Nutritional Support and Functional Capacity in COPD

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REVIEW

Nutritional support and functional capacity in chronic obstructive

pulmonary disease: A systematic review and meta-analysis

PETER F. COLLINS,1,2 MARINOS ELIA1 AND REBECCA J. STRATTON1

1Faculty of Medicine, Institute of Human Nutrition, Southampton General Hospital, University of Southampton,

Southampton, UK, and 2Faculty of Health, School of Exercise and Nutrition Sciences, Queensland University of Technology,

Brisbane, Australia

ABSTRACT

Currently, there is confusion about the value of usingnutritional support to treat malnutrition and improve

functional outcomes in chronic obstructive pulmonarydisease (COPD). This systematic review and meta-analysis of randomized, controlled trials (RCT) aimedto clarify the effectiveness of nutritional support inimproving functional outcomes in COPD. A systematicreview identified 12 RCT (n= 448) in stable COPDpatients investigating the effects of nutritional support(dietary advice (1 RCT), oral nutritional supplements(10 RCT), enteral tube feeding (1 RCT)) versus controlon functional outcomes. Meta-analysis of the changesinduced by intervention found that while respiratoryfunction (forced expiratory volume in 1 s, lung capac-ity, blood gases) was unresponsive to nutritionalsupport, both inspiratory and expiratory musclestrength (maximal inspiratory mouth pressure +3.86

standard error (SE) 1.89 cm H2O, P=0.041; maximalexpiratory mouth pressure +11.85 SE 5.54 cm H2O,P= 0.032) and handgrip strength (+1.35 SE 0.69 kg,P=0.05) were significantly improved and associatedwith weight gains of2 kg. Nutritional support pro-duced significant improvements in quality of life insome trials,although meta-analysis was not possible. Italso led to improved exercise performance andenhancement of exercise rehabilitation programmes.This systematic review and meta-analysis demon-strates that nutritional support in COPD results in sig-nificant improvements in a number of clinicallyrelevant functional outcomes, complementing a previ-ous review showing improvements in nutritionalintake and weight.

Key words: chronic obstructive pulmonary disease, functionalcapacity, meta-analysis, nutritional support.

Abbreviations: BMI, body mass index; COPD, chronicobstructive pulmonary disease; ETF, enteral tube feeding; FEV1,

forced expiratory volume in 1 s; HGS, handgrip strength; IBW,

ideal body weight; ONS, oral nutritional supplements; PE max,

maximal expiratory mouth pressure; PI max, maximal inspiratorymouth pressure; QoL, quality of life; RCT, randomized, controlled

trial; SD, standard deviation; SE, standard error.

INTRODUCTION

Chronic obstructive pulmonary disease (COPD) is aprogressive multi-organ systemic disease and a majorcause of morbidity and disability in aging. WhileCOPD has its primary effects in the lungs, adversestructural and functional changes also occur in thetissues of the heart and skeletal muscle, leading toindividuals with COPD experiencing a range of dis-

abilities that impact on their well-being and ability toperform daily activities. Reduced respiratory functionand a decline in fat-free mass result in reduced exer-cise tolerance1 and peripheral muscle weakness,2,3

both disabling features of COPD, which are associatedwith a poorer quality of life (QoL). Fat-free massdepletion (even if body mass index (BMI) is within theideal range)4,5 has recently been found to be a signifi-cant independent predictor of disability even afteradjustment for disease severity.6

Disease-related malnutrition is a common problemin individuals with COPD, with between 30% and 60%of inpatients and 10% and 45% of outpatients said tobe at risk.7 Malnourished COPD patients demonstrategreater gas trapping, lower diffusing capacity and areduced exercise performance when compared withheavier non-malnourished patients with a similarseverity of disease.8 However, the exact causal linksbetween malnutrition and COPD are difficult toestablish. Malnutrition may be the consequence ofgreater disease severity. Alternatively, malnutritionmay be responsible for the wasting of the musclesinvolved in breathing, exacerbating the progressivenature of COPD. Similarly, in chronic anorexianervosa, the loss of body weight includes substantialloss of lung tissue, which develops emphysematous-like changes.9 In addition to the uncertainty about thecausal links between malnutrition and COPD, there

Correspondence: Marinos Elia, Institute of Human Nutrition,

Faculty of Medicine, University of Southampton, MP 113, South-

ampton General Hospital, Southampton SO16 6YD, UK. Email:

[email protected]

Conflict of Interest Statement: Rebecca Stratton, PhD, RD,

RNutr, is also an employee of Nutricia Ltd.

Received 15 November 2012; invited to revise 9 January 2013;

revised 4 February 2013; accepted 7 February 2013 (Associate

Editor: Paul Thomas).

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2013 The AuthorsRespirology 2013 Asian Pacific Society of Respirology

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are controversies about how effective nutritionalsupport is in this patient group. Previous reviews andmeta-analyses1012 suggested that malnutrition fails torespond to nutritional treatment in COPD finding nosignificant improvements in anthropometric or func-tional measures. These conclusions have beenchallenged by several randomized, controlled trials(RCT),1316 and a recently published meta-analysis

concluded that nutritional support wasable to signifi-cantly increase nutritional intake (energy andprotein), which was associated with a significantimprovement in a variety of anthropometric meas-ures.17 The contrast in conclusions between thereviews has been largely attributed to methodologicaldifferences in data analysis discussed at length in thepaper.17 In essence, the previous Cochrane Collabora-tion review12 carried out cross-sectional analysisbetween intervention and control groups but failed toaccount for baseline variability. The other reviewaccounted for pre- and post-intervention variabilityfinding a number of significant within-group im-provements to be masked by cross-sectional analy-

sis.17

Nevertheless, confusion remains over whetherthe recent positive findings translate beyond nutri-tional intake and body weight, and into functionalimprovements. The aim of this current systematicreview is to establish whether nutritional supportresults in significant improvements in functionalcapacity and QoL in patients with COPD.

METHODS

Search strategy and identification of trialsThe review was planned, conducted and reportedaccording to published guidelines.1820 The same

methodological approach to that of the previousreview17 was used; however, an updated systematicsearch of the literature was carried out in July 2012(databases accessed up to 4 July 2012) in order toidentify any additional RCT investigating nutritionalsupport in COPD reporting functional outcomes(Fig. 1). Potentially relevant studies were identifiedby searching electronic databases. The databasessearched included PubMed (accessed 4 July 2012),

Web of Science (accessed 4 July 2012) and OVID(accessed 4 July 2012). In order to identify the largestnumber of trials, a broad search strategy was imple-mented, although trials were restricted to English lan-guage citations only. The search terms and meshheadings used included: chronic obstructive pulmo-nary disease, COPD, emphysema, weight, depletion,diet*, nutrition*, supplement*, protein, carbohydrate,

calori*, feed*, malnutrit*, nourish*, sip, nutritionintervention, nutrition support. These search termswere also systematically combined in order to identifytrials. In addition to electronic database searching,manual searching of previous reviews on nutritionalsupport in COPD as well as references of identifiedtrials was undertaken.

Studies were initially screened by reading theabstract, and where a study could not be excluded,the full article was reviewed. The assessment of trialeligibility was done by two independent assessors(P.F.C. and M.E.), with any disagreement discussedprior to inclusion.

Inclusion and exclusion criteriaStudies were deemed eligible for inclusion in thereview if they conformed to the pre-determinedinclusion criteria. To investigate the overall efficacy ofnutritional support (food strategies (food fortifica-tion, food snacks, dietary advice), oral nutritionalsupplements (ONS) and enteral tube feeding (ETF),the following inclusion criteria for trials were devised:(i) randomized trials; (ii) intervention with food strat-egies, ONS or ETF; (iii) duration of intervention >2weeks; (iv) control group receiving placebo or nodietary intervention (e.g. usual care, which couldinclude advice and encouragement to eat), but other-wise the same treatment as the intervention group; (v)

stable patients with a diagnosis of COPD (not exacer-bating); (vi) human studies only; and (vii) English lan-guage only.

The intervention could provide either a proportionor all of the daily nutritional requirements for energy,protein and micronutrients, and where feeds wereused (e.g. ONS), these could be nutritionally completeor incomplete. Studies using parenteral nutrition andsingle nutrient interventions were excluded.

Figure 1 Study selection process.

Nutrition support in COPD 617


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Data extractionFunctional outcome data sought included respiratoryfunction (forced expiratory volume in 1 s (FEV1)), res-piratory muscle strength (maximal inspiratory mouthpressure (PI max) and maximal expiratory mouthpressure (PE max)), peripheral muscle strength(maximum voluntary handgrip strength (HGS)), exer-cise performance (walking distance), QoL and addi-

tional outcomes including immunological measures.In trials where mean values were reported withoutstandard deviations (SD) or standard errors (SE), theywere calculated from reportedP-values. In one trialthat assessed HGS,15 data reported in kilograms wereconsidered to be unrealistic and therefore assumed tobe in pounds. Whenever possible, data from indi-vidual subjects were used to calculate the summaryvalues from specific studies.15,21 Graphical data werealso used to establish summary values either whenthere were no other data reported or when reportedresults were imprecise due to rounding.22

Quality assessmentThe quality of included studies was assessed by oneresearcher (P.F.C.) and independently verified byanother assessor (R.J.S.) using the most commonlyused scoring system (Jadad scoring system).23 TheJadad scoring system comprises of three componentsaddressing whether a study is described as rand-omized, whether it is double-blind and whether drop-outs were accounted for. It then scores on theappropriateness of the randomization and blinding.The Jadad scoring system does not assess the samplesize of trials.

Synthesis of data and statistical analysis

Following the extraction of data from included trials,where appropriate and feasible, the results of compa-rable outcome measures were combined in order tocarry out random effects meta-analyses using Com-prehensive Meta-analysis (Biostat, Inc., Englewood,

NJ, USA, version 2) (Table 1). The overall treatmentdifference was considered statistically significant ifthe P-value was


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Table

2

Summaryoftherandom

ized,controlledtrialsincludedinthe

systematicreviewaccordingtointervention

Study

Samplesize

(treatment/

control)

C

haracteristics/setting

(interventionvs

control)

Nu

tritionalintervention

(type/prescribed

amount/duration)

Co

ntrolgroup

Outcomemeasur

es

Studyquality

(Jadadscore)

ONSDeLetter66

(thesis)

18/17

Maln

ourished

82.8%

IBW

Outp

atients

ONS(Pulm

ocare,1.5kcal/mL)1can/day

ONStarget:+355kcal/dayand15g

protein/

day

9weeks

Usualdiet

FEV1,6MWT

11000(2)

Efthimiou

etal.13

7/7

Maln

ourished

79.5%

versus81.3%IBW

Outp

atients

59.9versus64.1years

ONS(Buil

dUp,1.13kcal/mL)

ONStarget:+6401280kcal/daysand

3672g

protein/day,encouragement

toeatp

rovidedtobothgroups

12weeks

Usualdiet(with

enco

uragement)

FEV1,PImax,PEma

x,

sternomastoid

strength,HGS,6M

WT,

breathlessnessscale,

generalwell-being

10000(1)

Knowles

etal.48

13/12

Nour

ishedandmalnourished

61108%IBW

Outp

atients

68ve

rsus70years

ONS(Sustacal,1kcal/mL,0.043g

protein/

kcal)

ONStarget:ToincreasetotalEIby50%

Weeklyen

couragement:8weeks

Usualdiet

FEV1,PImax,PEma

x,

lymphocytecount,

serumtransferring

11000(2)

Lewis

etal.50

10/11

Maln

ourished

86.3%

versus84.6%IBW

Outp

atients

65.1versus59.3years

ONS(Isoc

alHCN,2kcal/mL)

ONStarget:5001000kcal/dayand

1938g

protein/day,encouragement

8weeks

Usualdiet

FEV1,PImax,PEma

x,

HGS

10000(1)

Otte

etal.52

13/15

Maln

ourished

77%

versus73%IBW

Outp

atients

56.5years

ONS(Nov

o,1kcal/mL)


protein/

day,encouragement

13weeks

Placeb

o(blinded)

(encouragement)

FEV1,12MWT,well-b

eing

10111(4)

Fuenzalida

etal.14

5/4

Maln

ourishedinpatientsand

outpatients

78.5%

IBW

62.4years

ONS(SustacalHC,1kcal/mL)

ONStarget:Upto1080kcal/dayandup

to46gprotein/day

3weeksinpatient+

3weeks

outpatie

nt(6weekstotal)

Usualdiet

FEV1,Lymphocytecount,

T-helper/suppressor

cells

10000(1)

Rogers

etal.15

15/12

Maln

ourished

78%

versus79%IBW

64ye

ars

Outp

atients(interventiongroup

admittedforfirst4weeks)

ONS(various,self-selected)tailoredto

individu

aldietaryhabitsanddietary

advice

ONStarget:Intakes>1.7

REEand

minimu

m1.5gprotein/kgperday

15weeks

Usualdiet

PImax,PEmax,HGS,

12MWT,

breathlessnessrat

ing,

QoL

10000(1)

Schols

etal.16

33/38

Nour

ished

102.4

%IBW

inpatient

PRprogramme(nothospital)

meanageunclear

ONS(MixtureofNutridrink,Protifar,

Fantomalt,Oil;sevenmixturesof

differen

tflavours;2.1kcal/mL)


protein/

day,encouragementtoeat

regular

meals

8weeks

Usualdiet(and

enco

uragementwith

oral

diet)

FEV1,PImax,12MW

T

10001(2)



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Table

2

Continued

Study

Samplesize

(treatment/

control)

C

haracteristics/setting

(interventionvs

control)

Nu

tritionalintervention

(type/prescribed

amount/duration)

Co

ntrolgroup

Outcomemeasur

es

Studyquality

(Jadadscore)

Schols

etal.22

39/25

Maln

ourished

84.1%

IBW

Inpatient

PRprogramme(nothospital)

Meanageunclear

ONS(MixtureofNutridrink,Protifar,

Fantomalt,Oil;sevenmixturesof

differen

tflavours;2.1kcal/mL)


protein/

day,encouragementtoeat

regular

meals

8weeks

Usualdietand

enco

uragementwith

meals

FEV1,PImax,12MW

T

10001(2)

Steiner

etal.24

42/43

Nour

ished/malnourished

~105%IBW

(23.9

vs23.5kg/m2)

Outp

atients

PRprogramme

66ve

rsus68years

ONS(Respifor,1.5kcal/mL)


protein/

day

7weeks

Placeb

o(blinded)

HGS,ISWT,ESWT,Q

oL

10111(4)

ETF

Whittaker

etal.21

6/4

Maln

ourished

76%

versus82%IBW

Inpatients

71ve

rsus64years

Nocturnal

ETF(Isocal)

ETFtarget;feeddelivered:atleast

1000kcal/dayor1.7

REEwhichever

greater

and34gprotein

(nasodu

odenal/jejunaltubefeeding)

16days

Placeb

o

ETF(equivalent

volumeproviding

2 kgwere associated with significantly improved survivalin keeping with a previous review reporting that sig-nificant functional improvements were seen in mal-nourished patients receiving ONS when weight gainwas >2 kg.7 It appears that this level of weight gainshould be a therapeutic target in malnourished COPD

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patients, especially as recently reviewed evidencehighlights that this level of weight gain is achievablein malnourished COPD patients.17 The current reviewconfirms that weight gain of this magnitude is associ-ated with functional improvements in this patientgroup.

In the clinical setting, increasing importance isbeing placed on the assessment of functional out-

comes. HGS is not only a reliable marker of peripheralmuscle strength but it also predicts clinical out-comes69 such as mortality, morbidity, postoperativecomplications and increased length of hospital stay.Inthe elderly, a loss of grip strength often means a lossof independence. Although muscle strength is closelyrelated to mid-arm muscle area,70whole body proteincontent,71 and even body weight and BMI,72 a varietyof studies suggest that changes in muscle functioncan occur independently of muscle mass.7 It hasrecently been suggested that muscle strengthresponds faster to nutritional depletion and repletionthan anthropometric measures such as BMI andfat-free mass69 probably as a result of increased avail-

ability of energy, electrolytes and micronutrients inmuscle. Therefore, the improvement in musclestrength induced by nutritional intervention in mal-nourished COPD patients is likely to be due to a com-bination of increased force generated by the availablemuscle and increased muscle mass, which is consist-ent with the increase in mid-arm muscle circumfer-ence (or area) reported in RCT of COPD17 and otherconditions.73 Mid-arm muscle area has been found tobe a better predictor of mortality than BMI in patientswith COPD.74 Therefore, nutritional support leadingto weight gain (>2 kg) and increased mid-arm musclecircumference could confer survival benefits as sug-gested by previous studies.68,75

Exercise tests in COPD have also been found topredict outcomes,76 such as mortality and postopera-tive complications.77,78 This review examined theeffect of nutritional support in COPD patients under-taking different types of walking and shuttle tests per-formed on a flat surface, but the reviewed studieswere not amenable to meta-analysis. However, four ofthe five studies favoured the nutritional supportgroup, and the only studies reporting significantimprovements in performance also favoured thosereceiving nutritional support. While these tests havelimitations (e.g. some patients still have difficultieswalking faster on flat surfaces as their conditionimproves, but they can walk up a steeper slope), theyat least assess important aspects of the patientsability to function in ways that are relevant to every-day life.79

The evidence based on the effect of nutritionalsupport on immunological function is very limitednot least because none of the three studies14,21,48 thatassessed restricted aspects of immune functionreported the results separately for the interventionand control groups. In addition, the total absencefrom these studies of cytokine measurements andacute phase proteins as markers of the inflammatoryresponse highlights the need to examine immune/inflammatory-nutrition interactions. This is becausethe immune system not only helps prevent and aid

recovery from respiratory infections but also becauseit is linked to the processes involved in nutritionaldepletion and repletion of body tissues and theirresponsiveness to nutritional support.34 Whetherexercise has a pro- or anti-inflammatory role in COPDis unclear;80,81 however, a recent trial82 involving acombination of low-intensity exercise education ses-sions and an ONS with immunomodulatory proper-

ties (immunonutrition) in a cohort of malnourished(mean BMI 18.0 kg/m2) patients with moderate COPDproduced some very promising results that includedimprovements in weight, peripheral and respiratorymuscle strength, exercise capacity, QoL, and a reduc-tion in inflammation (measured by interleukin-6,interleukin-8, tumour necrosis factor-a, high sensi-tive C-reactive protein levels). Further work isrequired to examine whether these improvements aredue to the exercise intervention, the immunonutri-tion (or other components of the ONS) or a combina-tion of these. Further work is also needed to examinethe extent to which the changes in outcome could bereproduced by using a standard ONS.

An outcome that was found to be unresponsive tonutritional support in the current review was lungfunction (assessed by tests such as FEV1, forced vitalcapacity and blood gases), but this is likely to reflectthe irreversible nature of lung pathology in COPD. Itmay seem surprising that the lack of an effect of nutri-tional support on objective tests of lung function weresometimes associated with significant improvementsin subjective measures of breathlessness. However,because malnutrition has effects on the centralnervous system, including modulation of the sensitiv-ity of the respiratory centre to hypoxic stimulation,81

it is plausible that nutritional support influencesthe sensation of breathlessness through centrally

mediated mechanisms. Interestingly, cross-sectionalstudies of men with COPD have reported that breath-lessness is inversely related to BMI independently ofrespiratory function tests (diffusing capacity tocarbon monoxide, partial arterial oxygen concentra-tion, P0.1/PI max).83 Breathlessness influences QoL,which probably explains the striking concordancebetween them, both within and between groups ofthe reviewed RCT.

The extent to which changes in functional outcomemeasures reflect clinically relevant improvements inpatient well-being can be difficult to establish. Forexample, a small change in muscle strength (whichmay be as little as a few percent, as in some of thereviewed studies) may go totally unnoticed in strongwell-nourished subjects, but in malnourishedpatients who are close to the threshold of disability,84

they may be easily noticed and make the differencebetween being able to get up and not get up from abed or a chair, and between being independent anddependent on others. Nevertheless, attempts havebeen made to establish the minimum clinically rel-evant changes associated with some of these tests. Forexample, it has been conservatively estimated thatthe minimum clinically important difference in 6-minwalking distance is 5480 m85, which exceeds thatfound in the only two nutrition intervention studiesthat employed the 6-min walk test (an improvement



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in favour of ONS by a mean of 4713 and 37 m66).However, much larger changes have been found withthe 12-min walk test, for example, an improvement of143 m has been attributed to ONS in the study ofRogers et al..15 The minimum clinically importantimprovement in incremental shuttle walk test hasbeen estimated to be 47.5 m. The minimum benefitdistinguishable by patients relates to 78.7 m.86 Of the

studies considered in the present systematic review,the only one that used the incremental shuttle walktest to examine the effects of ONS during pulmonaryrehabilitation24 found improvements in walking dis-tance in favour of the nutrition intervention groupthat were less than the suggested thresholds.However, the patients were studied during pulmonaryrehabilitation and the effect of ONS in combinationwith the other treatments showed a statistically sig-nificant overall improvement of 60 m. Because bothnon-malnourished (87%) and malnourished patients(13%) received ONS if they were randomized to thenutritional support arm of the study, it is possible thatthose with malnutrition responded differently from

those without malnutrition, but such informationwas not reported. The benefits of exercise rehabilita-tion are well established;87 however, as alluded to bySteiner and colleagues,24 it can produce a negativeenergy balance that might require reversal by supple-mentation before an improvement in training out-comes can be demonstrated. A recent RCT of patientswith chronic respiratory failure, the majority of whomhad COPD, participating in an exercise rehabilitationprogramme and classified as malnourished (BMI21.5, SD 3.8 kg/m2 and fat-free mass deplete) foundthat nutritional support (ONS 3per day), educationand oral testosterone undecanoate led to significantimprovements in body weight, fat-free mass, strength

and function above control.

62

At present, it is unclearwhether all malnourished COPD patients undertak-ing exercise training should receive additional nutri-tional support or indeed whether training shouldcommence in those who are malnourished withoutnutritional support.61 It would appear pertinent torecommend that all COPD patients at risk of malnu-trition should receive some form of nutritionalsupport during rehabilitation and recommendationsare required.

The present analysis also examined the effect ofpotential explanatory variables, such as duration ofintervention with nutritional support, % IBW and ageof the participants, on functional outcomes (PI max,PE max and HGS), but generally, they were not foundto be significantly related to the outcomes. This is nottoo surprising given that the meta-regressionsinvolved a small numbers of studies that differed indesign and prescribed amounts of nutritional support(see Table 2), and also involved examination of eachvariable individually. In addition, there was only smallvariation between the mean age of the populationsinvolved with different studies (6269 years) and insome cases involved significant effects on outcomesfollowed short periods of supplementation (e.g. sig-nificant improvement in PE max reported in onestudy after 16 days of supplementation).21 Furtherinsights might emerge if individual patient data

(instead of mean study data) were analysed together,but unfortunately, such data are not available.

To understand the significance, strengths and limi-tations of this review and the way it differs from theupdated Cochrane review,88 it is necessary to considercertain methodological issues. Although the conclu-sions of both reviews appear to be similar (and both atvariance with those of the earlier Cochrane review,12

the two should not be confused because apartfrom not addressing the same issues, they have useddifferent methodology to meta-analyse differentstudies, which were selected according to differentcriteria.

The present review excluded three studies,61,63,82

which were also absent from the previous Cochranereview. However, in the updated Cochrane review,these three studies contributed to the assessment ofalmost all of the functional outcomes, dominatingsome of the analyses such as the overall health-related QoL (accounting for three out of the fourstudies) and their domains (two out of three studies ineach domain61,82) and the 6-min walk test(three out of

five studies). The studies totally dominated the meta-analyses of quadriceps strength (only two studies61,63),yet in the present review, data on quadriceps strengthfrom another paper were able to be used.24 Two of thethree papers were excluded from the present reviewbecause they both incorporated an exercise pro-gramme in the nutritional support arm of the studyand not in the control arm,61,63 and one of them63 alsoincluded additional interventions in the nutritionalsupport arm and not the control arm. (The depletedpatients who received nutritional support in thisstudy accounted for minority of the population,which was predominantly overweight with mildCOPD.) These study designs make it difficult to isolate

the effects of nutritional support. The multiplereported functional outcomes in favour of nutritionalsupport arm may have been due to the non-nutritional interventions or a combination of nutri-tional and non-nutritional interventions. The thirdstudy82 was not included in the present reviewbecause it became available after the literature searchwas carried out. It involved a nutritional supplementwith immunomodulatory properties, which can beattributed to an anti-inflammatory whey peptide,pharmacological doses of the anti-oxidant vitaminsC, E and A, and fish oils. Arguably, this study should betreated separately from other studies, none of whichinvolved an immunonutrition feed.

In the present review, the meta-analyses examinedwhether the changes induced by the interventionsdiffered between the two arms of studies, whereas inboth the previous and updated Cochrane reviews,most of the meta-analyses, including those involvingPI max and PE max, involved only the values at theend of the intervention period. It is considered pref-erable to generally use the change method than theend value method to assess the impact of interven-tions, especially when there is a relatively large base-line imbalance (which could fortuitously affect thetwo arms of individual studies in opposite directions(e.g. for variables such as PI max and PE max)).Another difference between the two reviews concerns

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the uncertainty associated with imputation ofmissing data (missing SE or SD). In the present review,imputation involved only 1 of the 12 studies,13

affected only the control group (for PI max, PE maxand HGS), and was alwaysaccompanied by sensitivity(uncertainty) analysis, which assessed the potentialerrors associated with imputation. The uncertaintyassociated with the some of the analyses in the

updated Cochrane review appears is less clearbecause imputation involved 5 out of 14 studies (andmore than half of the studies in some meta-analyses,such as those involving changes in anthropometryincluding weight, and 6-min walk test), often botharms of some studies or the difference between themand in the absence of sensitivity analyses.

Although the type of functional outcomes exam-ined by the two reviews was similar, the presentreview systematically considered HGS and immuno-logical function, which was not the case with either ofthe Cochrane reviews.12,88 In addition, the presentreview provided new data using meta-regression(involving duration of intervention, % IBW, age and as

moderators) and considered the minimally importantclinical differences and related the findings associ-ated with one type of outcome variable to that ofanother another (e.g. the extent of weight gain asso-ciated with improvements in functional outcomes).In contrast, the Cochrane review, following the formalformat of Cochrane Collaboration to produce a docu-ment of almost 100 pages long, included moredetailed information about individual studies, listedthe excluded studies and undertook some subgroupmeta-analyses, such as those involving the compo-nents of QoL (made possible by inclusion of the threenew studies that did not feature in this review).However, the present review included a semiquanti-

tative and narrative description of QoL data and well-being13,15,24,52 that were not synopsized by theCochrane review.

Because a cure is impossible for COPD patients, amajor goal in the management of the disease is theimprovement or maintenance of body function andQoL. This systematic review describes the types andmagnitude of functional benefits that are likely toarise through nutritional support. It suggests that atleast some of the adverse functional consequences ofsevere COPD are reversible by nutritional support.The review also suggests that while several of thestudies were judged to be of high quality, many wereof lower quality, and therefore, the evidence base forthe role of nutritional support in COPD needs to bestrengthened with sufficiently powered RCT.

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