perioperative use of arginine-supplemented diets: a ... · perioperative use of...

COLLECTIVE REVIEW

Perioperative Use of Arginine-supplemented Diets:A Systematic Review of the EvidenceJohn W Drover, MD, FRCSC, Rupinder Dhaliwal, RD, Lindsay Weitzel, PhD, Paul E Wischmeyer, MD,Juan B Ochoa, MD, FACS, Daren K Heyland, MD, FRCPC, MSC

Infections are the most frequent cause of morbidity aftersurgery and up to 54% of all hospital-acquired infectionsoccur in high-risk surgical populations.1 Infections result inprolongation of hospital stay2 and increased health carecosts by up to $10 billion per year in the United Statesalone.3 Multifaceted efforts to prevent infection are an es-sential component of any surgical practice.4

Surgical stress predisposes patients to immune dysfunc-tion, placing them at higher risk of infection, risks that areincreased even more if the patient is malnourished beforesurgical insult.5 Various nutrient and nutritional strategieshave been studied to evaluate their effect on immune functionand clinical outcomes. One pharmaconutrient that has beenthe center of much debate in the literature is arginine andarginine-supplemented nutritional formulas.6-9 Arginine is anamino acid involved in multiple metabolic processes. It is aprecursor of the formation of polyamines and hydroxypro-line, which is important for connective tissue repair, and isthe precursor for the formation of nitric oxide, an impor-tant signaling molecule.10 In addition to these vital roles,arginine is an essential metabolic substrate for immunecells and required for normal lymphocyte function.11

Arginine deficiency after surgical stress was reportedmore than 30 years ago, although the mechanisms behindthis have until recently remained unknown.11,12 More than20 years ago, supraphysiologic concentrations of argininewere added to the diets of critically ill and surgical patients.These diets were aimed at “enhancing immune function”and also contained increased amounts of omega-3 fattyacids, nucleotides, and other nutrients. These nutrients

were eventually incorporated into commercial diets with-out a rigorous evaluation of their individual effects or sideeffects in different patient populations. In 2001, Heylandand others reported a meta-analysis suggesting that thesearginine-supplemented diets were not beneficial in criti-cally ill patients and could even potentially adversely affectoutcomes in this population.9 In contrast, patients under-going elective surgery appeared to exhibit a benefit, with apossible decreased rate of infection. The treatment effect ofthese diets was systematically different in critically ill pa-tients compared with elective surgery patients, and it be-came apparent that a dedicated meta-analysis should bedone separately for patients undergoing elective surgery.Although subsequent meta-analyses have recently beendone,13,14 they were limited in scope, not including all per-tinent articles, included unpublished and duplicate publi-cations, and combined studies with different study designsin evaluating the role of perioperative nutrition. The pur-pose of this review is to provide an up-to-date systematicreview on all studies of arginine-supplemented diets inelective surgical patients. With a larger database, we mightbe able to shed some light on the perioperative role of suchdiets.

METHODSStudy identificationWe conducted a systematic review of the published litera-ture to identify all relevant trials. Using text word or MeSHheadings containing “randomized,” “blind,” “clinicaltrial,” “nutrition,” “arginine,” “glutamine,” “omega-3 fattyacids,” “fish oil,” “nucleotides,” “immune,” “immunonu-trition,” we performed computerized searches for relevantarticles on MEDLINE, EMBASE, BIIOSIS, CINAHLelectronic databases Cochrane Controlled Trials Registerfrom 1990 to March 2010. We also searched our personalfiles and reference lists of review articles and original stud-ies. There were no language restrictions.

Study selection criteriaCitations were classified as primary studies, review articles,or other. All primary studies were retrieved and reviewedindependently. We included primary studies if they wererandomized clinical trials (RCTs); studied elective surgical

Disclosure Information: Dr Heyland received a research grant as the prin-cipal investigator and an honorarium as a speaker for Nestle. Dr Ochoa wasa paid consultant for Nestle until July 2010, and receives a salary as MedicalScientific Director for Nestle since July 2010. All other authors have noth-ing to disclose.

Received August 12, 2010; Revised October 1, 2010; Accepted October 26,2010.From the Departments of Surgery (Drover) and Medicine (Heyland), ClinicalEvaluation Research Unit (Dhaliwal, Heyland), Kingston, Ontario, Canada,Department of Anesthesiology, University of Colorado School of Medicine,Aurora, CO (Weitzel, Wischmeyer), Department of Surgery, University ofPittsburgh, Pittsburgh, PA (Ochoa).Correspondence address: Daren Keith Heyland, MD, FRCPC, MSc, Angada4, Kingston General Hospital, 76 Stuart Street, Kingston, Ontario K7L 2V7,Canada. email: [email protected]

385© 2011 by the American College of Surgeons ISSN 1072-7515/11/$36.00Published by Elsevier Inc. doi:10.1016/j.jamcollsurg.2010.10.016

in adults; compared enteral nutrition supplemented witharginine with or without other immune-modulating agentswith standard enteral nutrition; and included clinically im-portant outcomes such as mortality, infectious complica-tions, and hospital length of stay.

To select studies with the greatest validity with respect torelative treatment effect, we included only RCTs. We ex-cluded the studies reporting only nutritional or immuno-logical outcomes. We defined elective surgical patients asthose undergoing a scheduled surgical procedure whetherthey were cared for in a critical care environment or not.We excluded studies of critically ill patients who underwenturgent or emergent operations (ie, trauma, ruptured aneu-rysms, etc.).

Using a scoring system that we have used in previousstudies,15 we scored the methodological quality of individ-ual studies considering the extent to which randomizationwas concealed, if the study was double-blinded and theanalysis was based on the intention-to-treat principle andother key features of high-quality studies, and abstractednecessary data in duplicate and independently. Disagree-ment in the individual scores of each of the categories (ie, 0,1, or 2) was resolved by consensus (see Appendix, availableonline only, for methodological scoring tool). We at-tempted to contact the authors of included studies andrequested additional information not contained in pub-lished articles.

Data synthesisAmong the primary outcomes of interest was the numberof patients with new infectious complications. We useddefinitions of infectious complications as defined by theoriginal authors, which usually included pneumonia, intra-abdominal abscess, sepsis, line sepsis, wound infection,anastomotic leak, fistula formation, and urinary tract in-fection. We included only infectious complications whenwe could abstract the number of patients with such com-plications. Secondary outcomes included hospital length ofstay and mortality. We combined data from all studies toestimate the pooled risk ratio (RR) with 95% confidenceintervals for death and infectious complications and overallweighted mean difference (WMD) with 95% confidenceintervals for hospital length of stay.

All analyses, except the test for asymmetry, were con-ducted using Review Manager 5.16 Pooled RRs were calcu-lated using the Mantel-Haenszel estimator and WMDswere estimated by the inverse variance approach. The ran-dom effects model of DerSimonian and Laird was used toestimate variances for the Mantel-Haenszel and inversevariance estimators.17 RRs are undefined and excluded forstudies with no event in either arm. When only 1 group has0 events then ½ was added to each cell to allow estimation.The presence of heterogeneity was tested by a weightedMantel-Haenszel chi-square test and quantified by the I2

statistic as implemented in Review Manager 5.18 The pos-sibility of publication bias was assessed by generating fun-nel plots and testing asymmetry of outcomes using meth-ods proposed by Rucker and colleagues.19 We consideredp ! 0.05 to be statistically significant.

We combined experimental arms for the purposes of theoverall analysis for studies that randomized patients tomore than 2 groups of interest. On review of the data set,we identified 2 studies that had used considerable amountsof glycine in an effort to create isonitrogenous enteral for-mulas in the control groups.20,21 To explore whether thisamino acid supplementation affected the results of themeta-analysis, a sensitivity analysis was undertaken by re-peating the analysis with these studies excluded.

Earlier hypotheses testingIn addition to the primary outcomes of interest in theoverall patient groups, a priori, we identified 4 questions orsubgroup analysis that we wished to explore within thecontext of the data set. The first was an analysis by type ofsurgery. As a larger number of studies were done in thecontext of gastrointestinal (GI) surgery, we planned tocompare studies that principally enrolled patients havingGI surgery and those having other surgical procedures. Sec-ond, within the group of patients having GI surgery, thereseemed to be 2 different cohorts. We compared outcomesfor those having only upper GI surgery with those studiesthat included only patients having lower GI surgery withthose with mixed upper and lower GI surgery. Third, manyformulations of arginine-supplemented diets have beenstudied. These have varying concentrations of arginine,and contain different additional supplemental agents. Themost frequently used product in these studies is Impact(Nestle, Inc). We compared studies that used Impact in theexperimental group with those that used other arginine-supplemented formulations. Finally, one of the outstand-ing issues for perioperative supplementation is whether it ismore important to give the supplements before or after thesurgery, or both. Unfortunately, there has been no consis-tent study design used to answer this question. We groupedlike studies based on whether the experimental diet was

Abbreviations and AcronymsGI " gastrointestinalMDSC " myeloid-derived suppressor cellsRCT " randomized clinical trialsRR " risk ratioWMD " weighted mean difference

386 Drover et al Arginine Supplementation in Surgical Patients J Am Coll Surg

used in the pre- or postoperative setting or both, and inrelation to what was provided to the control group (seeTable 1 for examples of various methodologies). Thesehypothesis-generating analyses can be used to help explainheterogeneity, if found, and could also be used to illumi-nate whether there is a different treatment effect in differ-ent patients or with different therapeutic strategies. Thereported subgroup-specific estimates use the same randomeffects models as the overall analysis. However, becauseReview Manager 5 does not support the random effectsmodel when comparing subgroups, the p value testing forsubgroup differences are based on a fixed-effects model.

RESULTSInitial screening for eligibility resulted in 54 publishedRCTs of arginine-supplementation in surgical patients. Ofthese, 35 included elective surgery patients only, met allother inclusion criteria, and were included in the currentreview (see Tables 2, 3, and 4)20-54 We excluded RCTs forthe following reasons: use of nonstandard therapy in thepostoperative control group (fasting/oral intake/IV fluids/omega-3 fatty acids),55-57 duplicated publications58-65;pseudorandomization,66,67 and absence of clinically impor-tant outcomes.68-73 The authors reached 100% agreementfor inclusion of articles in this systematic review. There wasno clear asymmetry or suggestion of publication bias forthe outcomes of infectious complications (n " 28 studies;p " 0.70), mortality (n " 21; p " 0.21) and hospitallength of stay (n " 29 studies; p " 0.22) (data not shown).

Twenty-eight studies reported infectious complicationson a per-patient basis. When they were combined statisti-cally, the results showed that arginine-supplemented dietswere associated with considerably reduced overall infec-tious complications when compared with standard formu-las in surgical patients (RR " 0.59; 95% CI, 0.50#0.70;p ! 0.00001; Fig. 1). The test for heterogeneity was notsignificant (p " 0.11, I2 " 26%). When the analysis was

repeated removing the 2 studies that used substantialamounts of glycine in the control group,20,21 the observa-tions were similar (RR " 0.56; 95% CI, 0.47#0.67; p !0.00001; test for heterogeneity p " 0.14, I2 " 24%).

Overall hospital length of stay, aggregated across 29studies, was reduced in surgical patients receiving arginine-supplemented diets when compared with patients receiv-ing standard formulas (WMD " #2.38; 95% CI, #3.39to #1.36; p ! 0.00001; Fig. 2). The test for heterogeneitywas significant, with an I2 test indicating the presence of alarge amount of heterogeneity (p ! 0.00001, I2 " 87%).When the analysis was repeated, removing the one studywith glycine in the control group that reported on thisvariable,20 the observations were similar (WMD " #2.38;95% CI, #3.42 to #1.34; p ! 0.00001, with significantheterogeneity present (p ! 0.00001, I2 " 88%).

Twenty-one studies reported mortality as one of the out-comes. When their results were statistically aggregated,arginine-supplemented diets did not have a significant ef-fect on mortality (RR " 1.08; 95% CI, 0.65#1.80; p "0.76; Fig. 3). The test for heterogeneity was not significant(p " 0.99, I2 " 0%). When the analysis was repeated,removing the one study with glycine in the control groupthat reported on this variable, the observations were simi-lar, as this study reported no deaths20 (RR " 1.08; 95% CI,0.65#1.80; p " 0.76; test for heterogeneity was not sig-nificant (p " 0.99, I2 " 0%).

Subgroup analysesWe compared the treatment effect in studies of GI surgerypatients (n " 25) and non-GI surgery patients (n " 10)separately. Of the 25 studies of GI surgery patients, 21clearly reported on patients with infections, and 7 of the 10studies of non-GI surgery patients reported this. Arginine-supplemented diets were associated with reduced infec-tious complications in both subgroups (Fig. 4). When thedata for the 21 studies in GI surgery were aggregated, RR "0.61 (95% CI, 0.50#0.74; p ! 0.00001; test for hetero-geneity p " 0.09, I2 " 31%) and for the 7 non-GI opera-tions, RR " 0.51 (95% CI, 0.35#0.72; p " 0.0002; testfor heterogeneity p " 0.41, I2 " 2%). The differencesbetween these subgroups was not statistically significant(p " 0.28, see Fig. 4). When the data on hospital length ofstay were aggregated, arginine-supplemented diets were as-sociated with a significant reduction in hospital length ofstay in the 21 GI studies (WMD " #2.11; 95% CI,#3.30 to #0.92; p " 0.0005; test of heterogeneity p !0.00001, I2 " 90%) and in the 8 non-GI studies, (WMD "#3.68; 95% CI, #4.35 to #3.01; p ! 0.00001; test forheterogeneity p " 0.46, I2 " 0%). There were significantdifferences between these 2 subgroups (p " 0.0007,Fig. 5).

Table 1. Classification of Studies of Perioperative Arginine-Supplemented Diets

Experimental ControlPre Post Pre Post

A1 Arginine Nothing, EN EN Nothing, ENB Arginine Arginine EN ArginineC1 Arginine Arginine EN ENC2 Arginine Arginine Nothing ENC3 Arginine Arginine Nothing NothingD Nothing Arginine Nothing EN

Individual studies included in this meta-analysis were categorized dependingon whether they were administered arginine in a preoperative or postoperativesetting or both, and by what was administered to the control group.EN, enteral nutrition.

387Vol. 212, No. 3, March 2011 Drover et al Arginine Supplementation in Surgical Patients

Table2.

Random

izedS

tudiesEvaluating

PreoperativeN

utritionin

ElectiveS

urgeryPatients

Firstauthor,

yearPopulation

Methodsscore

blinding

InterventionM

ortalityInfections

Hospitalstay,

d

Experimental

Control

Experimental

Control

Experimental

Control

Experimental

Control

n%

n%

n%

n%

Preoperativearginine

versusnoarginine

Wachtler,1995

50U

GIsurgery

(n"

40)5

YesIm

pactpreop$

5d

%hospital

foodIsoenergetic

supplement

preop%

hospitalfood

2/2010

2/2010

5/2025

5/2025

NR

NR

McC

arter,199827

UG

Icancer(n"

51)7

Yes1)Form

ulaw

/arginine750

mL/d

$7

dpreop

2)Formula

with

arginine%

omega-3

fattyacids(Im

pact)$

7d

preop

3)Standardform

ula$

7d

preop1)1/142)0/13

703)0/11

01)4/142)5/13

29383)2/11

181)15

&2.4

2)17&

3.73)13

&1.7

Braga,2002

34C

olorectalcancer(n

"200)

12N

o2)Im

pactpreop1

L/d$

5d

3)IsoC/IsoN

formula

preop1

L/d$

5d

2)0/503)0/50

2)6/5012

3)16/5032

2)9.5&

2.93)12

&4.5

Braga,2002

35U

GIand

LGIcancer

malnourished

(n"

150)

11N

o2)Im

pactpreop$

7d

%EN

standardpostop

3)IsoC/IsoN

standardEN

postop2)1/50

23)2/50

42)8/50

163)12/50

242)13.2

&3.5

3)15.3&

4.1

Gianotti,2002

37U

GI

%LG

Icancer!

10%w

eightloss(n

"305)

8N

o1)Im

pactpreop$

5d

3)None

pre/postop1)1/102

3)1/1021

1)14/10214

3)31/10230

1)11.6&

4.73)14

&7.7

Xu,2006

43C

olorectalandgastric

GIcancer(n

"60)

11N

oIm

pactpreop,standardEN

postopIsoC

/IsoNstandard

ENform

ulapostop

NR

NR

NR

NR

9&

3.212

&3.7

Okam

oto,200953

Gastric

cancerpatients(n

"60)

10N

oIm

pactpreop$

7d

%standard

postopStandard

ENpreop

$7

d%

standardpostop

NR

NR

2/307

8/3028

23.8&

16.625

&10.6

Perioperativearginine

versuspreoperativestandard

andpostoperative

arginine

Giger,2007

51Stom

ach,pancreascancer(n

"46)

10N

o1)Im

pactx5

dpreop

%7d

postop2)Im

pactPlus$

2dpreop

%7

dpostop

3)Impact$

7dpostop

1)1/142)0/17

3)0/151)2/142)5/17

3)10/151)13.7

&2.3

2)14.1&

1.33)23.1

&3.6

EN,enteralnutrition;G

I,gastrointestinal;IsoN,isonitrogenous;IsoC

,isocaloric;LGI,low

ergastrointestinal;N

R,notreported;postop,postoperative;preop,preoperative;U

GI,

uppergastrointestinal.M

cCarter

27:D

ataforgroups1

and2

combined

inthe

meta-analysis.

Braga

34,3

5:Data

forGroup

1(receiving

Impactperioperatively)show

nin

comparison

C2.

Gianotti 3

7:Data

forGroup

2(receiving

Impactperioperatively)show

nin

comparison

C3.

388DroveretalArginineSupplementationinSurgicalPatientsJAmCollSurg

Table3.

Random

izedS

tudiesEvaluating

PerioperativeArginine

inElective

Surgery

PatientsC

:Perioperative

arginine

Firstauthor,

yearPopulation

Methodsscore

blindingIntervention

experimentalcontrol

Mortality

experimental

control,n

(%)

Infectionsexperim

entalcontrol,

n(%

)H

ospitalstay(d)

Experimentalcontrol

C1:Perioperative

arginineversusperioperative

standard

Braga,1999

28Stom

ach,pancreas,colorectalcancer(n

"206)

12Yes

Impactpreop

%standard

ENpostop

IsoC/IsoN

ENpreop

%standard

ENpostop

0/102(0)

1/104(14)

14/102(14)

31/104(30)

11.1&

4.4(102)

12.9&

4.6(104)

Senkal,199929

UG

Icancer(n"

178)11Yes

Impactpre-

%postop

StandardEN

pre-%

postopIsoN

/IsoCN

RN

R10/78

(13)18/76

(24)22.2

&4.1

(78)25.8

&3.8

(76)

Snyderman,1999

30H

eadand

neckcancer(n

"136)

8Yes

Impactpre-

%postop

StandardEN

formulas

pre-andpost(m

ainlyreplete)

0/82(0)

0/47(0)

19/82(23)

19/47(40)

15.3&

9.1(82)

17.4&

11.9(47)

Tepaske,2001

32C

ardiacsurgery

(n"

50)7

YesIm

pact5#10

dpre-

%postop

StandardIsoC

al/IsoN5#

10d

preop1/23

(4)1/22

(5)4/23

(17)12/22

(55)7.5

(IQR

7#108)

9.6&

5.39.5

(IQR

6#12)

11.7&

12

vanB

okhorst-De

vanderSchueren,2001

33

Head

andneck

cancer,m

alnourished(n

"56)

6Yes

1)Arginine

formula

(12.5g/L)Pre-

%postop

2)StandardEN

pre%

post1)2/17

(12)2)1/15

(7)N

RN

R1)31

&23

2)46&

30

Finco,200742

Colon

disease(n

"28)

9N

oIm

pact%low

-fiberdiet750

mL/d,6

dpre

%3

dpost

StandardEN

%low

-fiberdiet$

6d

pre-%

3d

standardpost-EN

NR

NR

NR

NR

7.7&

2.36.8

&1.6

Sakurai,200745

Esophagectomy

(n"

30)6

No

Impact3

dpre-

%14

dpost

IsoCEnsure

3d

pre%

14d

postN

RN

RN

RN

R26.6

&14

31.3&

1.6

Tepaske,2007

22C

ardiopulmonary

bypass(n

"70)

10Yes

1)Impact5#

10d

pre%

postop2)Im

pact%glycine,

5#10

dpre-

%postop

3)IsoC/IsoV

olControl

5#10

dpreop

NR

NR

1)4/24(17)

2)5/22(23)

12/24(50)

1)6.5(IQ

R6-8)

2)7(IQ

R6-13)

8(IQ

R6-10)

Celik,2009

54G

YNcancer(n

"50)

8N

oIm

pactpreop$

2days

%7

dpostop

StandardEN

pre-%

postop0/25

(0)0/25

(0)1/25

(4)7/25

(28)4.1

&1.3

7.8&

1.2

C2:Perioperative

arginineversusnothing

preoperativeand

postoperativestandard

vanB

okhorst-De

vanderSchueren,2001

33

Head

andneck

cancer,m

alnourished(n

"49)

6Yes

1)Arginine

formula

(12.5g/L)pre-

%postop

3)StandardIsoC

al/IsoNEN

postoponly

1)2/17(12)

3)0/17(0)

NR

NR

1)31&

233)41

&32

Braga,2002

35U

GIand

LGIcancer,

malnourished

(n"

150)11N

o1)Im

pactpreop$

7d

%Im

pactpostop3)IsoC

/IsoNEN

postop1)0/50

(0)3)2/50

(4)1)5/50

(10)3)12/50

(24)1)12

&3.8

3)15.3&

4.1

C3:Perioperative

arginineversusnone

Braga,2002

34C

olorectalcancer(n"

200)12N

o1)Im

pactpreop1

L/d$

5d

%postop

4)None

pre-/postop1)1/50

(2)4)1/50

(2)1)5/50

(10)4)15/50

(30)1)9.8

&3.1

4)12.2&

3.9

Gianotti,2002

37U

GI

%LG

Icancer!

10%w

eightloss(n"

305)8

No

2)Impactpreop

$5

d%

postop3)N

onepre-/postop

2)2/101(2)

3)1/102(1)

2)16/101(16)

3)31/102(30)

2)12.2&

4.13)14

&7.7

EN,enteralnutrition;G

YN,gynecological;IQ

R,interquartilerange;IsoN

,isonitrogenous;IsoC,isocaloric;IsoVol,isovolem

ic;LGI,low

ergastrointestinal;NR

,notreported;postop,postoperative;preop,preoperative;U

GI,uppergastrointestinal.

14:Snyderman

30:D

ataforgroups1

and2

combined

(Impactpre

%post)and

compared

with

groups3and

4com

bined(standard

pre%

post).15a:van

BokhorstD

evan

derSchueren33:D

ataforG

roup3

(controlnothingpreop

andEN

postop)appearsinC

2.Tepaske

22:G

roups1and

2com

binedin

them

eta-analysis.C

elik54:Infection

datanotincluded

inm

eta-analysisasonlyreported

aswound

infection,nottotalnumberofinfections.

vanB

okhorstDe

vanderSchueren

33:D

ataforG

roup2

(ControlEN

pre-andpostop)appearsin

C1.

Braga

35:D

ataforG

roup2

(Impactpreop

andstandard

postop)appearsinA

1.G

ianotti 37:D

ataforG

roup1

(Impactpreop)appearsin

A1.

389 Vol.212,No.3,March2011DroveretalArginineSupplementationinSurgicalPatients

Table4.

Random

izedS

tudiesEvaluating

PostoperativeArginine

inElective

Surgery

Patients

Firstauthor,

yearPopulation

MethodsScore

Blinding

InterventionM

ortality,n

(%)

Infections,n

(%)

Hospitalstay,

d

Experimental

Control

Experimental

Control

Experimental

Control

Experimental

Control

Postoperativearginine

versusstandard

Daly,1990

21U

GIsurgery

(n"

30)4

No

Arginine

25g/d

with

modular

feedpostop

Glycine

43g/d

modularfeed

postopN

RN

R10/16

(63)9/14

(64)N

RN

R

Daly,1992

23U

GIcancer(n

"85),32%

weightloss

'10%

10N

oIm

pactviaN

CJ

postopO

smolite

HN

viaN

CJ

non-IsoN

postop2/41

(5)0/44

(0)5/41

(12)13/44

(30)18.8

&11.1

(41)20.4

&9.6

(44)

Daly,1995

24Esophageal,pancreatic

andgastric

cancer(n"

60),37%!

10%usualw

eightloss

9Yes

1)Impactpostop

andas

outpatient2)Im

pactpostopsm

allbowel

3)Traum

acalpostopand

asoutpatient

4)Traum

acalpostopsm

allbow

elIsoN/IsoC

1/30(3)

2/30(7)

1/30(10)

9/30(30)

16&

0.9(30)

22&

2.9(30)

Braga,1996

20Pancreatic,gastric

cancer(n"

60),50%w

ithw

eightloss'

10%

9N

oIm

pactpostopSam

eEN

formula

w/o

arginineand

omega-3

fattyacids,w

ithglycine

%om

ega-6fatty

acidsIsoNpostop

0/20(0)

0/20(0)

2/20(10)

3/20(15)

13.2&

6.1(20)

15.5&

3.5(20)

Schilling,199625

GIcancer(upperand

lower)(n

"45),body

massindex

23#24

6N

oIm

pactpostopvia

nasojejunalFresubin

(StandardEN

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forpancreas,stomach,

esophagealcancer(n"

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feedw

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deLuis,2007

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Casas-R

odero,2008

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omega-3

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(continued).

390DroveretalArginineSupplementationinSurgicalPatientsJAmCollSurg

Outcomes were also analyzed separately for studies ofupper GI operations only (n " 18), lower GI operationsonly (n " 2), and studies of mixed (both upper and lowerGI surgery) (n " 5). When the 16 trials of patients withupper GI surgery only that reported on infectious com-plications were aggregated, patients receiving arginine-supplemented diets experienced fewer infectious com-plications than those receiving standard diet therapies(RR " 0.69; 95% CI, 0.55#0.87; p " 0.002; test forheterogeneity p " 0.15, I2 " 27%). In the one study oflower GI surgery, RR " 0.34 (95% CI, 0.17#0.68, p "0.002; test for heterogeneity not applicable). In the 4 stud-ies of mixed GI surgery, RR " 0.49 (95% CI, 0.36#0.66;p ! 0.00001; test for heterogeneity p " 0.99, I2 " 0%).Differences between these subgroups were not statisticallysignificant (p " 0.06, see Fig. 4).

When the data on hospital length of stay were aggre-gated, arginine-supplemented diets were associated with asignificant reduction in hospital length of stay in the 14upper GI studies (WMD " #2.12, 95% CI, #3.85 to#0.39; p " 0.02; test of heterogeneity p ! 0.00001, I2 "93%) and in the 5 studies of upper and lower GI studies(WMD " #2.36; 95% CI, #3.09 to #1.64; p !0.00001, test of heterogeneity p " 0.66, I2 " 0%). Whenthe data from the 2 studies of lower GI studies were aggre-gated, arginine-supplemented diets had no effect on hospi-tal length of stay (WMD " #0.74; 95% CI, #3.92 to#2.45; p " 0.65; test for heterogeneity p " 0.002, I2 "90%). There were significant differences between thesesubgroups (p " 0.004, Fig. 5).

We compared the data from the trials that used Impact(n " 23) with those that used other formulations (n " 12).The use of Impact was associated with a greater reductionof infectious complications in the 21 trials that reported onoutcomes (RR " 0.49; 95% CI, 0.41#0.58; p ! 0.00001;test of heterogeneity p " 0.74, I2 " 0%) than the use ofother formulations in the 7 trials (RR " 0.95; 95% CI,0.75#1.21; p " 0.68; test of heterogeneity p " 0.98, I2 "0%). The differences between these 2 subgroups was statis-tically significant (p ! 0.0001, see Fig. 4). When the dataon hospital length of stay were aggregated and compared,the 21 studies using Impact formulas were associated witha statistically significant reduction (WMD " #2.62; 95%CI, #3.65 to #1.59; p ! 0.00001; test for heterogeneityp ! 0.00001; I2 " 87%) compared with the 8 studiesusing non-Impact formulas (WMD " #0.89; 95% CI,#3.21 to #1.44; p " 0.45; test for heterogeneity p "0.05; I2 " 49%). Differences between the subgroups weresignificant (p ! 0.00001, see Fig. 5).

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who received an arginine-supplemented diet both pre- andpostoperatively (13 trials), and those who received thearginine-supplemented diet postoperatively (n " 18) wereanalyzed separately. In all subgroups, patients experiencedfewer infectious complications if they were fed thearginine-supplemented diets (see Fig. 4). There was a sta-tistically significant difference across groups, suggesting agreater treatment effect with the perioperative administra-tion of arginine-supplemented diets (perioperative: RR "0.46; 95% CI, 0.36#0.59; p ! 0.00001, test for hetero-geneity p " 0.89; I2 " 0%; preoperative: RR " 0.57; 95%CI, 0.37#0.88; p " 0.01, test for heterogeneity p " 0.24;I2 " 26%, and postoperative: RR " 0.78; 95% CI,0.64#0.95; p " 0.01, test for heterogeneity p " 0.52; I2 "0%, the test of significance between subgroups, p " 0.03,see Fig. 4). Arginine-supplemented diets were associatedwith a significant reduction in hospital length of stay in the11 studies of perioperative intervention (WMD " #2.38;95% CI, #3.44 to #1.32; p ! 0.0001, test for heteroge-neity p ! 0.0001; I2 " 74%) and in the 14 studies ofpostoperative intervention only (WMD " #2.23; 95%CI, #3.80 to #0.65; p " 0.006; test for heterogeneity p !

0.00001; I2 " 85%), but there was no significant effect in6 studies of preoperative intervention (WMD " #1.38;95% CI, #3.49 to 0.73; p " 0.20; test for heterogeneityp ! 0.00001; I2 " 87%). There were significant differ-ences between the subgroups, again suggesting a greaterbenefit to the perioperative administration of arginine-supplemented diets (p " 0.001, see Fig. 5).

DISCUSSIONWe have systematically reviewed all RCTs evaluatingthe effect of perioperative administration of arginine-supplemented diets in elective surgical patients. We found35 eligible RCTs in elective surgery patients for consider-ation. When statistically aggregated, there is a substantialreduction in infectious complications and shorter hospitallength of stay associated with the use of these specialtydiets, with no overall effect on mortality compared withstandard care. These findings are insensitive to the use ofglycine in the control diets and are consistent with earliermeta-analyses on more limited samples of RCTs than wereincluded in our comprehensive analysis.9,13

Figure 1. Effect of arginine-supplemented diets on infections. Events, number of patients with infections; Total, totalnumber of patients in group; M-H, Random, Mantzel-Haenzel Random effects.


Figure 3. Effect of arginine-supplemented diets on mortality. Events, number of patients that died; Total, total number ofpatients in group; M-H, Random, Mantzel-Haenzel Random effects.

Figure 2. Effect of arginine-supplemented diets on hospital length of stay. Mean, mean hospital length of stay; SD,standard deviation; Total, total number of patients in group; IV, Random, inverse variance, random effects.


Admittedly, there is considerable heterogeneity in ouranalysis of arginine-supplemented diets, particularly in theevaluation of their effect on hospital length of stay. Thisheterogeneity is likely due to differences in patients, prac-tice patterns, health care systems, study designs, treatmentdiets, and other methodologies across all studies. Becauseof the presence of heterogeneity, we pursued severalhypothesis-generating subgroup analyses. We first demon-strated that the treatment effect of arginine-supplementeddiets seems to be consistent across all types of GI andnon-GI operations. There might be a greater reduction inhospital length of stay associated with these diets in thenon-GI surgery patients compared with GI surgery (reduc-tion of 3.7 versus 2.1 days). However, this observationshould by no means diminish enthusiasm for using theseproducts in GI surgery because they are associated with an

average reduction of 2 days in hospital, which can translateinto considerable cost savings for institutions and healthcare systems.74-76 There was no substantial reductionin hospital length of stay associated with arginine-supplemented diets in lower GI surgery. However, the riskratio was similar to that of other GI operations, but therewere only 2 studies of lower GI surgery and the findingswere not statistically significant. We conclude thatarginine-supplemented diets should be prescribed to allpatients undergoing elective surgery with substantial risk ofinfectious complications.

We then explored the potential benefits of the differentarginine-supplemented formulas by analyzing the RCTsthat used Impact in the experimental arm and comparedwith RCTs that used other formulas.The treatment effect islarge and statistically significant in the group of RCTs that

Figure 4. Results of subgroup analyses examining the effect of arginine-supplemented diets oninfection. Numbers in parentheses indicate number of studies. RR, risk ratio; p values: refer to thedifferences in the effect of arginine-supplemented diets on infections between subgroups (gas-trointestinal [GI] versus non-GI studies, p " 0.28; lower GI, upper GI, and mixed GI studies, p "0.06; Impact versus non-Impact studies; p ! 0.0001; preoperative, perioperative, and postop-erative; p " 0.03).


used Impact, and aggregation of the data from the RCTs ofother formulations showed no substantial reduction in in-fectious complications or hospital length of stay. Impactcontains a combination of arginine, omega-3 fatty acids,and nucleotides, but it is hard to make generalizationsabout the formulations used in the non-Impact RCTs, ex-cept that no 2 studies used the same formulation. It isdifficult to ascertain the exact amount of arginine deliveredin these studies, but it was generally of a lower concentra-tion than is found in Impact. Three of the studies supple-mented with some amount of omega-3 fats, 1 study used aformula with RNA, and 2 studies also used formulas withglutamine.

The only inference from these data is that infectiouscomplications are reduced with use of Impact and notother arginine formulations. It is possible that the specificcombination of nutrients in Impact is necessary and these

nutrients can interact to produce benefit. In addition, it isnot possible to say what the optimal combination or dosageof specialized nutrients is from this data set. Because theclinical benefit observed relates to a substantial reductionof infections, one might postulate (at least in part) thatthese diets work by improving the immune response aftersurgery.

A causal relationship has been shown to exist betweenphysical injury (surgery and trauma) and the predisposi-tion for infectious complications to develop in these pa-tients.11 This increased infectious risk has been hypothe-sized to be related to an acquired arginine-deficient state,which leads to substantial immune dysfunction. Recentinvestigations suggest that arginine metabolism is inti-mately regulated by the immune system.11 Soon after phys-ical injury (surgery or trauma), an accumulation of imma-ture cells of myeloid origin has been discovered in the

Figure 5. Results of subgroup analyses examining the effect of arginine-supplemented diets onhospital length of stay. p Values: refer to the differences in the effect of arginine-supplementeddiets on hospital length of stay between subgroups (gastrointestinal [GI] versus non-GI studies;p " 0.0007; lower GI, upper GI, and mixed GI studies; p " 0.004; Impact versus non-Impactstudies; p ! 0.00001; preoperative, perioperative, and postoperative; p " 0.001).


circulation and lymph tissue. These cells express arginase 1,which efficiently depletes arginine. Coupled with poor ar-ginine intake and inadequate endogenous generation, argi-nase 1 serves to create a state of arginine deficiency. Anincreasing amount of evidence has accumulated in the last10 years to demonstrate that suppression of T-lymphocytefunction can be caused through arginine depletion by my-eloid cells expressing arginase 1, giving these cells the namemyeloid-derived suppressor cells (MDSC).77 Several clinicalstudies suggest that use of arginine supplementation alongwith omega-3 fatty acids restores T-lymphocyte function,including CD4 counts and interleukin-2 production.78,79

We speculate that arginine-supplemented diets can over-come arginine deficiency caused by MDSC through thesynergistic effect of several components. First, arginine issupplemented in supraphysiologic quantities, helping in-crease systemic arginine availability. Second, omega-3 fattyacids can “blunt” upregulation of MDSC and arginase 1,the enzyme responsible for arginine destruction.80-82 In ad-dition, vitamin A (and vitamin A analogues) has beenshown under certain circumstances to induce maturationof MDSC and a decrease in arginase 1 expression.83,84 Ad-ditional investigation will be necessary to test thesepossibilities.

Finally, we explored a priori the question of whetherproviding the specialized formula is better done before sur-gical insult, after the surgical insult, or both. We observedthat all 3 strategies are associated with a substantial reduc-tion in infectious complications. Both perioperative andpostoperative use of these diets were associated with a re-duction in hospital length of stay and, used in the preop-erative setting, were not associated with a substantial reduc-tion in hospital length of stay (WMD " #1.38, 95%, CI,#3.49 to 0.73; p " 0.20). In addition, when we comparedthe estimates of treatment effect across these 3 subgroups,we observed that the largest treatment effect was associatedwith the perioperative administration of the arginine-supplemented diets. We are cautious not to overstate thesefindings, as this comparison is an indirect comparison ofstudies—we are comparing RRs across 3 subgroups. Thereis only 1 head-to-head study that compares perioperativeadministration of arginine-supplemented diets with post-operative use only.51 In this study of 46 patients with stom-ach or pancreas cancer, use of perioperative arginine dietswas associated with a reduction in infection (RR " 0.34;95% CI, 0.16#0.71; p " 0.004) and a reduction in hos-pital length of stay (WMD " #9.18; 95% CI, #11 to#7.26; p ! 0.00001) compared with the group that justreceived arginine-supplemented diets in the postoperativephase. Although this hypothesis warrants additional inves-tigation, it appears, based on these results, that use of

arginine-supplemented diets in both the pre- and postop-erative phase are superior to either phase alone. That is notto say that use in the preoperative only or postoperativephase only is not worthwhile. It means that we can expect agreater treatment effect if we use them both before and aftersurgery.

We would like to acknowledge some of the limitations ofthis review. The studies included in this review, althoughRCTs and of reasonable methodological quality (as evi-denced by an average scoring of 8.2 of a maximum of 14),cover a span of almost 2 decades. Recent advances in dis-charge management (affecting hospital length of stay), glu-cose and antibiotic therapy (affecting infection control),and surgery (eg, minimally invasive surgery) could affectresults from later studies. Some of the included studies hadsmall samples sizes (n ! 100) with more than 1 interven-tion and/or control group, and in other studies the sameintervention was used in varying settings, ie, pre-, post-,and/or perioperatively. Although we have separated thesevarying interventions into the various subgroups, the ap-propriateness of the study design in some cases is question-able. Lastly, many studies, despite reporting a reduction ininfectious morbidity, failed to report data related to infec-tions in a clear, meaningful way, and these studies had to bedeleted from our analyses. Despite these limitations, thestrong signals for a reduction in infections from our anal-yses cannot be ignored.

In conclusion, in this review we have demonstratedsome clinical evidence that use of nutrition therapy con-taining arginine and omega-3 fatty acids used both pre-and postoperatively in high-risk elective surgical patients isassociated with a substantial reduction in infection andshorter length of hospital stay. Efforts to implement the useof these diets in the perioperative setting are worthwhile.These efforts will result in considerable reduction in mor-bidity for our patients and substantial reductions in costsfor the health care system.

Author Contributions

Study conception and design: Drover, Dhaliwal, Weitzel, Wis-chmeyer, Ochoa, Heyland

Acquisition of data: Wischmeyer, Drover, Heyland, DhaliwalAnalysis and interpretation of data: Dhaliwal, HeylandDrafting of manuscript: Drover, HeylandCritical revision: Wischmeyer, Dhaliwal, Ochoa

Acknowledgment: We would like to thank Sarah Maddenand Gina Haeussner for their assistance with abstraction andchecking of data and Mr Andrew Day for his assistance withthe statistical analysis.


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Appendix 1Methodological Scoring Tool

Score0 1 2

Randomization — Not concealed or not sure Concealed randomizationAnalysis Other — Intention to treatBlinding Not blinded Single blind Double blindedPatient selection Selected patients or unable to tell Consecutive eligible patients —Comparability of groups at baseline No or not sure Yes —Extent of follow-up !100% 100% —Treatment protocol Poorly described Reproducibly described —Co-interventions Not described Described but not equal or not sure Well-described and all equalOutcomes Not described Partially described Objectively defined

399.e1 Drover et al Arginine Supplementation in Surgical Patients J Am Coll Surg

perioperative use of arginine-supplemented diets: a ... · perioperative use of...

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