1
7]Ra
ndom
ized
con-
trol
led
cros
sove
rst
udy
18cr
itica
llyill
patie
nts
(str
atifi
edby
dise
ases
:10
seve
rese
psis
and
8AR
DS)
rand
omiz
edto
eith
erto
rece
ivin
gTP
Nov
er6
h(n¼
18)
or24
h(n¼
18),
alte
rnat
ivel
y
TPN
LCT
20%
(Lip
oven
os)
1.1–
1.3
g/kg
inse
p-si
sgr
oup
and
1.29
–1.3
1g/
kgin
ARD
Sgr
oup
Pre-
infu
sion
and
ever
y6
hfo
r24
hSu
bgro
upco
mpa
rison
:In
the
ARD
Sgr
oup
with
rapi
din
fusi
on,t
here
was
anin
crea
sein
card
iac
inde
xas
com
pare
dto
the
seps
isgr
oup
with
rapi
din
fusi
on.
[19]
Rand
omiz
edco
n-tr
olle
dtr
ial
20pa
tient
spo
stm
ajor
gast
ro-
inte
stin
alsu
rger
yra
ndom
ized
toLi
posy
nTMII
(n¼
10)
orIn
tral
ipid
VR
(n¼
10)
TPN
LCT
10%
Lipo
synTM
IIve
rsus
Intr
alip
idVR
1.2
g/kg
(12
mL/
kg)
Base
line
and
240
min
afte
rst
art
ofin
fusi
on
Gro
upco
mpa
rison
:No
card
iova
scul
arad
vers
eev
ent.
[10]
Obs
erva
tiona
lcoh
ort
stud
y(p
rosp
ectiv
e)19
adul
tpa
tient
sfo
llow
ing
anun
com
plic
ated
isol
ated
coro
nary
arte
ryby
pass
rece
ivin
gIL
Eat
ara
teof
2m
L/m
in(n¼
12)
vers
us1
mL/
min
follo
wed
by2
mL/
min
(n¼
7)
TPN
LCT
20%
(Intr
alip
idVR
)12
0m
Lve
rsus
60m
Lþ
120
mL
Pre-
infu
sion
,dur
ing
infu
sion
(5,1
0,15
,30
,45
and
60m
info
llow
ing
itsin
iti-
atio
n)an
d2
haf
ter
itste
rmin
atio
n
Pre-
/pos
t-co
mpa
rison
:An
8%de
crea
sein
card
iac
inde
xoc
curr
edat
30m
inin
the
high
erra
tein
fu-
sion
(p�
0.02
).An
incr
ease
inpu
lmon
ary
capi
llary
wed
gepr
essu
reoc
curr
edat
10–1
5m
inin
the
con-
trol
grou
p.G
roup
com
paris
on:A
sign
ifica
ntde
crea
sein
card
iac
outp
utan
din
crea
sein
pulm
onar
yw
edge
pres
sure
inth
ehi
gher
rate
infu
sion
,whi
leno
neoc
curr
edin
the
cont
rolg
roup
.Als
o,on
eca
seof
card
iac
isch
e-m
iaaf
ter
30m
inof
infu
sion
inth
ehi
gher
rate
infu
sion
ngr
oup.
[14]
Obs
erva
tiona
lcoh
ort
(pro
spec
tive
pre-
/po
st-in
terv
entio
n)
12pa
tient
s(7
criti
cally
illpa
tient
san
d5
heal
thy
volu
ntee
rs)
TPN
LCT
20%
(Intr
alip
idVR
)50
0m
LPr
e-in
fusi
on,2
and
4h
afte
rst
art
ofin
fusi
on
Pre-
/pos
t-co
mpa
rison
:All
patie
nts
expe
rienc
eda
sign
ifica
ntris
ein
card
iac
outp
ut(fr
om5.
8to
6.7
L/m
in,p¼
0.05
),H
Rre
mai
ned
unch
ange
d,in
crea
sed
inpu
lmon
ary
vasc
ular
resi
stan
ce(fr
om64
.7dy
ne/s
to13
1.9
dyne
/s,p¼
0.05
).N
oad
vers
eef
fect
son
hem
odyn
amic
s.[1
1]Ca
sese
ries
Two
pois
oned
patie
nts
(1w
ithm
etop
rolo
lþbu
prop
rion
and
1w
ithdi
ltiaz
emþ
prop
rano
lol)
Resc
ueLC
T20
%(In
tral
ipid
VR
)10
0m
Lof
20%
ILE
and
150
mL
of20
%IL
E
30s–
1m
inaf
ter
ILE
give
nBo
thcr
itica
llyill
patie
nts
rece
ived
lipid
resc
ueth
erap
yfo
rbr
adyc
ardi
aan
dhy
pote
nsio
nre
frac
tory
tova
sopr
esso
rsan
dhi
gh-d
ose
insu
lin.B
oth
suf-
fere
dbr
ady/
asys
tolic
arre
stsh
ortly
afte
rIL
Ead
min
istr
atio
n.(c
ontin
ued)
CLINICAL TOXICOLOGY 377
Dow
nloa
ded
by [
Uni
vers
ity o
f Sy
dney
Lib
rary
] at
17:
44 1
6 A
ugus
t 201
7
Tabl
e2.
Cont
inue
d
Refe
renc
esSt
udy
type
Type
ofpo
pula
tion
(num
ber)
Indi
catio
nof
ILE
Type
ofIL
ETo
tald
ose/
dura
tion
ofIL
ETi
min
gof
adve
rse
even
tsAd
vers
eev
ents
[12]
Case
repo
rt1
(70
year
s)TP
NLC
T10
–20%
(Intr
alip
idVR
)25
80m
L/24
hfo
r4
days
4da
ysaf
ter
ILE
star
ted.
ILE
was
stop
ped
whe
nth
ehe
mof
iltra
tion
line
was
foun
dto
con-
tain
milk
yflu
id,b
utpa
tient
had
card
iac
arre
stso
onaf
ter
Dea
th(c
ardi
acar
rest
)
[13]
Case
repo
rt1
(34
wee
ks)
TPN
ILE
10%
(Intr
alip
idVR
)0.
08g/
h(8
mL/
hIL
E)�
8h¼
0.64
g8
haf
ter
ILE
star
ted
Card
iac
arre
stan
dde
ath
[18]
Case
repo
rt1
TPN
NR
NR
NR
Tam
pona
defr
omTP
Nin
fuse
din
tope
ricar
dium
Hem
atol
ogic
effe
cts[2
1]D
escr
iptiv
eco
hort
(ret
rosp
ectiv
e)N
ine
adul
tpa
tient
sw
ithca
rdio
-va
scul
ardr
ugto
xici
tyRe
scue
LCT
20%
(Intr
alip
idVR
)Bo
lus6
Infu
sion
unkn
own
amou
ntN
R1
out
of9
had
DIC
with
fata
lout
com
e(1
1.1%
)
[22]
Case
repo
rt1
(34
year
s)TP
N10
%M
CT/L
CT50
0m
L/da
yfo
r2
days
Just
afte
rse
cond
dose
ofIL
Eon
day
2
Cata
toni
a,th
rom
bocy
tope
nia,
leuk
open
iano
ted
afte
rtw
odo
ses
ofIL
E.
[23]
Case
repo
rt1
(30
wee
ks)
TPN
LCT
20%
(Intr
alip
idVR
)87
mL
over
12h
(79
mL/
kg)
Star
ting
durin
gth
eer
rone
ous
infu
sion
Dos
ing
erro
rin
prem
atur
ein
fant
resu
lting
inpe
r-si
stin
ghy
pona
trem
ia(fo
rth
efo
llow
ing
5da
ys),
elev
ated
liver
enzy
mes
and
intr
aven
tric
ular
hem
orrh
age.
[24]
Case
repo
rt1
(54
year
s)TP
NLC
T10
%(In
tral
ipid
VR
)50
0m
L/da
yfo
r3
wee
ks6
haf
ter
rece
ivin
g50
0m
Lin
2h
inst
ead
of8
h(2
50m
L/h)
Dev
elop
edin
trav
ascu
lar
hem
olys
is.A
bnor
mal
bone
mar
row
.
Acut
eki
dney
inju
ry[2
9]O
bser
vatio
nalc
ohor
tst
udy
(pro
spec
tive)
104
prem
atur
ein
fant
sre
ceiv
ing
eith
erTP
N(n¼
50)
orEN
(n¼
54)
TPN
NR
0.5
g/kg
/day
(2.5
mL/
kg/d
ayus
ing
20%
ILE
or5
mL/
kg/d
ayus
ing
10%
ILE)
for
unkn
own
dura
tion
Betw
een
third
day
and
30th
day
oflif
ePr
e-/p
ost-
com
paris
on:S
igni
fican
tin
crea
sein
seru
mcy
stat
inC
(from
1.2
to1.
6m
g/L)
,urin
ary
b2
mic
ro-
glob
ulin
(from
3.8
to10
.6m
g/L)
,glu
that
ione
-S-
tran
sfer
ase
p(fr
om6.
7to
44.3
ng/m
L)an
dN
-ace
-ty
l-b-D
gluc
osam
inid
ase
(from
2.9
to7.
3lg
/L)
inTP
Ngr
oup
(Ps
all<
0.00
1),w
hile
the
leve
lsin
the
cont
rolg
roup
rem
aine
dco
mpa
rabl
e.G
roup
com
paris
on:S
igni
fican
tde
crea
sed
ingl
om-
erul
aran
dtu
bula
rfu
nctio
nat
30th
day
oflif
ein
TPN
grou
pas
com
pare
dto
the
EN(h
ighe
rm
arke
rle
vels
inTP
Ngr
oup,
Psal
l<0.
05).
No
stat
istic
aldi
ffere
nce
inBU
Nor
crea
tinin
e.[2
1]D
escr
iptiv
eco
hort
(ret
rosp
ectiv
e)N
ine
patie
nts
with
card
iova
scul
ardr
ugto
xici
tyRe
scue
LCT
20%
(Intr
alip
idVR
)Bo
lus6
Infu
sion
NR
Thre
eou
tof
nine
patie
nts
had
rena
lfai
lure
(33.
3%).
No
valu
ere
port
ed.A
llth
ree
surv
ived
.[2
6]Ca
sere
port
One
with
amitr
ipty
line
OD
Resc
ueLC
T20
%(In
tral
ipid
VR
)25
0m
Lbo
lus,
then
100
mL/
hfo
r24
h,th
en18
mL/
hfo
r17
days
NR
Acut
ere
nalf
ailu
reob
serv
ed,n
ova
lues
repo
rted
.
[28]
aCa
sere
port
One
with
Dilt
iaze
mO
Dre
frac
-to
ryto
stan
dard
ther
apy
Resc
ueLC
T20
%(In
tral
ipid
VR
)1
mg/
kg(5
mL/
kg)
bolu
sth
en0.
5m
g/kg
/min
(2.5
mL/
kg/
min
)dr
ip
NR
Rena
lfai
lure
nova
lue
repo
rted
(con
tinue
d)
378 B. D. HAYES ET AL.
Dow
nloa
ded
by [
Uni
vers
ity o
f Sy
dney
Lib
rary
] at
17:
44 1
6 A
ugus
t 201
7
Tabl
e2.
Cont
inue
d
Refe
renc
esSt
udy
type
Type
ofpo
pula
tion
(num
ber)
Indi
catio
nof
ILE
Type
ofIL
ETo
tald
ose/
dura
tion
ofIL
ETi
min
gof
adve
rse
even
tsAd
vers
eev
ents
[27]
aCa
sere
port
1TP
NLC
T20
%(In
tral
ipid
VR
)10
0m
Lof
20%
NR
Iatr
ogen
icO
Din
prem
atur
ein
fant
,ele
vatio
nin
bloo
dur
eani
trog
en.
[12]
Case
repo
rt1
(70
year
sm
anw
ithco
mpl
i-ca
ted
post
-ope
rativ
eco
urse
afte
rem
erge
ncy
surg
ery)
TPN
LCT
10–2
0%(In
tral
ipid
VR
)25
80m
L/24
hN
RRe
nalf
ailu
rere
quire
dhe
mof
iltra
tion.
BUN
20.4
mm
ol/L
(57
mg/
dL),
crea
tinin
e30
0m
mol
/L(3
.4m
g/dL
.
Met
abol
icac
idos
is[2
1]D
escr
iptiv
eco
hort
(ret
rosp
ectiv
e)N
ine
patie
nts
with
card
iova
scul
ardr
ugto
xici
tyRe
scue
LCT
20%
(Intr
alip
idVR
)Bo
lus6
Infu
sion
NR
One
out
ofni
neha
dm
etab
olic
acid
osis
resu
lting
inde
ath
(11.
1%)
[30]
Case
repo
rt1
(32
wee
ksol
din
fant
)TP
NLC
T20
%(In
tral
ipid
VR
)25
0m
Lof
20%
–24
gLi
pid/
kgbo
dyw
eigh
t
On
day
5of
life
imm
edia
tely
afte
rin
fusi
on
Mas
sive
OD
ofTP
N:P
atie
ntde
velo
ped
met
abol
icac
idos
is,a
mon
got
her
effe
cts
–Tr
eate
dw
ithex
chan
getr
ansf
usio
n,fu
llre
cove
ry
AE:A
dver
seev
ents
;AKI
:acu
teki
dney
inju
ry;A
MS:
alte
red
men
tals
tatu
s;AR
DS:
acut
ere
spira
tory
dist
ress
synd
rom
e;BB
:bet
abl
ocke
r;BM
:bon
em
arro
w;C
CB:c
alci
umch
anne
lblo
cker
;CVC
:cen
tral
veno
usca
thet
er;C
VVH
F:co
ntin
u-ou
sve
no-v
enou
she
mof
iltra
tion;
DIC
:dis
sem
inat
edin
trav
ascu
lar
coag
ulat
ion;
CO:c
arbo
nm
onox
ide;
DKA
:dia
betic
keto
acid
osis
;DLC
O:c
arbo
nm
onox
ide
diffu
sion
capa
city
;DVT
:dee
pve
inth
rom
bosi
s;EC
MO
:ext
raco
rpor
ealm
em-
bran
eox
ygen
atio
n;Fi
O2:
frac
tion
ofin
spire
dox
ygen
;FO
BLE:
fish
oil-b
ased
lipid
emul
sion
;GA:
gest
atio
nala
ge;H
PF:h
igh
pow
ered
field
;ICU
:int
ensi
veca
reun
it;IL
E:in
trav
enou
slip
idem
ulsi
on;L
CT:l
ong
chai
ntr
iacy
lgly
cero
ls;
LFT:
liver
func
tion
test
s;LP
L:lip
opro
tein
lipas
e;M
CT:m
ediu
mch
ain
tria
cylg
lyce
rols
;MO
DS:
mul
tiorg
andy
sfun
ctio
nsy
ndro
me;
NA:
nota
vaila
ble;
NIC
U:n
eona
tali
nten
sive
care
unit;
NR:
notr
epor
ted;
OD
:ove
rdos
e/po
ison
ing;
PAP:
pulm
onar
yar
tery
pres
sure
;P(A
–a)O
2:Al
veol
arAr
teria
lgra
dien
t;Pa
O2:
arte
rialp
artia
lpre
ssur
eof
oxyg
en;P
AI-1
:pla
smin
ogen
activ
ator
inhi
bito
rty
peI;
Pt:p
atie
nt;P
VR:p
erip
hera
lvas
cula
rre
sist
ance
;R/Q
:res
pira
tory
quot
ient
;SV
C:su
perio
rve
naca
va;T
AT:t
hrom
bin
antio
thro
mbi
n;TC
A:tr
icyc
lican
tidep
ress
ants
;TG
:tria
cylg
lyce
rols
;TPN
:tot
alpa
rent
eral
nutr
ition
;Tx:
trea
tmen
t;V/
Q:v
entil
atio
npe
rfus
ion;
VCO
2:ca
rbon
diox
ide
prod
uctio
n;VO
2:ox
ygen
cons
umpt
ion.
a Ast
udy
avai
labl
ein
abst
ract
only
.
CLINICAL TOXICOLOGY 379
Dow
nloa
ded
by [
Uni
vers
ity o
f Sy
dney
Lib
rary
] at
17:
44 1
6 A
ugus
t 201
7
Tabl
e3.
Pulm
onar
yad
vers
eef
fect
sre
port
edin
hum
anst
udie
s.
Refe
renc
esSt
udy
type
Type
ofpo
pula
tion
(num
ber)
Indi
catio
nof
ILE
Type
ofIL
ETo
tald
ose/
dura
tion
ofIL
ETi
min
gof
adve
rse
even
tsAd
vers
eev
ents
ARDS
/ALI/
Hypo
xia/V
/QM
ismat
ch[3
2]Ra
ndom
ized
con-
trol
led
tria
l60
poly
trau
ma
patie
nts
rand
om-
ized
tore
ceiv
e10
days
ofei
ther
stan
dard
TPN
with
ILE
(n¼
30)
orTP
Nw
ithou
tIL
E(n¼
27)
TPN
LCT
10or
20%
10or
20%
ILE
for
12h
Dur
atio
nof
hosp
italiz
atio
nGr
oup
com
paris
on:T
otal
num
ber
ofpn
eum
onia
durin
gho
spita
lizat
ion
was
27in
the
ILE
grou
pas
com
pare
dto
14in
the
cont
rolg
roup
(p¼
0.05
)Th
eIL
Egr
oup
also
expe
rienc
eda
long
erco
urse
ofm
echa
nica
lven
ti-la
tion
(p¼
0.01
).[3
3]Ra
ndom
ized
con-
trol
led
tria
l41
very
low
birt
hw
eigh
tne
o-na
tes
rand
omiz
edto
eith
er1
g/kg
/day
on24
hw
ithsu
bseq
uent
incr
easi
ngdo
sage
(n¼
15),
orsa
me
inte
rven
tion
on16
h(n¼
14),
or4
g/kg
/day
on24
h(n¼
12)
TPN
LCT
10%
or20
%(In
tral
ipid
VR
)M
axdo
se4
g/kg
/da
y(4
0m
L/kg
/day
)�
8da
ys
Atba
selin
ean
dev
ery
12h
for
8da
ys
Pre/
post
and
grou
pco
mpa
rison
s:Va
rious
regi
men
san
dra
tes
ofin
fusi
onha
dno
effe
cton
bloo
dpH
and
alve
o-la
r-ar
terio
lar
oxyg
endi
ffusi
ongr
adie
nt.
[45]
Rand
omiz
edco
n-tr
olle
dtr
ial
21se
ptic
patie
nts
with
ARD
Sra
ndom
ized
toei
ther
LCT
(n¼
10)
orLC
T/M
CT(n¼
11)
TPN
LCT
20%
(Intr
alip
idVR
)&
LCT/
MCT
20%
(Lip
ofun
dinVR
)
50%
ofda
ilyno
n-pr
otei
nca
loric
requ
irem
ent
give
nov
er8
h
Pre-
infu
sion
,30
min
befo
reth
een
dof
infu
sion
and
4h
fol-
low
ing
the
infu
sion
Pre-
/pos
t-co
mpa
rison
:Sig
nific
ant
and
tran
sien
tin
crea
sein
pulm
onar
yve
nous
adm
ixtu
re(fr
om24
%to
37%
)an
da
decr
ease
inPa
O2/
FiO
2(fr
om24
0to
180)
durin
gLC
Tin
fusi
on.S
igni
fican
tin
crea
sein
VO2
(from
329
to39
6m
L/m
in)
durin
gLC
T/M
CTin
fusi
on.
Grou
pco
mpa
rison
:Tra
nsie
nthi
gher
pulm
onar
yve
nous
adm
ixtu
rean
dVO
2an
dlo
wer
PaO
2/Fi
O2
durin
gLC
Tin
fusi
on(p<
0.05
).[1
6]Ra
ndom
ized
con-
trol
led
cros
sove
rtr
ial
Nin
epa
tient
sw
ithpa
ncre
atiti
san
dAR
DS
rand
omiz
edto
eith
erLC
T(n¼
9)or
LCT/
MCT
(n¼
9),
alte
rnat
ivel
yfo
r24
h
TPN
LCT
20%
(Intr
alip
idVR
)&
LCT/
MCT
20%
(Lip
ofun
dinVR
)
50%
ofda
ilyno
n-pr
otei
nca
loric
requ
irem
ent
give
nov
er8
h
Pre-
infu
sion
,30
min
befo
reth
een
dof
infu
sion
and
4h
fol-
low
ing
the
infu
sion
Pre-
/pos
t-co
mpa
rison
:Sig
nific
ant
and
tran
sien
tin
crea
sein
pulm
onar
yve
nous
adm
ixtu
re(fr
om26
%to
36%
)an
da
decr
ease
inPa
O2/
FiO
2(fr
om21
0to
170)
durin
gLC
Tin
fusi
on.S
igni
fican
tin
crea
sein
VO2
(from
340
to39
8m
L/m
in)
and
VCO
2(fr
om24
7to
282
mL/
min
)du
r-in
gLC
T/M
CTin
fusi
on.
Grou
pco
mpa
rison
:Tra
nsie
nthi
gher
pulm
onar
yve
nous
adm
ixtu
rean
dVO
2,an
dlo
wer
PaO
2/Fi
O2
durin
gLC
Tin
fusi
on(p<
0.05
).Tr
ansi
ent
high
erVC
O2
durin
gLC
T/M
CTin
fusi
on(p<
0.05
).[1
7]Ra
ndom
ized
con-
trol
led
cros
sove
rst
udy
18cr
itica
llyill
patie
nts
(str
atifi
edby
dise
ases
:10
seve
rese
psis
and
8AR
DS)
rand
omiz
edei
ther
tore
ceiv
ing
TPN
over
6h
(n¼
18)
or24
h(n¼
18),
alte
rnat
ivel
y
TPN
LCT
20%
(Lip
oven
os)
1.1–
1.3
g/kg
inse
p-si
sgr
oup
and
1.29
–1.3
1g/
kgto
ARD
Sgr
oup
Pre-
infu
sion
and
ever
y6
hfo
r24
hPr
e/po
stan
dgr
oup
com
paris
on:I
nth
eAR
DS
grou
pw
ithra
pid
infu
sion
,the
rew
asan
incr
ease
inP/
Tra
tio,
inpu
lmon
ary
shun
tfr
actio
nan
din
P(A�
a)O
2/Pa
O2
whi
leth
ere
was
ade
crea
sein
pulm
onar
yva
scul
arre
sist
ance
and
PaO
2/Fi
O2.
The
oppo
site
occu
rred
inth
eAR
DS
grou
pw
ithsl
owin
fusi
onas
wel
las
inth
ese
psis
grou
pw
ithra
pid
infu
sion
(inw
hich
P/T
ratio
rem
aine
dun
chan
ged
atei
ther
infu
sion
rate
).[1
9]Ra
ndom
ized
con-
trol
led
tria
l20
patie
nts
post
maj
orga
stro
-in
test
inal
surg
ery
rand
omiz
edto
Lipo
synTM
II(n¼
10)
orIn
tral
ipid
VR
(n¼
10)
TPN
LCT
10%
Lipo
synTM
IIve
rsus
Intr
alip
idVR
1.2
g/kg
(12
mL/
kg)
Base
line
and
240
min
afte
rst
art
ofin
fusi
on
Grou
pco
mpa
rison
:No
resp
irato
ryad
vers
eev
ent.
[38]
Obs
erva
tiona
lco
hort
stud
y(p
rosp
ectiv
e)
12pr
emat
ure
low
birt
hw
eigh
tin
fant
sei
ther
rece
ivin
gIL
E(n¼
6on
13in
fusi
ons)
vers
usno
tre
ceiv
ing
ILE
(n¼
6)
TPN
LCT
10%
(Intr
alip
idVR
)0.
2–0.
9g/
kg(2
–9m
L/kg
)ov
er2
h
Base
line
and
90m
inaf
ter
star
tof
infu
sion
Pre-
/pos
t-co
mpa
rison
:In
ILE
infu
sion
,inc
reas
ein
the
ratio
ofrig
htve
ntric
ular
pre-
ejec
tion
perio
dto
ejec
tion
time
(from
0.23
2to
0.28
5;p¼
0.00
01),
from
whi
ch43
%of
patie
nts
had
pulm
onar
yhy
pert
ensi
on.N
och
ange
inth
eco
ntro
lgro
up.
Grou
pco
mpa
rison
:ILE
infu
sion
was
asso
ciat
edw
ithec
hoca
rdio
grap
hic
pulm
onar
yhy
pert
ensi
on.
(con
tinue
d)
380 B. D. HAYES ET AL.
Dow
nloa
ded
by [
Uni
vers
ity o
f Sy
dney
Lib
rary
] at
17:
44 1
6 A
ugus
t 201
7
Tabl
e3.
Cont
inue
d
Refe
renc
esSt
udy
type
Type
ofpo
pula
tion
(num
ber)
Indi
catio
nof
ILE
Type
ofIL
ETo
tald
ose/
dura
tion
ofIL
ETi
min
gof
adve
rse
even
tsAd
vers
eev
ents
[35]
Obs
erva
tiona
lco
hort
stud
y(p
rosp
ectiv
e)
19ad
ult
patie
nts:
8w
ithAD
RSan
dre
ceiv
ing
TPN
with
ILE;
5w
ithAR
DS
rece
ivin
gTP
Nw
ith-
out
ILE;
6w
ithou
tAR
DS
rece
iv-
ing
TPN
with
ILE
(n¼
6)
TPN
LCT
&M
CT20
%(L
ipof
undi
nVR
)0.
21g/
kg(1
.05
mL/
kg)
over
1h
Pre-
infu
sion
and
atth
een
dof
the
infu
sion
Pre-
/pos
t-co
mpa
rison
:Dec
reas
ein
PaO
2/Fi
O2
(from
129
to95
)an
din
com
plia
nce
ofre
spira
tory
syst
em(fr
om39
.2to
33.1
mL/
cmH
2O),
and
anin
crea
sein
pulm
on-
ary
vasc
ular
resi
stan
ce(fr
om25
8to
321
dyne�
s�
cm(�
5))
inth
eAR
DS
with
ILE
grou
p.N
osi
gnifi
cant
chan
gew
asob
serv
edin
the
two
othe
rgr
oups
.Gr
oup
com
paris
on:I
LEbo
lus
inAR
DS
grou
pre
sulte
din
dete
riora
tion
inpu
lmon
ary
gas
exch
ange
and
incr
ease
dpu
lmon
ary
vasc
ular
resi
stan
ceas
com
pare
dw
ithco
ntro
ls.
[43]
Obs
erva
tiona
lco
hort
stud
y(p
rosp
ectiv
e)
19pr
eter
min
fant
sei
ther
with
resp
irato
rydi
stre
ssw
ith1.
5g/
kg/d
ayfo
r24
hfo
llow
edby
3g/
kg/d
ayfo
r24
h(n¼
11)
orhe
alth
ypr
eter
min
fant
s(n¼
8)
TPN
LCT
20%
(Intr
alip
idVR
)1.
5–3
g/kg
/day
(7.5
–15
mL/
kg/d
ay)
for
2da
ys
Atba
selin
ean
daf
ter
24h
ofin
fusi
on
Pre-
/pos
t-co
mpa
rison
:Inc
reas
edra
tioof
right
vent
ricu-
lar
pre-
ejec
tion
perio
dto
ejec
tion
time
inth
e1.
5g/
kg/
day
infu
sion
grou
p(fr
om0.
225
to0.
287)
and
inth
e3
g/kg
/day
infu
sion
grou
p(u
pto
0.32
6).N
osi
gnifi
cant
chan
gew
asob
serv
edin
the
cont
rols
.Gr
oup
com
paris
on:C
ontin
uous
24h
ILE
infu
sion
caus
edsi
gnifi
cant
dose
and
time
depe
nden
tin
crea
ses
inpu
l-m
onar
yva
scul
arre
sist
ance
.[4
9]O
bser
vatio
nal
coho
rtst
udy
(pro
spec
tive)
15pr
eter
min
fant
sre
ceiv
ing
eith
erol
ive-
oilb
ased
emul
sion
(n¼
5)or
soy-
oilb
ased
emul
sion
(n¼
10)
TPN
LCT
20%
(Clin
olei
c&
Intr
alip
idVR
)1–
3g/
kg/d
ay(5
–15
mL/
kg/d
ay)
Atba
selin
ean
dat
max
imum
lipid
infu
sion
Pre-
/pos
t-co
mpa
rison
:Est
imat
edPA
Pfe
llin
both
grou
ps:o
live-
oil-b
ased
emul
sion
grou
p(8
3%)
and
soy-
oilb
ased
emul
sion
(12%
)Gr
oup
com
paris
on:E
stim
ated
fall
inPA
Pw
asgr
eate
stin
the
oliv
e-oi
l-bas
edem
ulsi
ongr
oup
than
inth
eso
y-oi
lbas
edem
ulsi
on(p¼
0.02
).[1
4]O
bser
vatio
nal
coho
rt(p
rosp
ectiv
epr
e-/p
ost-
inte
rven
tion)
12pa
tient
s(7
criti
cally
illpa
tient
san
d5
heal
thy
volu
ntee
rs)
TPN
LCT
20%
(Intr
alip
idVR
)50
0m
LPr
e-in
fusi
on,2
and
4h
afte
rst
art
ofin
fusi
on
Pre-
/pos
t-co
mpa
rison
:All
patie
nts
expe
rienc
edan
incr
ease
inVO
2an
din
VCO
2(1
9%an
d17
%In
heal
thy
volu
ntee
rs,a
nd31
and
37%
incr
itica
llyill
patie
nts)
.RQ
rem
aine
dco
nsta
nt.N
oad
vers
eef
fect
son
pulm
on-
ary
gas
exch
ange
and
bloo
dga
ses.
[39]
Obs
erva
tiona
lco
hort
(pro
spec
tive
pre-
/pos
t-in
terv
entio
n)
Seve
nin
fant
sw
ithhy
alin
em
em-
bran
edi
seas
eor
bron
chop
ulm
o-na
rydy
spla
sia
TPN
LCT
20%
(Intr
alip
idVR
)0.
05–0
.027
g/kg
/h(0
.25–
0.13
5m
L/kg
/h)
for
10h/
day
Pre-
infu
sion
and
afte
rlip
idin
fusi
onPr
e-/p
ost-
com
paris
on:S
igni
fican
tde
crea
sein
tran
scut
a-ne
ous
PO2
afte
rlip
idin
fusi
on(m
ean
decr
ease
of10
%).
No
chan
gein
tran
scut
aneo
usPC
O2
[41]
Obs
erva
tiona
lco
hort
(pro
spec
tive
pre-
/pos
t-in
terv
entio
n)
Thre
eno
rmal
fast
ing
patie
nts
TPN
LCT
20%
(Intr
alip
idVR
)20
0m
Lov
er30
min
Befo
rean
daf
ter
infu
sion
Pre-
/pos
t-co
mpa
rison
:No
sign
ifica
ntdi
ffere
nce
indi
ffu-
sion
ofCO
[42]
Obs
erva
tiona
lco
hort
(pro
spec
tive
pre-
/pos
t-in
terv
entio
n)
16pr
emat
ure
neon
ates
TPN
LCT
10%
(Intr
alip
idVR
)1
g(1
0m
L)ov
er4
hBa
selin
e,at
4an
d8
hPr
e-/p
ost-
com
paris
on:D
ecre
ase
inPa
O2
(from
80.6
to59
.1an
dto
65.3
mm
Hg)
.Inf
ants
less
than
aw
eek
old
had
sign
ifica
ntde
clin
ein
PaO
2af
ter
lipid
,whi
leth
ose
aged
2–3
wee
ksdi
dno
t.O
ther
bloo
dga
spa
ram
eter
sw
ere
not
alte
red.
[47]
Obs
erva
tiona
lco
hort
(pro
spec
tive
pre-
/pos
t-in
terv
entio
n)
Eigh
tpr
emat
ure
infa
nts
TPN
LCT
10%
(Intr
alip
idVR
)1
g/kg
(10
mL/
kg)
Base
line
and
15m
inaf
ter
star
tof
ILE
infu
sion
Pre-
/pos
t-co
mpa
rison
:Dec
reas
ein
umbi
lical
arte
ryox
y-ge
nte
nsio
n(fr
om70
.9to
62.0
mm
Hg)
,fro
mw
hich
6ha
dgr
eate
rth
an10
mm
Hg
drop
[48]
Obs
erva
tiona
lco
hort
(pro
spec
tive
pre-
/pos
t-in
terv
entio
n)
Five
full
term
neon
ates
TPN
NR
2g/
kg(1
0m
L/kg
usin
g20
%IL
Eor
20m
L/kg
usin
g10
%IL
E)
Base
line
and
afte
r6
hof
ILE
infu
sion
Pre-
/pos
t-co
mpa
rison
:Sig
nific
ant
decr
ease
inal
veol
arox
ygen
tens
ion
(from
107
to97
mm
Hg)
and
resp
irato
ryqu
otie
nt(fr
om1.
0to
0.8)
,but
not
inal
veol
ar-a
rter
ial
O2
grad
ient
.[2
1]D
escr
iptiv
eco
hort
(ret
rosp
ectiv
e)N
ine
patie
nts
with
card
iova
scul
ardr
ugto
xici
tyRe
scue
LCT
20%
(Intr
alip
idVR
)Bo
lus6
Infu
sion
NR
Acut
eLu
ngIn
jury
repo
rted
inth
ree
out
ofni
nepa
tient
s(3
3.3%
).Al
lthr
eesu
rviv
ed(c
ontin
ued)
CLINICAL TOXICOLOGY 381
Dow
nloa
ded
by [
Uni
vers
ity o
f Sy
dney
Lib
rary
] at
17:
44 1
6 A
ugus
t 201
7
Tabl
e3.
Cont
inue
d
Refe
renc
esSt
udy
type
Type
ofpo
pula
tion
(num
ber)
Indi
catio
nof
ILE
Type
ofIL
ETo
tald
ose/
dura
tion
ofIL
ETi
min
gof
adve
rse
even
tsAd
vers
eev
ents
[34]
aD
escr
iptiv
eco
hort
(pro
spec
tive)
Nin
epa
tient
sw
ithca
rdio
vasc
ular
colla
pse
(with
poor
resp
onse
tova
sopr
esso
rs)
seco
ndar
yto
lipo-
solu
ble
agen
tspo
ison
ing
Resc
ueLC
T20
%(In
tral
ipid
VR
)50
0–10
00m
LBo
lus
NR
One
case
ofAR
DS
inse
vere
vera
pam
ilto
xici
ty.
Out
com
eno
tre
port
ed.
[26]
Case
repo
rtO
nepa
tient
with
amitr
ipty
line
OD
Resc
ueLC
T20
%(In
tral
ipid
VR
)25
0m
Lbo
lus,
then
100
mL/
hfo
r24
h,th
en18
mL/
hfo
r17
days
NR
ARD
San
dre
spira
tory
failu
rere
port
edno
deta
ilsgi
ven.
Surv
ival
with
out
sequ
elae
[37]
Cons
ecut
ivec
ase
serie
sN
ine
patie
nts
with
lipop
hilic
drug
toxi
city
Resc
ueLC
T20
%Va
rious
NR
Thre
ede
velo
ped
ARD
S
[40]
Case
repo
rtO
nepa
tient
with
vera
pam
ilO
DRe
scue
LCT
20%
100
mL
bolu
sth
en0.
2m
L/kg
/min
NR
ARD
Sfr
omIn
tral
ipid
VR
used
for
vera
pam
ilto
xici
ty.
Surv
ival
.[4
4]Ca
sere
port
One
(3yo
)pa
tient
with
Bupi
vaca
ine
toxi
city
Resc
ueLC
T20
%17
0m
LN
RRe
susc
itate
dsu
cces
sful
ly.V
Qm
ism
atch
note
daf
ter
resu
scita
tion
[31]
Case
repo
rtO
nepa
tient
TPN
LCT
10%
(Intr
alip
idVR
)N
RN
RAR
DS
from
Intr
alip
idVR
.Car
ew
ithdr
awn
and
patie
ntex
pire
d.[3
0]Ca
sere
port
One
patie
ntTP
NLC
T20
%(In
tral
ipid
VR
)25
0m
Lof
20%
–24
gLi
pid/
kgbo
dyw
eigh
t
NR
Mas
sive
OD
ofTP
Nin
32w
eeks
old
infa
nt-
resp
irato
rydi
stre
ss,T
reat
edw
ithex
chan
getr
ansf
usio
n,fu
llre
cove
ry[3
6]Ca
sese
ries
Eigh
tpr
emat
ure
infa
nts
TPN
LCT
20%
(intr
alip
idVR
)To
talN
R-ra
tefr
om0.
07g/
kg/h
to0.
44g/
kg/h
(0.3
5–2.
2m
L/kg
/h)
for
4h–
27da
ys
NR
Auto
psie
ssh
owed
fat
accu
mul
atio
nin
pulm
onar
yva
s-cu
latu
reco
nsis
tent
with
V/Q
mis
mat
ch,i
ncon
sist
ent
with
fat
over
load
synd
rom
eor
embo
lism
.
[46]
aCa
sere
port
One
prem
atur
ein
fant
TPN
LCT
20%
(Intr
alip
idVR
)14
.5m
Lov
er1.
75h
NR
Rece
ived
anac
cide
ntal
OD
ofLi
pid,
was
hypo
xic
for
12h
but
retu
rned
tono
rmal
with
out
sequ
elae
AE:A
dver
seev
ents
;AKI
:acu
teki
dney
inju
ry;A
MS:
alte
red
men
tals
tatu
s;AR
DS:
acut
ere
spira
tory
dist
ress
synd
rom
e;BB
:bet
abl
ocke
r;BM
:bon
em
arro
w;C
CB:c
alci
umch
anne
lblo
cker
;CVC
:cen
tral
veno
usca
thet
er;C
VVH
F:co
ntin
u-ou
sve
no-v
enou
she
mof
iltra
tion;
DIC
:dis
sem
inat
edin
trav
ascu
lar
coag
ulat
ion;
CO:c
arbo
nm
onox
ide;
DKA
:dia
betic
keto
acid
osis
;DLC
O:c
arbo
nm
onox
ide
diffu
sion
capa
city
;DVT
:dee
pve
inth
rom
bosi
s;EC
MO
:ext
raco
rpor
ealm
em-
bran
eox
ygen
atio
n;Fi
O2:
frac
tion
ofin
spire
dox
ygen
;FO
BLE:
fish
oil-b
ased
lipid
emul
sion
;GA:
gest
atio
nala
ge;H
PF:h
igh
pow
ered
field
;ICU
:int
ensi
veca
reun
it;IL
E:in
trav
enou
slip
idem
ulsi
on;L
CT:l
ong
chai
ntr
iacy
lgly
cero
ls;
LFT:
liver
func
tion
test
s;LP
L:lip
opro
tein
lipas
e;M
CT:m
ediu
mch
ain
tria
cylg
lyce
rols
;MO
DS:
mul
tiorg
andy
sfun
ctio
nsy
ndro
me;
NA:
nota
vaila
ble;
NIC
U:n
eona
tali
nten
sive
care
unit;
NR:
notr
epor
ted;
OD
:ove
rdos
e/po
ison
ing;
PAP:
pulm
onar
yar
tery
pres
sure
;P(A
–a)O
2:Al
veol
arAr
teria
lgra
dien
t;Pa
O2:
arte
rialp
artia
lpre
ssur
eof
oxyg
en;P
AI-1
:pla
smin
ogen
activ
ator
inhi
bito
rty
peI;
Pt:p
atie
nt;P
VR:p
erip
hera
lvas
cula
rre
sist
ance
;R/Q
:res
pira
tory
quot
ient
;SV
C:su
perio
rve
naca
va;T
AT:t
hrom
bin
antio
thro
mbi
n;TC
A:tr
icyc
lican
tidep
ress
ants
;TG
:tria
cylg
lyce
rols
;TPN
:tot
alpa
rent
eral
nutr
ition
;Tx:
trea
tmen
t;V/
Q:v
entil
atio
npe
rfus
ion;
VCO
2:ca
rbon
diox
ide
prod
uctio
n;VO
2:ox
ygen
cons
umpt
ion.
a Ast
udy
avai
labl
ein
abst
ract
only
.
382 B. D. HAYES ET AL.
Dow
nloa
ded
by [
Uni
vers
ity o
f Sy
dney
Lib
rary
] at
17:
44 1
6 A
ugus
t 201
7
acids. The authors suggested that the increased plasma cat-echolamine level could have been the mechanism by whichILE affected cardiac repolarization. Eighteen critically illpatients (stratified by disease – 10 with severe sepsis andwith eight with ARDS) were randomized to receive TPN overeither 6 h or 24 h.[17] In the ARDS group with rapid infusion,a decrease in pulmonary vascular resistance and systemic vas-cular resistance occurred, while there was an increase in car-diac index. The authors attributed these effects to ILEadministration and concluded that linoleic acid administra-tion, regardless of infusion rate, may be unwanted in patientswith pulmonary organ failure. One patient experienced tam-ponade from TPN infused into the pericardium.[18] After majorgastrointestinal surgery, 20 patients were randomized toLiposynTM II or IntralipidVR .[19] No cardiovascular events werenoted. Liposyn II is a 50% soy/50% safflower oil emulsion.
Smyrniotis et al. studied nine patients with pancreatitis andARDS who were randomized to receive either long-chain tria-cylglycerols (LCT) or LCT/medium-chain triacylglycerols (MCT)alternately for 24 h in a crossover trial.[16] An example of LCTis IntralipidVR , while LipofundinVR represents a LCT/MCT mixture.When comparing the two treatment conditions, there was atransient higher mean pulmonary artery pressure from 28 to35 mm Hg during LCT infusion (p<0.05) and a transient highercardiac output from 8.8 to 9.5 L/min during LCT/MCT infusion(p<0.05). In an observational cohort, 12 patients (5 volunteers,7 critically ill) received IntralipidVR 2.1 mL/min for 4 h (500 mLtotal volume).[14] All of the critically ill patients experienced asignificant rise in cardiac output (5.8–6/7 L/min) and anincrease in pulmonary vascular resistance (64.7–131.9 dyne/sec/cm5). No adverse effects on hemodynamics were reported.
Hematological effectsFour articles described hematological effects after administra-tion of TPN containing lipid.[21–24] McGrath and associatesdescribed a patient in whom intravascular hemolysis devel-oped following an infusion of 500 mL of IntralipidVR 10% over2 h.[24] For 3 weeks, the patient had received the same dailyamount infused over 8 h without any symptoms. The reactionto the faster administration indicated that the reaction waslikely due to the rate of infusion. The authors speculated thatIntralipidVR might cause changes in the phospholipid compos-ition of the red cell membrane; or alternatively, a product ofIntralipidVR breakdown (e.g., lysolecithin) might have acted asa direct hemolysin. Two other author groups reportedthrombocytopenia in the setting of lipid administration forTPN.[22,25] Geib and colleagues described the emergence ofdisseminated intravascular coagulation (DIC), which had afatal outcome.[21] Low and Ryan determined that a dosingerror in a premature infant resulted in persistent hyponatre-mia (for 5 days), elevated liver enzymes, and intraventricularhemorrhage.[23]
Acute kidney injurySix articles focused on adverse effects classified underAKI.[12,21,26–29] Three of them involved the use of ILE forpoisoning,[21,26,28] and three described patients receivingTPN.[12,27,29] AKI requiring continuous renal replacement
therapy (CRRT) was noted in a patient who received 20% ILEfor 18 h as treatment for tricyclic antidepressant overdose.[26]A serum creatinine was not reported. AKI occurred in three ofnine patients receiving various doses of 20% IntralipidVR foroverdose of various cardiotoxic medications, though AKI wasnot defined and no laboratory markers were reported.[21] AKIdeveloped in an 47-year-old female after IntralipidVR adminis-tration in the setting of diltiazem poisoning.[28] A serum cre-atinine was not reported.
Crook reported AKI in a patient who received 2580 mL ofILE (combined dose for 10% and 20% ILE) over 24 h.[12] Anelevation in blood urea nitrogen from 7 to 28 mg/dL wasdetected in a premature infant after an iatrogenic overdoseof IntralipidVR intended for TPN.[27] No change in serum cre-atinine was observed. In the largest of the reports, reducedglomerular and tubular function, manifested by increasedurine protein markers, was detected in 50 premature infantsreceiving TPN, including 0.5 g/kg/day (equivalent to 2.5 mL/kg/day of 20% ILE) of a lipid emulsion that was not specific-ally described.[29] The two groups were significantly differentat baseline in this non-randomized, observational study. 80%of the neonates in the TPN group were born at 28–30 weeksgestation; 80% of the enterally-fed infants were older than 30weeks. Likewise, the mean birth weight for the enteral groupwas 30% higher than the mean birth weight of the TPNgroup. Mothers of the TPN-fed babies were more likely tohave hypertension or eclampsia.
Metabolic acidosisTwo articles addressed metabolic acidosis after ILE administra-tion.[21,30] One case series reported metabolic acidosis inone of nine patients being treated with ILE in response todrug-induced cardiotoxicity.[21] The magnitude of this acid-osis and the amount of lipid received were not reported.Fairchild and associates described the clinical course of a pre-term infant who received an overdose of IntralipidVR 20%(24 g/kg or 250 mL) over 60 min.[30] The child had laboratoryvalues of a pH of 7.25, a PCO2 of 35 mm Hg, and a PaO2 64of mm Hg, which improved with administration of sodiumbicarbonate, 2 mEq/kg. The patient’s oxygen saturation was92%, with evidence of ARDS. It is unclear how, or if, ILEadministration and the metabolic acidosis were related.
Pulmonary adverse effects
26 articles addressed pulmonary adverse effects, includingARDS, ALI, hypoxia, and V/Q mismatch (Table 3).[14,16,17,19,21,26,30–49] Six of these cases were reported inthe context of rescue ILE, while the remaining 20 were in thecontext of TPN. The articles reporting ARDS after administra-tion of ILE for poisoning describe a total of ninecases.[26,34,37,40,50] All patients were critically ill prior toreceiving rescue ILE, so the authors could not implicate ILE asa single direct causative factor in development of ARDS. Fourof the TPN articles cited or speculated a mechanism ofIntralipidVR -induced ARDS in which fatty acid precursors to ara-chidonic acid resulted in inflammatory cascade and prosta-glandin production.[16,35,45,51] One patient of particular
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interest was a 68-year-old man who developed ARDS anddied after receiving a first dose of lipid for TPN.[31] Anotherarticle described a premature infant who received an uninten-tional overdose of almost 30 mL/kg of 20% IntralipidVR over1.75 h and then became dusky and hypoxic.Echocardiography demonstrated pulmonary hypertension.The effect was transient and self-resolved, so TPN with ILEwas eventually resumed.[46]
Several articles specifically addressed V/Q mismatch as acomplication of ILE.[17,36,44] The earliest one describes eightpreterm infants who died after administration ofIntralipidVR .[36] The dose did not exceed 3 g/kg/day (15 mL/kg/day of 20% ILE). Signs of lipid deposits could be seen as earlyas 4 h after the first infusion. At autopsy, the lungs of thesebabies were found to have significantly greater lipid depositsthan a matched group of infants who had not received ILE.One of the eight infants died within 3 days after ILE adminis-tration. Another child presented with perfusion mismatch 4 hafter cardiac arrest induced by a local anesthetic.[44] Thedose of ILE given was 3 g/kg/h (15 mL/kg/h of 20% ILE)instead of 0.125 g/kg/h, as recommended by the AmericanSociety for Parenteral and Enteral Nutrition (ASPEN).Nonetheless, the causes of this child’s pulmonary dysfunctionare likely multifactorial.[52] A prospective controlled random-ized crossover study of 10 ARDS and eight septic adultpatients reported an increased prostaglandin/thromboxaneratio matching and an increase in pulmonary shunting witheither slow (24 h) or rapid (6 h) ILE infusion given for nutri-tional support at rates of 0.050–0.054 g/h (0.25–0.27 mL/h for20% ILE) over 24 h or 0.2–0.217 g/h (1–1.09 mL/h for 20% ILE)over 6 h.[51] The authors of this study recommended cautionin using ILE in patients with pulmonary disease. In a prospect-ive, observational cohort of 12 patients receiving TPN, allpatients experienced an increase in VO2 (oxygen consump-tion) and in VCO2 (carbon dioxide excretion) (19% and 17% inhealthy volunteers; 31% and 37% in critically ill patients).[14]No adverse effects on pulmonary gas exchange or bloodgases were reported. Conversely, three articles cited noadverse pulmonary effects from lipid used for TPN.[19,33,41]Forty-one very-low-birth weight neonates were randomizedto either 1 g/kg/day over 24 h with subsequent increasingdoses (n¼ 15), the same intervention over 16 h (n¼ 14), or4 g/kg/day over 24 h (n¼ 12). The various regimens and ratesof infusion had no effect on blood pH or alveolar-arteriolaroxygen diffusion gradient.[33] Following major gastrointes-tinal surgery, Tomassetti and associates randomized 20patients to receive IntralipidVR or LiposynTM II for TPN. Noadverse respiratory events were reported.[19] Partridge andcolleagues found no significant difference in diffusion of car-bon monoxide in three normal, fasting volunteers whoreceived 200 mL of 20% IntralipidVR over 30 min.[41]
Hypersensitivity and allergic adverse effects
Eight articles addressed hypersensitivity, a reaction with anincidence of less than 1% in clinical trials (Table4).[31,53–58] Published reports of hypersensitivity involve1–3 cases and include adult and pediatric patients.
Reaction severity includes diffuse pruritus[56]; diffuse urti-caria and dyspnea[55]; urticarial rash[54,59]; skin blister-ing[53]; and diffuse erythema, shortness of breath, andtachypnea with subsequent development of ARDS anddeath.[31] In most cases, the reactions resolved when ILEwas stopped and without treatment with antihistaminesand/or glucocorticoid therapy. One report indicated hyper-sensitivity to ILE containing LCT in three cancer patients.Re-exposure to LCT and exposure to marginally differentformulations of MCT solutions without soybean lecithinwere well tolerated.[57] One out of 48 patients receivingILE rescue was reported to have bronchospasm afteradministration.[60] In the study by Tomassetti et al., men-tioned above, no adverse allergic events were reported intwenty patients who were randomized to receiveIntralipidVR or LiposynTM II for TPN after major gastrointes-tinal surgery.[19]
Vascular occlusion
PriapismFive articles addressed priapism (Table 5).[61–65] Klein andcolleagues reported the development of priapism in twopatients after infusion of 500 mL of IntralipidVR 20% orLiposynTM (a safflower oil emulsion) during long-term TPNtherapy.[63] Hebuterne and associates described their man-agement of a man who experienced priapism as a reaction toparenteral nutrition, and summarized four other cases frompreviously published articles.[64] Chapuis and Stratt reportedpriapism in a 70-year-old man who received 1500 mL ofIntralipidVR 20% daily following emergency surgery.[62]Priapism occurred at the end of his daily infusion on the 34thday of TPN therapy. While this interval exceeded the criterionfor the article selection process, it is reasonably likely that thisadverse effect may be attributable to a single infusion of ILEand not to the cumulative dosage of the previous 34 days.The rate of infusion was not reported. Collectively, these fivearticles present eight cases of priapism associated with TPN.Half of them had received heparin in addition to ILE. Thereaction occurred under a range of circumstances: at a widerange of intervals (45 min to 11 days) and doses (between500 and 1500 mL daily).
Deep vein thrombosis/phlebitis/coagulation biomarkersFour articles addressed DVT in a context that could apply tothe use of ILE in toxicology.[21,66–68] Phlebitis was devel-oped at the site of ILE administration shortly after the onsetof infusion during resuscitation from a diphenhydramine poi-soning; DVT was confirmed on a return visit.[66] Geib and col-leagues diagnosed DVT in 3 of 9 patients who received ILEfor poisoning. Two of them received a bolus with a subse-quent infusion, and one patient received three boluses. Thetotal doses of ILE were not reported.[21] In a prospective,observational cohort study in patients receiving TPN,Altomare and co-workers found that tissue plasminogen acti-vator concentrations were significantly lower in a groupreceiving 500 mL ILE over 5–6 h than in a control group.[67]
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Fat embolismSix articles addressed fat embolism in patients receivingTPN.[13,20,69–72] The majority occurred after at least 7 daysof therapy. No cases were associated with administration ofILE in the treatment of poisoning. It is unknown if the risk offat embolism occurs with each infusion or is a cumulative risk.
CVVHF circuit and ECMO line interferenceThree case reports or series described line complica-tions.[40,73,74] Rodriguez et al. described a 26-year-old manwith refractory hypotension and bradycardia following anintentional overdose of amlodipine, metoprolol, and lisinopril.He received a bolus of ILE 20% followed by a continuous
infusion after other treatments had failed.[74] He continuedto deteriorate, and he underwent continuous veno-venoushemofiltration. Lipemic blood appeared immediately in theCVVHF filter, and the filter become completely obstructedand unusable. The patient died despite ongoing resuscitationefforts. Buck and colleagues conducted a prospective studythat identified nine neonates who received ILE for nutritionand were on simultaneous extracorporeal membrane oxygen-ation (ECMO). Five patients received ILE through the ECMOcircuit and four patients received ILE through a separate line.All five patients receiving ILE through the ECMO circuit devel-oped clots in the circuit. Two of the four patients in the IVaccess group developed blood clots, though it is not men-tioned if clotting in the circuit occurred.[73]
Table 4. Hypersensitivity and allergic adverse effects reported in human studies.
References Study typeType of population
(number)Indication
of ILE Type of ILETotal dose/
duration of ILETiming of adverse
events Adverse events
[19] Randomized con-trolled trial
20 patients post majorgastrointestinal surgeryrandomized toLiposynTM II (n¼ 10) orIntralipidVR (n¼ 10)
TPN LCT 10% LiposynTM
II versus IntralipidVR
1.2 g/kg(12 mL/kg)
Baseline and240 min after startof infusion
Group comparison: Noallergic adverse event.
[60] Descriptivecohort(prospective)
48 patients with drugtoxicity (online lipidregistry): 10 with LA,38 other OD)
Rescue Multiplepreparations
Variable NR Bronchospasm 1/48 cases(2.1%)
[53] Case report One patient TPN NR Unknown NR Severe skin erythema,edema, and blistering atsite of infusion. Resolutionafter 2 months with ste-roids and antibiotics.
[54] Case report One patient TPN LCT 20%(IntralipidVR )
650 mL total NR Urticarial rash, resolutionwith diphenhydramine
[55] Case report One patient TPN LCT 10%(IntralipidVR )
500 mL NR Prior history of allergy tolegume and bean prod-ucts developed urticariaand dyspnea thatresponded todiphenhydramine.
[59] Case report 1 (9 years) TPN LCT 20%(IntralipidVR )
NR NR After 19 days of TPN,developed urticarial rashthat resolved with cessa-tion and recurred with re-challenge. Disparity notedbetween skin testing andintravenous challenge.
[56]a Case report 1 (2 years) TPN LCT 20%(IntralipidVR )
NR NR Developed allergic reac-tion, resolved with cessa-tion. Subsequent positiveegg white allergy.
[57] Case series Three patient TPN MCT & LCT? % NR NR Hypersensitivity to LCTbut not MCT in cancerpatients. Symptomsresolved with steroids andtermination of infusion.
AE: Adverse events; AKI: acute kidney injury; AMS: altered mental status; ARDS: acute respiratory distress syndrome; BB: beta blocker; BM: bone marrow; CCB: calciumchannel blocker; CVC: central venous catheter; CVVHF: continuous veno-venous hemofiltration; DIC: disseminated intravascular coagulation; CO: carbon monoxide;DKA: diabetic ketoacidosis; DLCO: carbon monoxide diffusion capacity; DVT: deep vein thrombosis; ECMO: extracorporeal membrane oxygenation; FiO2: fraction ofinspired oxygen; FOBLE: fish oil-based lipid emulsion; GA: gestational age; HPF: high powered field; ICU: intensive care unit; ILE: intravenous lipid emulsion; LCT: longchain triacylglycerols; LFT: liver function tests; LPL: lipoprotein lipase; MCT: medium chain triacylglycerols; MODS: multiorgan dysfunction syndrome; NA: not available;NICU: neonatal intensive care unit; NR: not reported; OD: overdose/poisoning; PAP: pulmonary artery pressure; P(A–a)O2: Alveolar Arterial gradient; PaO2: arterial partialpressure of oxygen; PAI-1: plasminogen activator inhibitor type I; Pt: patient; PVR: peripheral vascular resistance; R/Q: respiratory quotient; SVC: superior vena cava;TAT: thrombin antiothrombin; TCA: tricyclic antidepressants; TG: triacylglycerols; TPN: total parenteral nutrition; Tx: treatment; V/Q: ventilation perfusion; VCO2: carbondioxide production; VO2: oxygen consumption.aA study available in abstract only.
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Table 5. Vascular occlusion adverse effects reported in human studies.
References Study typePopulation
(number and type)Indication
of ILE Type of ILE Total dose of ILETiming of adverse
events Adverse events
Priapism[62] Case report One patient TPN LCT 20%
(IntralipidVR )1500 mL/day � 34days
At the very end of1500 mL ILE on the34th day
Priapism, remained impotentat 3-year follow up
[61] Case series Three patient TPN LCT (20%IntralipidVR )
500–1000 mL/day One patient devel-oped priapism after5 days, two patientsafter 11 days
Priapism developed 5–11days following TPN. Treatedsurgically. One out of threepatients remained impotentat 6-month follow up.
[64] Case report One patient TPN LCT 20% 500 mL/12 h Within 24 h of theonset of ILE
Priapism, continued impo-tence at 3-year follow up
[63] Case series Two patient TPN LCT (LiposynTM)20%
Unclear within 1 hof 500 mL infusionrate not reported
45 min after start ofILE infusion
Two patients with priapism,one remained impotent, onehad resolution after treat-ment. Incidence of 5.7%(from an 8-year TPN programincluding 35 males).
[65] Case report One patient TPN LCT 20%(IntralipidVR )
500 mL for 5 daysthen 1000 mL for1 day
12 h after infusionon the 6th day ofILE
Priapism, treated surgically.No erections at 2 months fol-low up
Deep vein thrombosis/phlebitis/coagulation biomarkers[67] Observational
500 mL over 5–6 h Baseline, at the endof the infusion and24 h later
Pre-/post-comparison: Tissuesplasminogen activator levelswere significantly lower atthe end of the infusion and24 h later (Ps < 0.001 and<0.05), while they wereincreased in the controls atthe end of the infusion only(p < 0.01).Group comparison: Tissueplasminogen activator levelswere significantly lower inthe ILE group than in thecontrol group, while PAI-1levels were comparable at alltimes between the twogroups.
[68] Observationalcohort study(prospective)
10 healthy menreceived IV endo-toxin after eitherILE (n¼ 5) or dex-trose 5% (n¼ 5)
TPN LCT 20%(IntralipidVR )
500 mL Pre-infusion andevery hour for 6 h
Pre/post and group compari-son: Peak levels of prothrom-bin fragment Fiþ 2, TATcomplexes and PAI-1increased to 6.88 nM,63.1 lg/L, and 622.3 lg/L inthe ILE group as comparedto 4.93 nM, 37.1 lg/L, and337.7 lg/L in the controlgroup, which was statisticallyhigher in the ILE group (Psall < 0.05). Infusion of lipidemulsion potentiated endo-toxin induced coagulationactivation in compared tocontrols
[21] Descriptive cohort(retrospective)
Nine patients withcardiovascular drugtoxicity
Rescue LCT 20%(IntralipidVR )
Bolus 6 Infusion NR Three out of nine had DVT(33.3%). Two survived.
[66] Case report One patientwith Diphenhydrami-ne OD
Rescue LCT 20% 8 mL/kg 2 weeks after ILE Observed phlebitis duringadministration. On 2-weekfollow-up the patient wasfound to have a deep veinthrombosis in the brachialvein and a superficial throm-bosis in the proximal basilicvein.
Fat embolism[20] Case series Four infants TPN LCT 20%
(IntralipidVR )0.08–0.15 g/kg/h(0.4–0.75 mL/kg/h)for 11–18 days
No specific timing Autopsies showed evidenceof fat emboli at autopsy. Allhad received prolonged ILE.
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Infection susceptibility and inflammation adverse effects
Nine articles discussed the adverse effect of immune modula-tion in the context of ILE administration (for rescue therapy inonly one case) (Table 6).[19,21,22,32,75–79] Battistella andassociates conducted a prospective, randomized trial of 57trauma patients randomized to receive 20% ILE or no ILE aspart of the TPN during the first 10 days of TPN. The groupthat received ILE had a higher rate of infectious complica-tions.[32] This scenario may not apply to the short courses ofILE for acute poisoning. In acute poisoning, treatment withILE seldom continues for many days, although Agarwala and
colleagues describe a patient with a massive and severe ami-triptyline overdose treated with ILE at 18 mL/h for a total of19 days with no complication other than lipemia.[26]
In a study of the effect on neutrophil function, Cury-Boaventura and colleagues gave volunteers a single infusionof 500 mL of a 20% soybean oil over 6 h.[76] The obtained-blood sample before, immediately after, and 18 h after infu-sion, and then cultured lymphocytes and neutrophils for 0,24, or 48 h after sampling. Compared with samples takenprior to ILE infusion, samples taken immediately after the endof ILE infusion had decreased levels of lymphocytes and neu-trophils. The authors pointed to mitochondrial membrane
Table 5. Continued
References Study typePopulation
(number and type)Indication
of ILE Type of ILE Total dose of ILETiming of adverse
events Adverse events
[69] Case report One patient TPN LCT? % (IntralipidVR ) 500 mL/15 min Immediately afterILE
Developed fever, Vision Loss,Seizure and coma after lipidinfusion – Complete reso-lution by 2 weeks
[13] Case report One prematureinfant
TPN ILE 10% (IntralipidVR ) 0.08 g/h (8 mL/hILE) � 8 h¼ 0.64 g
8 h after the begin-ning of infusion
Pulmonary microembolifound at autopsy death 12 hpost-ILE
[70] Case series Two patients (aged22 and 76)
TPN NR Unknown NR Suspected cerebrovascular fatemboli due to developmentof permanent neurologicaldeficits while receiving ILE
[71] Case report One child TPN LCT 20%(LipofundinVR )
60.7 g/kg (303.5 mL/kg) over 7 weeks
NR Autopsy showed fat embol-ism of pulmonary smallarteries and giant-cell reac-tion in lumen.
[72] Case report One pediatricpatients
TPN LCT 20%(IntralipidVR )
5.1 mg/kg/day(25.5 mL/kg/day) for1 day
24 h after infusion Fat emboli in multiple capilla-ries and arterioles in organsincluding the brain, spleen,liver, kidney, and lymphnodes
CVVHF circuit clot or ECMO line interference[73] Randomized con-
trolled trialNine neonates onECMO randomizedto TPN either bythe ECMO circuit(n¼ 5) or separateIV access (n¼ 4)
TPN LCT 20%(IntralipidVR )
3 g/kg (15 mL/kg)max
During the 24 h fol-lowing the start ofinfusion
Group comparison: 100%developed clots in the ECMOcircuit versus 50% in the IVaccess (p¼NR). Clot forma-tion trended to occur morefrequently when ILE is admin-istered by the ECMO circuit.
[40] Case report One patient withVerapamil OD withARDS, treated withVA-ECMO and CVVH
Rescue LCT 20%(IntralipidVR )
100 mL if ILE withinfusion 0.2 mL/kgduration unknown
NR Filter needed to be changedthree times
[74] Case report One patient with BBand CCB refractoryto standard therapytreated with CVVHFfor volume overloadand acidosis
Rescue LCT 20%(IntralipidVR )
1.5 mg/kg (7.5 mL/kg) bolus � 2
NR CVVHF unsuccessful due tolipemic blood and filterobstruction
Table 6. Infection susceptibility/inflammation adverse effects reported in human studies.
References Study typePopulation
(number and type)Indication
of ILE Type of ILE Total dose of ILETiming of adverse
events Adverse events
[32] Randomized con-trolled trial
60 polytraumapatients randomizedto standard TPNwith ILE (n¼ 30) orTPN without ILE forthe first 10 days(n¼ 27)
TPN LCT 10 or 20% 10 or 20% ILE for12 h
Clinical outcomes:duration of hospital-ization. T-cell func-tion: baseline andday 5
Pre-/post-comparison: T-cell func-tion improved in the controlgroup contrary to the ILE groupwhich deteriorated by day 5.Group comparison: Total numberof infectious episodes was 72(from which 27 pneumonia and15 line sepsis) in the ILE groupand 39 (from which 14 pneumo-nia and 6 line sepsis) in the con-trol group. ILE group had morefrequent infectious complications(pneumonia (p¼ 0.05) and linesepsis (p¼ 0.04)) than the con-trol group.
[19] Randomized con-trolled trial
20 patients postmajor gastrointes-tinal surgeryrandomized toLiposynTM II (n¼ 10)or IntralipidVR
(n¼ 10)
TPN LCT 10% LiposynTM
II versus IntralipidVR
1.2 g/kg (12 mL/kg) Baseline and240 min after startof infusion
Pre/post and group comparison:No change in inflammatory C4CRP
[79] Randomized con-trolled crossovertrial
10 patients withgastric cancerrandomized toeither LCT (n¼ 10)or MCT/LCT (n¼ 10)emulsion, alterna-tively for 48 h each
Pre-/post-comparison: Neutrophilbacterial killing was reducedafter LCT emulsion (from 79%killed bacteria to 67%, p<0.05),although remaining in normalrange for 80% of the patients.Group comparison: LCT alonehad decreased neutrophil bacter-ial killing activity as comparedwith LCT/MCT (p<0.01), withoutany difference in phagocytosisindex, chemotaxis, spontaneousmigration, or oxidativemetabolism
[78] Observationalcohort study(prospective)
Seriously ill generalsurgery patientsreceiving ILE infu-sion (n¼ 8) versushealthy volunteersreceiving ILE bolus(n¼ 20)
TPN LCT 20%(IntralipidVR )
In seriously illpatients: 500 mLover 8 h versushealthy volunteers:bolus
Baseline and after3 h of infusion onseriously ill patientsor 15 min afterbolus in healthyvolunteers
Pre/post comparison: Decrease inmonocyte chemotaxis from 150to 94 cells/hpf in seriously illpatients after 3 h of infusion (p< 0.05) versus 96–60 cells/hpfin healthy volunteers 15 minafter bolus (p¼ 0.0002).Preserved lymphocytes function.Group comparison: Similardecreased monocyte function(chemotaxis) in both groups fol-lowing IntralipidVR . Also, heparinprevented the changes in mono-cytes function.
500 mL over 6 h Baseline, immedi-ately post-infusionand 18 h post-infusion
Pre-/post-comparison: Variousneutrophils and lymphocytesbiomarkers showed significantalteration immediately post-infu-sion, with a persistent effect inmany biomarkers 18 h post-infu-sion. Decrease in lymphocyteproliferation and enhancedlymphocyte and neutrophilapoptosis after infusion
[21] Descriptive cohort(retrospective)
Nine patients withcardiovascular drugtoxicity
Rescue LCT 20%(IntralipidVR )
Bolus 6 Infusion NR One case of sepsis survived.
[77] Descriptive cohort(prospective)
103 TPN bottleswere collected atcompletion of5–12 h infusionsand 5–10 mL cul-tured for measure-ment of bacterialcontamination
TPN LCT 10%(Travalmulsion)
NA After completion ofinfusion
7.8% were positive for bacterialgrowth with various bacterialcontaminant. No reported casesof bacteremia
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depolarization and nucleus lipid accumulation to explain celldeath, which occurred without alteration in reactive oxygenspecies (ROS) production. This presumed mechanism mightenhance patients’ susceptibility to infections. The cell deathpercentage increased from less than 5% immediately afterinfusion to 15% at 24 h. The decrease in lymphocyte prolifer-ation was greater immediately following infusion than at 18 hafterward.[76]
Liang and colleagues gave a patient 500 mL of an ILE 10%for 2 days (total dose, 1 L) for nutritional support followingingestion of a corrosive agent, which caused an esophagealinjury.[22] He experienced an acute catatonia, mutismepisode associated with ecchymosis. Severe thrombocyto-penia (platelet count of 11,000 cells/lL) and leukopenia(1500/cells/lL) were reported. All symptoms and types ofcytopenias resolved within 24 h after discontinuation of theILE infusion. The hematology team eliminated other possiblecauses such as thrombotic thrombocytopenic purpura, disse-minated intravascular coagulation, and hemolysis. The specu-lative mechanism was N-methyl-D-aspartate (NMDA) receptorhyperactivity at a high plasma dilution of ILE (1:80 to 1:5).A dose of 50 mL/h for 10 h (500 mL/day) would yield dilutionof 1:70.
In a randomized crossover trial of patients receiving LCT orLCT/MCT TPN, Waitzberg and co-workers observed that LCTalone had decreased neutrophil bacterial killing activity com-pared with LCT/MCT (p< 0.01), without any difference inphagocytosis index, chemotaxis, spontaneous migration, oroxidative metabolism.[79] In a separate observational cohort,Fraser and associates found decreased monocyte function(chemotaxis) following administration of IntralipidVR .[78]
A patient being treated with ILE for rescue therapy byGeib and colleagues developed sepsis but survived. The asso-ciation between ILE and sepsis is not described, and it is
unclear whether ILE played a causative role.[21] Tomassettiand associates reported no infection susceptibility adverseevents in 20 patients who were randomized to receiveIntralipidVR or LiposynTM II for TPN following major gastrointes-tinal surgery.[19]
Ebbert and colleagues collected 103 TPN bottles at thecompletion of 5–12 h infusions and 5–10 mL samples and cul-tured them to measure bacterial contamination.[77] Almost8% of the samples were positive for various bacterial contam-inants. None of the patients who received the contents ofthose bottles experienced bacteremia.
Fat overload syndrome, hypertriglyceridemia, lipemia,hyperamylasemia, pancreatitis, and cholestasis are among themost commonly reported adverse effects associatedwith ILE rescue and TPN therapy (Table 7). Of the 41 articlesthat describe these effects, 33 were from TPN[12,14,15,19,20,23,24,27,30,33,41,47,72,73,80–98] and eightwere from ILE rescue therapy for over-dose.[21,26,28,37,60,99–101] IntralipidVR 20% was the mostcommon formulation used in the articles that reported thetype of lipid (27/38). In most cases, the laboratory abnormal-ities were transient and did not appear to play a role in thepatient’s outcome. Most of the patients who died were neo-nates or premature infants, or had been on long-term TPNtherapy. It is unclear what role, if any, the laboratory abnor-malities contributed to mortality when ILE was used in themanagement of a poisoning. Eight articles addressed fat over-load syndrome, a constellation of many of the isolated com-plications reported and generally accompanied by
Table 6. Continued
References Study typePopulation
(number and type)Indication
of ILE Type of ILE Total dose of ILETiming of adverse
events Adverse events
[75] Case report One neonate TPN (IntralipidVR ) NR Unclear but duringfirst 6 weeksunknown whenscalp vein inserted
ILE infusion into brain matter(accidental).Died 62 days later.No local immune response onpathology.
[22] Case report One patient TPN MCT/LCT 10% 500 mL/day Symptoms startedafter the 2nd doseof ILE on the 3rdhospital day
Catatonia, thrombocytopenia,leukopenia noted after twodoses of lipid.
intravascular lipid deposition in organs such as the liver, kid-ney, or brain (found at autopsy).[12,72,89,90,102–104]
Animal studies
The animal studies reported in the literature were arrangedinto the following categories: organ failure (including cardiac,hematological, fat overload syndrome, hypertriglyceridemia/pancreatitis/lipemia); pulmonary (including acute respiratorydistress syndrome [ARDS], hypoxia, and ventilation/perfusion(V/Q) mismatch); and infection susceptibility (including sepsisand systemic inflammatory response syndrome [SIRS]).
Organ dysfunction adverse events
Cardiac effectsOne study addressed the cardiac and circulatory effects of ILE(Table 8).[107] In a study of cardiac arrest resulting from hyp-oxia (not poisoning), rabbits given ILE instead of normal
saline resuscitation had a much lower rate of return of spon-taneous circulation (1/11 versus 7/12).[107]
Hematologic effectsThree studies reported hematological effects related to ILEgiven as part of TPN.[108–110] A canine model demonstratedhemoglobin and hematocrit decrease after 21 days of soy-bean-oil fat emulsion administration.[110] A rabbit modeldemonstrated that thrombocytopenia occurred more oftenwith cottonseed oil than IntralipidVR soybean oil.[108] A separ-ate rabbit model found increased production of tissue factorfrom phagocytes with IntralipidVR infusion.[109]
Fat overload (hypertriglyceridemia, pancreatitis, andlipidemia)Three studies demonstrate a predictable rise in serum trigly-cerides but minimal organ damage in the pancreas and bil-iary system after short-term ILE.[111–113] In a dog model,
Table 8. Organ dysfunction adverse effects reported in animal studies.
References Study design Type of ILE Indication Total dose Outcome
AE group Cardiac effects[107] Experimental Rabbit
modelLCT 20%(IntralipidVR )
Bolus Rescue 3 mL/kg In asphyxia induced cardiac arrest rab-bits who received ILE had lower rate ofROSC (1/11) than did rabbits receivingnormal saline (7/12). All animals hadreceived epinephrine in this study.
Hematologic effects[108] Experimental Rabbit
modelLCT 10% (IntralipidVR
and LipofundinVR )TPN 1 g/kg/h (10 mL/kg/h) Infusion of LipofundinVR resulted in
thrombocytopenia more so thanIntralipidVR . 35/40 animals died of DICwhen co-administered endotoxin
[109] Experimental Rabbitmodel
LCT 10%(IntralipidVR )
TPN 7 mL/kg � 2 h ILE infusion resulted in increased pro-duction of tissue factor from phagocytes.When phagocytes were exposed toendotoxin this finding was enhanced
[110] Experimental Caninemodel
LCT 15% (FE-S15) TPN 4–9 g/kg/day(26.7–60 mL/kg/day)for 28 days
Significant decrease in Hgb/Hct after 21days of ILE infusion in the 9 g/kg/daygroup
Fat Overload (Hypertriglyceridemia, Pancreatitis, and Lipemia)[111] Experimental
Murine modelLCT 20%(IntralipidVR )
Bolus Rescue 20–80 mL/kg Hypertriglyceridemia, hyperamylasemia,hyperphosphatemia, elevated amino-transferases in all ILE treated animals.Hepatic and pulmonary histologic abnor-malities noted. LD50 w/in 48 h is 68 610 mL/kg in rats, human equivalent is10.5 mL/kg. No cause of death noted forthree animals deaths at 48 h after ILE.
[112] Experimental Caninemodel
LCT 10%(IntralipidVR )
TPN Variable Administration of ILE at a rate of 0.8 g/kg/h resulted in accumulation of trigly-cerides in circulation
[113] ExperimentalMurine modela
LCT 20%(IntralipidVR )
TPN Pancreatic duct100 mL versus 5 mL IV
Pancreatitis seen if ILE injected directlyinto pancreatic duct. Not observed whenintravenously
[149] Experimental Rabbitmodel
LCT 20%(IntralipidVR )
Bolus Rescue 6, 12, and 18 mL/kg ILE rescue bolus after Haloperidol over-dose. Reported increased transaminaselevels in the 18 mL/kg group as com-pared with control. Also reported dosedependent lung infiltration due to fatemboli.
ARDS: Acute respiratory distress syndrome; DIC: disseminated intravascular coagulation; GBS: Group B Streptococcus; ILE: intravenous lipid emulsion; IV: intravenous;LCT: long chain triacylglycerols; LD50: median lethal dosage; LPS: lipopolysaccharide; NEFA: non-esterified fatty acids; MCT: medium chain triacylglycerols; NA: notavailable; NR: not reported; RBC: red blood cell; ROSC: return of spontaneous circulation; Rxn: reaction; SVC: superior vena cava; TG: triacylglycerols; TNF: tumornecrosis factor; TPN: total parenteral nutrition; V/Q: ventilation perfusion.aA study available in abstract only.
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Table 9. Pulmonary adverse events reported in animal studies.
References Study design Type of ILE Indication Total dose Outcome
AE group ARDS/Acute lung injury/Hypoxia[117] Experimental Canine
TPN 0.03 g/kg Oleic Acidversus 0.5 mL/kg of20% ILE
Oleic acid alone increased shuntfraction and decreased lobar perfu-sion. ILE had no side effects
[115]a Experimental Porcinemodel
LCT 20% (IntralipidVR ) TPN N/A ILE infusion results in more hypox-emia. Endotoxinþ ILE resulted in arapid (within 15 min) and sustaineddecrease in PaO2 (85.2 versus76.4 Torr at 0 and 180 min, respect-ively, p < 0.01), whereas nochange (8l.4 versus 84.4 Torr,p¼NS) was observed in Endotoxinalone. Suspected to be prostaglan-din mediated.
[150]a Experimental Murinemodel
LCT (20% Clinoliec ver-sus 20% Lipoven)
TPN Unclear Measurement of inflammatorymarkers in an E. Coli LPS model ofAcute Lung Injury following TPNadministration. No significant differ-ence in survival between groups.Lipoven group had a more pro-nounced inflammatory response asmeasured by higher concentrationsof TNF alpha and Macrophageinflammatory protein
[106] Experimental Murinemodel
LCT 20% (IntralipidVR ) TPN 40 mL/kg/day �1/3/7 days
SVC thrombosis, pancytopenia,granulomatous lung Inflammatoryreaction on autopsy
TPN 3.6 mL/kg No significant hemodynamic orrespiratory change over 2 h infusion
[116] ProspectiveRandomized Murinemodel
LCT 20% (IntralipidVR ) TPN 6 g/kg/day (30 mL/kg/day) for 7 days
ILE infusion in rats with normallungs produced structural changesin pulmonary vasculature similar tothose seen in conditions producingpulmonary hypertension. IntralipidVR
administration did not cause add-itional remodeling to the pulmon-ary vasculature of rats withbaseline pulmonary vasculatureremodeling.
[149] Experimental Rabbitmodel
LCT 20% (IntralipidVR ) Bolus Rescue 6, 12, and 18 mL/kg ILE rescue bolus after Haloperidoloverdose. Reported increased trans-aminase levels in the 18 mL/kggroup as compared with control.Also reported dose dependent lunginfiltration due to fat emboli.
Endotoxin challenge in control, pro-pofol infusion, and IntralipidVR infu-sion groups. All groups notedhypoxia and Increased pulmonaryresistance. Increased ThromboxaneA2 production in high doseIntralipidVR group
h) � 2 hIntralipidVR infusions resulted in hyp-oxia improved by thromboxane A2receptor antagonist
[121] Experimental Rabbitmodel
LCT 10% (IntralipidVR
) TPN 4 mL/kg � 1 h Rabbits with ARDS induced by oleicacid were treated with ILE. Hypoxiaafter lipid infusion did not correlatewith TG increase. Hypoxia bluntedby indomethacin. Suggested V/Qmismatch is due to prostaglandinproduction
ARDS: Acute respiratory distress syndrome; DIC: disseminated intravascular coagulation; GBS: Group B Streptococcus; ILE: intravenous lipid emulsion; IV: intravenous;LCT: long chain triacylglycerols; LD50: median lethal dosage; LPS: lipopolysaccharide; NEFA: non-esterified fatty acids; MCT: medium chain triacylglycerols; NA: notavailable; NR: not reported; RBC: red blood cell; ROSC: return of spontaneous circulation; Rxn: reaction; SVC: superior vena cava; TG: triacylglycerols; TNF: tumornecrosis factor; TPN: total parenteral nutrition; V/Q: ventilation perfusion.aA study available in abstract only.
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triglycerides rose after the administration of 10% lipid emul-sion and normalized quickly at a dose of 0.4 mg/kg/h(0.004 mL/kg/h), reflecting rapid clearance from the circula-tion. This was not observed at the higher dose of 0.8 mg/kg/h (0.008 mL/kg/h), which was associated with prolongedabnormalities in serum triglycerides and fatty acids.[114] In amurine model of high-dose, rapidly administered ILE 20%(ranging from 20 to 80 mL/kg over 30 min), all subjects hadelevations in triglycerides, serum amylase, and aspartate ami-notransferase; however, histological examination of the pan-creas and liver at autopsy was normal.[111] A lower-dosemodel in rats demonstrated a similar safety profile of ILEwith respect to pancreatitis, demonstrating no sucheffect.[113]
Pulmonary adverse events
ARDS and hypoxiaSeven studies reported pulmonary adverse effects in animalmodels, all related to TPN administration (Table 9).[115–120]A porcine model demonstrated elevated thromboxane B2 lev-els after ILE, which might be causative in pulmonary hyper-tension and correlate with the degree of hypoxemia.[119]Another porcine model demonstrated an association betweenILE and hypoxemia. [115] In a murine model, IntralipidVR infu-sion in rats with normal lungs produced structural changes inpulmonary vasculature, similar to those seen in conditionsthat produce pulmonary hypertension.[116] IntralipidVR admin-istration did not cause additional remodeling in the
Table 10. Immunologic effects reported in animal studies.
References Study design Type of lipid Indication Total dose Outcome
AE group Infection risk[124] Prospective
Randomized Murinemodel
LCT 10% or 20%(IntralipidVR )
TPN 6.48 mL versus 10.8 mL 0.6 mL/h group haddecreased S. aureus clear-ance, and decreased granulo-cyte function
TPN 3 g/kg (15 mL/kg) Mild impairment of reticulo-endothelial function
[127]a Experimental Murinemodel
LCT 20% (IntralipidVR ) TPN N/A Impaired radiolabeled RBCclearance by reticuloendothe-lial system, and decreasedneutrophil activity
[128] Experimental Murinemodel
LCT assumed 20%(IntralipidVR )
TPN 10 g/kg (50 mL/kg) 9/10 deaths from GBS bacter-emia in IntralipidVR emulsiongroup. 3/10 death in controlgroup. Hypothesized to bedue to impaired neutrophilchemotaxis
[130] Experimental Murinemodel
20% (Nutrilipid) TPN 4 g/kg/day (20 mL/kg/day) for 4 days
Lipid emulsion decreasedhepatic phagocytosis,increased pulmonary localiza-tion of E. coli.
[123] Experimental Murinemodel
LCT 10% (IntralipidVR ) TPN 5 mL/kg No Lymphocyte suppression– primary end point
Decreased bacterial clearancein LCT, and MCTþ LCT groupcompared to controls andOleic Acid group
[131] Experimental Bovinemodel
LCT 20% Multipletypes: tallo, Linseedoil, fish oil emulsions
TPN 0.54 g/kg (2.7 mL/kg)over 4 h for 4 days
Leukocytes demonstrateddecreased ability to respondto mitogens after Tallowderived LCT emulsions ascompared with linseed oiland fish oil derived LCTemulsions
[105] Experimental Murinemodel
LCT 20% (LiposynTM III) TPN 2.5 mL Increased endoplasmic reticu-lum stress. Marker for Insulinresistance
ARDS: Acute respiratory distress syndrome; DIC: disseminated intravascular coagulation; GBS: Group B Streptococcus; ILE: intravenous lipid emulsion; IV: intravenous;LCT: long chain triacylglycerols; LD50: median lethal dosage; LPS: lipopolysaccharide; NEFA: non-esterified fatty acids; MCT: medium chain triacylglycerols; NA: notavailable; NR: not reported; RBC: red blood cell; ROSC: return of spontaneous circulation; Rxn: reaction; SVC: superior vena cava; TG: triacylglycerols; TNF: tumornecrosis factor; TPN: total parenteral nutrition; V/Q: ventilation perfusion.aA study available in abstract only.
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pulmonary vasculature of guinea pigs. Infusion of unstablelipid emulsion might cause oxidative stress in the lungs. [118]Two canines models demonstrated no acute deleteriouseffects from 20% fat emulsion on pulmonary gas exchange,blood flow distribution, or edema.[117,120] After prolongedinfusion (3–7 days), superior vena cava thrombosis and pan-cytopenia occurred in a murine model, in addition to a granu-lomatous reaction in alveolar macrophages.[106]
Lung ventilation–perfusion (V/Q) mismatchTwo studies reported V/Q mismatch related to lipid adminis-tration as a component of TPN. A porcine model and a rabbitmodel both demonstrated a decrease in pO2 and paO2,respectively, following lipid infusions.[121,122] Both werethought to be related to prostaglandin mediation.
Immunologic effects
Infection susceptibilityTen studies in primarily murine and rabbit models examinedthe effects of short-term TPN (24 h to 4 days) on cell-medi-ated immune function and survival in response to a bacter-emia challenge (Table 10).[106,123–131] IntralipidVR 10–20%was the primary source of ILE used; however, total doses,rates of infusion, and duration of treatment varied signifi-cantly between the studies. These studies did demonstratemild to moderate impairments of reticuloendothelial cell-mediated function as well as somewhat higher rates of bac-teremia in the TPN groups.[124,125,127,128,130] Similareffects on insulin resistance, measured by endoplasmic reticu-lum stress, occurred with the administration of glucose andILE to rats.[105]
Special populations
The administration of lipid emulsion to children warrants spe-cial mention. Several reports of children receiving TPN werefound, in whom fat overload syndrome developed (headaches,fever, jaundice, hepatosplenomegaly, respiratory distress, andspontaneous hemorrhage), particularly neonates. One reportdescribed a 3-year-old child who experienced pulmonaryinsufficiency, fever, lethargy, and tachycardia after the admin-istration of an excess of ILE (170 mL or 15 mL/kg total) forbupivacaine toxicity.[44] Another report described an acuteoverdose of ILE in a 5-day-old infant after 32 weeks of gesta-tion, who received 250 mL of 20% ILE and experienced respira-tory distress, metabolic acidosis, lethargy, and apnea;treatment was successful with double-volume exchange trans-fusion.[30] Hojsak and colleagues reported their managementof a 2-year-old child with short gut, who was given a novellipid formulation, SMOFlipids (20% soy, MCT, olive oil, and fishoil), in whom fat overload developed after ultra-rapid infusion(100 mL over 30 min [total 20 g, 1.75 g/kg/day, 3.6 g/kg/h]).[90]
Discussion
The first ‘‘safe’’ ILE was developed over 50 years ago as anutritional therapy, then later as a carrier for lipid-soluble
drugs.[1] Subsequently, ILE has been employed as a treat-ment in toxicology, often as a last resort for the most critic-ally ill poisoned patients. However, this therapy is notwithout adverse effects. Although lipid emulsions vary incomposition, the majority of case reports found in thisreview used 10 or 20% soybean oil emulsion, such asLiposynTM III, IntralipidVR , and NutrilipidVR . It is unclear if allILEs are associated with the same adverse effects. Newerlipid emulsions, which do not contain high omega-6 fattyacid oils, could have other adverse effects that are not wellrepresented in the literature.
Much of the published evidence about the adverse effectsof ILE comes from the early years of its use in nutrition ther-apy, when adverse effects were not uncommon. Adverseeffects are rare when the current nutritional guidelines for ILEuse are followed. The guidelines include a general limit of2 g/kg body weight/day (10 mL/kg/day of 20% ILE) and amaximum of 3g/kg (15 mL/kg/day of 20% ILE) without specialprecautions in adults. The rate of infusion typically should notexceed 0.11 g/kg/h (0.55 mL/kg/h of 20% ILE) with a max-imum of 0.125 g/kg/h (0.625 mL/kg/h of 20% ILE).[58] For neo-nates and infants, the dose should not exceed 4 g/kg/day(20 mL/kg/day of 20% ILE) and the rate not more than0.17 g/kg/h (0.85 mL/kg/h of 20% ILE). Relatively few adverseeffects associated with the treatment of various drug toxic-ities are reported in the clinical toxicology literature. However,given that the doses and infusion rates used in the toxicologysetting often exceed those used for nutritional therapy, thedearth of reported adverse effects may represent a reportingbias or inadequate follow-up.[1]
Adverse effects of ILE fall into two major categories basedon the duration of therapy. Immediate or short-term effectsoccur quickly, often within minutes to a few days (48 h), whiledelayed effects typically require much longer exposure to ILEtherapy, as occurs with outpatient parenteral nutrition ther-apy. With the exception of hypersensitivity/allergic reactions,immediate or short-term effects tend to be associated withthe dose and/or infusion rate of the ILE.
Some adverse effects of lipid emulsion appear to arise pri-marily in the setting of TPN and have not been reported withthe use of high-dose, short-term ILE. These include cholesta-sis, catheter-related complications (infection, phlebitis, andthrombosis), predisposition to sepsis and immune deficiency,and catatonia.[22,63,64,132] Although there are at least fourreports in the nutrition literature, no reports of these sequelaeattributed to ILE therapy for poisoning were found.Comparing different lipid emulsions for TPN in surgicalpatients, a systematic review and meta-analysis of random-ized controlled trials found no difference in adverse effects orhospital length of stay among SMOFlipidVR 20% and Lipoven20%, ClinOleic 20%, or MCT/LCT 20%.[133]
Adverse effects of ILE which have occurred either in thetreatment of poisoning, or in the TPN setting at faster infu-sion rates similar to those administered in poisoning, includehypoxia, ARDS, priapism, fat overload syndrome, and fatemboli. The spectrum of respiratory complications, rangingfrom simple hypoxia to ventilator-dependent respiratory fail-ure, has been repeatedly described in both settings. Thepotential for lipid administration to interfere with gas
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exchange and create a ventilation–perfusion mismatch is sup-ported by a controlled study in ICU patients, which demon-strated a detrimental effect on bronchial inflammatorymarkers in patients with ARDS receiving ILE.[134] Critically ill-poisoned patients, especially those suffering cardiac arrest,often develop ARDS as an evolution of illness. It is impossibleto determine which of these reported effects is directly dueto ILE without a more controlled study design.
AKI as a result of ILE administration is controversial, andthe clinical relevance is unknown.[135] In a critically ill pois-oned patient, AKI can develop for a number of reasons,including decreased renal perfusion in the setting of a shockstate. When the origin of AKI is likely multifactorial, it isimpossible to determine what role, if any, ILE played in itsdevelopment. In addition, a transient rise in creatinine oftendoes not translate into a true negative outcome, such as theneed for CRRT. In the observational study by Tabel et al.,treated with TPN tended to be younger, smaller, sicker, andat higher risk of complications.[29] Because the infants onlyhad laboratory comparisons at 3 and 30 days, it was impos-sible to determine if the AKI began prior to the 14th day.However, it seems more likely than not that the modestchanges in biomarkers of renal function developed graduallythroughout the 30-day study period.
Differentiating adverse effects of TPN from those specific tolipid emulsion is challenging. Phlebitis is a problem with TPNdue to its very high osmolarity (>1100 mOsm).[136] ILE has alower risk from the osmolarity standpoint, as its osmolarity isabout 300 mOsm, compared with a maximum of 900 mOsmfor peripheral parenteral nutrition and >1500 mOsm for mostTPN products. An ex vivo study using six simulated real-lifeECMO circuits utilized a 3 mL/min infusion of IntralipidVR 20%with a constant flow rate of 200 mL/min and heparin doses tomaintain a clotting time greater than 200 seconds.[137]Agglutinations and layering occurred in all six circuits, andclotting occurred in five of them, especially at areas of stasis(ports), within 30 min after ILE infusion. In addition, increasedcircuit pressure caused the tubing to crack. The authors rec-ommended that ILE be administered via its own line duringECMO treatment of a neonate. This article was actuallyexcluded by the search criteria, but it is mentioned herebecause the model circuit mimicked real-life conditions.
The fat overload syndrome is a constellation of many ofthe isolated complications; the sudden onset of hypoxia,respiratory insufficiency, fever, lethargy, hepatosplenomegaly,jaundice, coagulopathy, and neurologic compromise, includ-ing altered mental status and seizures. Fat embolic complica-tions, both pulmonary and cerebral, are more commonlyreported in association with TPN than with rescue therapy forpoisoning (perhaps because rescue therapy is in its relativeinfancy). Complications which appear to be unique to high-dose, rapidly administered ILE continue to emerge. They havebeen reported in the context of inadvertent TPN error leadingto rapid infusion of a high dose, defined as exceeding theestimated maximum oxidation rate of 1.2–1.7 mg/kg/min (forILE 20%, this is 0.35–0.51 mL/kg/h or 8.6–12.24 mL/kg/day).The physiologic consequences of such doses can be expectedto be similar to those of rescue therapy. However, the paucityof human toxicological literature and the lack of necropsy
and lung examination in the animal studies on the use of ILEin poisoning make it impossible to evaluate the true risk offat emboli with ILE administration.
The risk of infection in patients receiving ILE is difficult toanticipate. Neutrophil and lymphocyte counts decreasealmost immediately after an ILE bolus, but it is unclear howthis effect translates to meaningful outcomes when treatingpoisoned patients.[76] Measurement of counts could also beaffected by dilution after bolus administration. Most of thehuman research on immunologic function as it relates to ILEcomes from studies that evaluated long-term effects, that is,from 4 to 14 days of therapy.[138] For most cases of poison-ing, treatment lasted less than 4 days, although at least onepoisoned patient received ILE for 19 days.[26] Overall,immune function seems to be most affected by the durationof ILE therapy, but the applicability of this observation to toxi-cological use is uncertain because the length of therapy isnot standard.
Patients at the extremes of age present challenges withdrug therapy, as do pregnant women. Prescribing informationfor ILE from the US Food and Drug Administration includes awarning of death reported in preterm infants following ILEadministration, with pulmonary intravascular fat accumulationnoted at autopsy.[58] One report indicated development ofhypertriglyceridemia without hypoxia in low-birth-weightinfants receiving 10% or 20% ILE at a maximum of 4 g/kg/day(20 mL/kg/day using 20% ILE) for 8 days [33]; however, mostreports involving neonates describe adverse pulmonaryevents.[30,39,42,43,46–49] Preterm infants appear to be par-ticularly susceptible to hypoxia associated with ILE-inducedhypertriglyceridemia during their first week of life.[42] Thecause of ILE-associated hypoxia might be a dose- and time-dependent increase in pulmonary vascular resistance inresponse to increased prostaglandin synthesis from higherfree fatty acid concentrations following ILE infusion, ratherthan hypertriglyceridemia itself.[43] Alterations in pulmonaryvascular resistance occur with short-term ILE doses of 1.5–3 g/kg/day (7.5–15 mL/kg/day of 20% ILE). Doses as low as 1 g/kg/day (5 mL/kg/day using 20% ILE) in premature infantsreduced arterial oxygen tension in a high percentage ofpatients.[47] Alveolar oxygen tension is reduced in full-terminfants receiving ILE 2 g/kg/day (10 mL/kg/day of 20% ILE).[48]Reduced transcutaneous PO2 also appears to be prominentfollowing ILE doses as small as 0.5 g/kg/day (2.5 mL/kg/day of20% ILE) given over 10 h (0.05 g/kg/h; 0.25 mL/kg/h with 20%ILE) in infants with underlying pulmonary disease.[39]
Disturbances of fat metabolism in elderly patients, includ-ing reduced skeletal muscle fat oxidation, may occur due tolower oxidative enzyme concentrations, inhibited fatty acidtransport into the mitochondria, or reduced activation of fattyacid transport.[139] Lipid oxidation during TPN, however,appears to be higher in elderly patients compared with mid-dle-aged people.[140] Capacity for fat oxidation and plasmaremoval of ILE appears to be as good in elderly men as inyoung men.[141] This suggests that elderly patients are nomore likely to develop hypertriglyceridemia or other problemsrelated to ILE clearance than younger patients. One casereport of ILE use for local anesthetic poisoning in a 91-year-old man indicated successful reversal of central nervous
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system and cardiac toxicity without any indication of adverseevents with the ILE.[142] None of the adverse events in thisliterature review showed an increased incidence among eld-erly patients.
All ILE products are listed as pregnancy category C, except10% Soyacal, which is category B. Concerns about the use ofILE during pregnancy come primarily from adverse eventsassociated with a cottonseed oil emulsion that was removedfrom the market in 1965, but there are still at least tworemaining concerns.[143] ILE is used routinely at recom-mended doses and infusion rates for pregnant women requir-ing TPN. However, high ILE infusion rates (actual rates are notreported) may induce uterine contractions.[144] In addition, astudy evaluating the effect of TPN on the placenta reportedone case out of the 20 evaluated with placental fat depositsevident before fetal death occurred at 22 weeks’ gesta-tion.[145] Successful rescue ILE occurred in an 18-year-oldprimigravida patient at 38 weeks gestation with no reportedadverse effect.[146] Pregnant women are at increased risk oflocal anesthetic toxicity; thus there is potentially an increasedneed for ILE in pregnancy.[147]
Limitations
The search criteria and citation screening were designed tobe as inclusive as possible in order to estimate the clinicaladverse effects associated with ILE given in doses typicallyused to treat acute poisonings, but the studies included inthis systematic review were consistently of low or very lowquality according to GRADE criteria. Furthermore, includedstudies could have suffered from reporting bias, in that notall adverse effects reported were related to the use of ILE andthose that do occur were not always reported. Neonates andsmall children seem to be at higher risk of adverse events asreported in the TPN literature, however as the care of neo-nates has significantly changed in the last three decadessince these reports were published, it is unclear if the adverseevents reported are only associated with the administrationof ILE. The patient populations were also quite heterogeneousin terms of age and medical comorbidities, which limits gen-eralizability of the incidence and nature of adverse eventsassociated with the administration of ILE in the managementof poisonings. For example, gut malabsorption would be oflittle consequence to the use of ILE for TPN, but it could be amajor issue when treating patients who have been poisoned.Nonetheless, cohort and observational studies on adverseevents in the TPN setting that are applicable to clinical toxi-cology may answer the many questions which have arisen onthe risks of this therapy at various dosages and infusionrates.[76,138]
Conclusion
This systematic review reported adverse effects from ILEadministration, as reported from clinical settings and animalstudies, with a focus on those most generalizable to clinicaltoxicology. Because few publications describe adverse eventsfollowing antidotal use of ILE, the true incidence remains
unknown. Extrapolation from TPN cases suggests that adverseeffects might occur with the use of ILE for poisoning. Thepotential for significant adverse effects seems to be associ-ated with higher doses and rapid infusion rates. Therefore,the suggestions in many case reports and review articles thatlarge doses of ILE are safe for the purpose of reversal of drugtoxicity and may not pose a risk of immediate adverse eventsseems to be inaccurate or at the very least unproven. Furtherstudies in both the TPN setting and the poisoned patient willhopefully shed additional light on the risks of this therapy.
Acknowledgements
Ahmed Al-Sakha, Saad Al-Juma, Daniel Morris, Tudor Botnaru, Aftab Azad,Anne-Ericka Vermette-Marcotte, and the other members of the LipidEmulsion Workgroup retrieved the full text of the articles used in thisreview. Sarah Shiffert and Ellen Pak from AACT arranged meetings andconference calls. The manuscript was copyedited by Linda J. Kesselring,MS, ELS, the technical editor/writer in the Department of EmergencyMedicine at the University of Maryland School of Medicine.
Disclosure statement
Drs Lavergne and Turgeon are recipients of salary support awards fromthe Fonds de la Recherche du Qu�ebec – Sant�e (FRQS). All members com-pleted a conflict of interest form for AACT and received no honoraria.Webcast conference and rooms for meeting were provided by AACT. Nomember has a financial or an academic conflict of interest that preventedhis/her neutral assessment of the articles reviewed in this study (i.e., nocommittee member’s livelihood or academic career depends on grantfunding the study of lipid emulsion in poisoning).
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Appendix
Medline (Ovid) search strategy for adverse effects1. exp Fat Emulsions, Intravenous/2. lipid rescue.ti,ab,kw.3. (lipid adj3 emulsi*).mp.4. (fat adj3 emulsi*).mp.5. ((lipid or fat*) adj5 bolus).mp.6. (lipid adj3 (resuscitat* or therap* or infus*)).mp.7. (ILE adj5 (lipid* or emulsi* or fat*)).mp.8. (IFE adj5 (lipid* or emulsi* or fat*)).mp.9. (lipid adj3 sink*).mp.
19. to.fs.20. po.fs.21. co.fs.22. (safe or safety).ti,ab.23. side effect$.ti,ab.24. ((adverse or undesirable or harm$or serious or toxic) adj3 (effect$
or reaction$ or event$ or outcome$)).ti,ab.25. exp Product Surveillance, Postmarketing/26. exp Adverse Drug Reaction Reporting Systems/27. exp Clinical Trials, Phase IV as Topic/28. exp Poisoning/29. exp Substance-Related Disorders/30. exp Drug Toxicity/31. exp Abnormalities, Drug-Induced/32. exp Drug Monitoring/33. exp Drug Hypersensitivity/34. (toxicity or complication$ or noxious or tolerability).ti,ab.35. exp Postoperative Complications/36. exp Intraoperative Complications/37. or/18-3638. 17 and 3
