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Hindawi Publishing CorporationBioMed Research InternationalVolume , Article ID ,pageshttp://dx.doi.org/.//

Review ArticleAlbumin Reduces Paracentesis-Induced Circulatory Dysfunctionand Reduces Death and Renal Impairment among Patients withCirrhosis and Infection: A Systematic Review and Meta-Analysis

Chun Shing Kwok,1 Lukasz Krupa,1Ash Mahtani,2 Duncan Kaye,2 Simon M. Rushbrook,1

Martin G. Phillips,1 and William Gelson1

Norfolk and Norwich University Hospital, Colney Lane, Norwich NR UY, UK Norwich Medical School, University of East Anglia, Norwich NR J, UK

Correspondence should be addressed to William Gelson; [email protected]

Received April ; Revised July ; Accepted August

Academic Editor: Ahmed Abdel-Lati

Copyright Chun Shing Kwok et al. Tis is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Background.Studies have suggested that albumin has a value in cirrhotic patients undergoing paracentesis but its value in inectionand sepsis is less clear. We planned to perorm a meta-analysis o the risk o adverse outcomes in cirrhotic patients with andwithout albumin use.Methods.We searched MEDLINE and EMBASE in January or randomized studies o cirrhotic patientsthat reported the risk o adverse events and mortality with albumin and no albumin exposure. We perormed random effectsmeta-analysis and assessed heterogeneity using theI2 statistic.Results.Our review included studies covering , patients. Teuse o albumin in paracentesis was associated with signicantly reduced risk o paracentesis-induced circulatory dysunction (OR. %, CI ..) and there was a nonsignicant difference in death, encephalopathy, hyponatraemia, readmission, and renalimpairment. Comparedto the other volume expanders, albumin use showed no difference in clinical outcomes. In cirrhotic patientswith any inection, there was a signicant reductionin mortality (OR .%, CI ..) andrenal impairment (OR .%,CI ..) when albumin was used. Conclusion. Te use o albumin in cirrhotic patients is valuable in patients with any inectionand it reduces the risk o circulatory dysunction among patients undergoing paracentesis.

1. Introduction

Intravenous administration o human albumin solution is

requently used in patients with decompensated liver cir-rhosis during the drainage o ascites. In the absence ointravenous albumin, postparacentesis circulatory dysunc-tion occurs in approximately % o patients [, ] and isassociated with increased mortality because o hepatorenalsyndrome and dilutional hyponatraemia [,]. In addition,albumin administration is recommended in patients withspontaneous bacterial peritonitis (SBP) [,].

Albumin is a plasma expander that increases car-diac preload and peripheral vascular resistance, attenuatesendothelial dysunction, reduces renal ailure, and improvessurvival [, ]. As a result, albumin is widely accepted asa therapy in large volume paracentesis and spontaneous

bacterial peritonitis, but the evidence supporting this therapyin other settings is less clear.

Bacterial inections are common in patients with

advanced cirrhosis and are a major cause o hospitaladmissions and mortality []. Approximately % ocirrhotic patients with severe inection develop renal ailureand this is a poor prognostic actor []. Te inectionthat most ofen causes renal ailure is spontaneous bacterialperitonitis, ollowed by urinary tract inection and cellulitis.

Few data exist regarding the effect o albumin adminis-tration in patients with non-SBP inections. Te question owhether albumin inusion also improves outcome in patientswith bacterial inections otherthan SBP remains unanswered.Studies to date ailed to answer this question due to smallsample size [] and urther research should be perormed toanswer this question.


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BioMed Research International

In this systematic review, we provide a comprehensiveand up-to-date overview o the existing evidence regardingthe use o albumin in cirrhotic patients. We were speci-cally interested in three questions. Is albumin benecial incirrhotic patients undergoing large volume paracentesis? Isalbumin useul in cirrhotic patients with inections, with

particular ocus on SBP and non-SBP inections? Is albuminsuperior to other volume expanders in cirrhotic patients?

2. Methods

.. Eligibility Criteria. We selected randomized controlledtrials (RCs) that evaluated the use o human serum albuminin patients with cirrhosis. Te specic inclusion criteria orthe studies were () parallel group randomized trial withalbumin in one o the treatment arms or any duration otherapy; () placebo or alternative control arm; () clearreporting o adverse events. Te adverse events o interestwere death, encephalopathy, hyponatraemia, paracentesis-

induced circulatory dysunction, readmission, renal impair-ment, gastrointestinal bleeding, inection resolution, andsepsis/severe inection. Tere was no restriction on cirrhoticpatients and those with tense ascites requiring paracentesis,and those with inections including SBP were included.

.. Search Strategy. We searched MEDLINE and EMBASEthrough OvidSP in January using the Haynes opti-mized search strategy (Health Inormation Research Unit,McMaster University) (see Supplementary Material avail-able online athttp://dx.doi.org/.//) []. Wealso checked the bibliographies o the included trials and

recent review articles or relevant studies.

.. Study Selection and Data Extraction. One reviewer(Chun Shing Kwok) and one o two other reviewers (AshMahtani or Duncan Kaye) independently scanned all titlesand abstracts or studies that met the inclusion criteria andexcluded any articles that clearly did not ull the selectioncriteria. Full reports o potentially relevant trials and studieswere retrieved and independently checked by two reviewers(Lukasz Krupa and William Gelson). We then independentlycollected inormation on study design, drug exposure, studylocation, characteristics o participants, and relevant out-comes onto a spreadsheet (Chun Shing Kwok, Ash Mahtani,

and Duncan Kaye). Where there was any uncertainty ordiscrepancies, the article was discussed between the reviewers(Lukasz Krupa, Simon M. Rushbrook, Martin G. Phillips,and William Gelson) to determine i the studies should beincluded. We also contacted authors i there were any areasthat required clarication.

.. Risk of Bias Assessment. We evaluated the quality ostudies in accordance with the recommendations o theCochrane Handbook and this assessment included sequencegeneration, allocation concealment, blinding o participant,personnel and outcome assessors, incomplete outcome data,

Articles retrieved

rom PubMed

Articles selected afer screening o title and

Articles excluded afer detailed screening to

16 different articles selected or inclusion in

the meta-analysis

Articles retrieved

rom Embase search

search (N = 223)

abstract (N = 74)

specic criteria (N = 39)

(N = 500)

F : Flow diagram o the process o article selection or meta-analysis.

selective reporting, and baseline differences in participants[].

We aimed to generate unnel plots to assess the possibilityo publication bias, provided that there were > studiesavailable in the meta-analysis, with no evidence o substantialstatistical heterogeneity.

.. Data Analysis. We used RevMan . (NordicCochrane Centre) to conduct random effects meta-analysisusing pooled odds ratios (OR). We chose to pool rawoutcome data to yield unadjusted risk ratios (which maybe particularly susceptible to conounding). In view o thepotential diversity o study participants and interventions,we chose to perorm sensitivity analysis based on groupings:

() cirrhotic patients receiving paracentesis,

() cirrhotic patients receiving albumin compared toother volume expanders,

() cirrhotic patients with inections, SBP, and non-SBPinections.

.. Statistical Heterogeneity. Statistical heterogeneity was

assessed using 2 statistic, with 2 values o % repre-senting a moderate level o heterogeneity [].

3. Results

Te search results yielded relevant RCs with , patientsrom Egypt, France, Korea, Argentina, Mexico, Spain, USA,Italy, andChina. Four studies [, , , ] evaluated albumin

versus no albumin/saline, and eight studies [, , , ,


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: Study design, patient characteristics and selection criteria.

Study Design; year o study;

country Number o participants

Meanage

Male%

Selection criteria

Abdel-Khalek andAri []

Randomized trial; Apr to Feb ; Egypt.

; albumin; hydroxyethyl starch.

Patients with cirrhosis and tenseascites which were unresponsive tolow-sodium diet and diuretic therapy.

Altman et al. []

Randomized trial; uncleardates; France.

; albumin; hydroxyethyl starch.

Patients with cirrhosis and tense

ascites.

Choi et al. [] Randomized trial; Jun

to Feb ; Korea.; albumin; noalbumin.

Patients with cirrhosis and

spontaneous bacterial peritonitis.

Fassio et al. []Randomized trial; Apr to Mar ; Argentina.

; albumin ; dextran-.


ascites.

Garcia-Compeanet al. []

Randomized trial; uncleardates; Mexico.

; albumin; noalbumin.


ascites.

Garca-Compeanet al. []

Randomized trial; uncleardates; France.

; albumin ; dextran-.


ascites.

Gines et al. [] Randomized trial; Jul to

Dec , Spain.; albumin; noalbumin.


ascites.

Gines et al. [] Randomized trial; uncleardates, Spain.

; albumin ;dextran- ; polygeline.

Patients with cirrhosis and tenseascites.

Guevara et al. []

Randomized trial; uncleardates; Spain.

; albumin andantibiotics; antibiotics.

Patients with cirrhosis andnon-spontaneous bacterial peritonitisinections.

Moreau et al. []

Randomized pilot study;May Jun ; France.

; albumin; polygeline.

Patients with cirrhosis and ascites whoneeded to receive a plasma expanderbecause o paracentesis, renalimpairment or marked hyponatraemia.

Nazar et al. []Randomized trial; uncleardates; Spain.

; albumin andantibiotics; antibiotics.

NA NA Patients with cirrhosis and non-SBP

inections.

Planas et al. [] Randomized trial; USA. ; albumin;

dextran-.

Patients with cirrhosis and tenseascites treated with paracentesis.

Salemo [] Randomized trial; MayJuly ; Italy.

; albumin; hemaccel.

Patients with cirrhosis and reractoryascites.

Sola-Vera et al. []

Randomized trial; JanDec ; Spain.

; albumin; saline. Patients with cirrhosis and tense

ascites.

Sort et al. [] Randomized trial; Nov

Sept ; Spain.; ceotaxime andalbumin; ceotaxime.

Patients with cirrhosis and


Xue et al. [] Randomized trial; unclear

dates; China.; albumin andcefriaxone; cefriaxone.

NA NA Patients with cirrhosis, ascites and


NA: not available.

,,,] compared plasma expander to albumin. Fourother studies [,,] o cirrhotic patients with inection

compared the use o antibiotics with and without albumin.Study durations varied rom days to months. Te processo selection is shown in Figureand the main characteristicso the included studies are described in able . Te outcomes,interventions,and quality assessments o the included studiesare shown in ableand Supplementary Material .

For methodological quality assessment, the majority otrials ( trials) had adequate sequence generation or ran-domization but only two trials had adequate allocation con-cealment (Supplementary Material ). Blinding o patients,personnel, andoutcome assessors was unclear in the majorityo studies and most studies did not have any evidence oselective reporting and baseline difference.

.. Is Albumin Useful in Paracentesis? Tree studies wereincluded in the analysis o whether albumin was useul in

paracentesis [,, ]. Te use o albumin was associatedwith signicant reduction in paracentesis-induced circula-tory dysunction (OR . % CI ..). No signicantdifference was observed or the risk o any other outcomeswith and without albumin use. Tere was a nonsignicanttrend towards reduction in hyponatraemia, paracentesis-induced circulatory dysunction, readmission, and renalimpairment.

.. Is Albumin Better Tan Other Volume Expanders in Para-centesis? Eight studies evaluatedthe use o volume expanderscompared to albumin [, ,, , , , , ]. None


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: reatment groups, ollowup, and results.

Study Albumin group Control group Duration o ollowup Results

Abdel-Khalek andAri []

Paracentesis and IV %albumin g/L o ascitic uidremoved.

Paracentesis andhydroxyethyl starch%.

Up to months.

Bacterial inection / versus /,death / versus /, encephalopathy/ versus /, GI bleeding /versus /, readmissions / versus

/.

Altman et al. []

Paracentesis and IV %albumin mL i


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: Continued.

Study Albumin group Control group Duration o ollowup Results

Sola-Vera et al. []

Paracentesis and IV %albumin g/L o ascitic uidremoved.

Paracentesis and mL o .%saline/L o ascitesremoved.

NA.

Death / versus /, hyponatraemia/ versus /, PICD / versus/, renal impairment / versus/.

Sort et al. []

IV ceotaxime g dosingbased on serum creatinineand % albumin . g/kgduring rst hours, then g/kg on day .

IV ceotaxime dosingbased on creatinine.

NA.

Death in hospital / versus /,death at three months / versus/, inection resolution /versus /, renal impairment /versus /.

Xue et al. []

IV cefriaxone plus IValbumin .. g/kg within hours o enrolment, thensame amount on rd day andevery days thereafer.

IV cefriaxone g/dayadjusted based onserum creatinine.

NA. Renal impairment / versus /,

deaths / versus /.

NA: not available.

o these studies compared the use o albumin versus othervolume expanders outside o the paracentesis context. Teuse o albumin resulted in no signicant advantage in risko death, encephalopathy, hyponatraemia, gastrointestinalbleeding, readmission, renal impairment, and sepsis/severeinection.

.. Is Albumin Useful in Infections/Sepsis?Five studies wereincluded in the analysis o albumin use in sepsis. wo studies[,] included participants with non-SBP inection whilethree studies included participants with SBP [,,]. In thecontext o any inection, the use o albumin was associated

with reduced risk o death OR . % CI ..,2

= 24% and renal impairment OR . % CI .., 2 = 34%. Tere was a nonsignicant trend towardsinection resolution and increased risk o hyponatraemia.Subgroup analysis considering SBP showed that the albuminuse was associated with reduced risk o death. No signicantdifference was observed or non-SBP inection (able). Tepooled results o the risk evaluations are shown in Figure and able.

4. Discussion

Our results suggest that albumin has a value in the treatment

o cirrhotic patients in the contexts o large volume para-centesis and inections. Tere is no signicant advantage oalbumin compared to other plasma expanders or paracente-sis. In paracentesis, albumin reduces the risk o paracentesis-induced circulatory dysunction. In cases o cirrhotic patientswith inections, death and renal impairment can be reducedwith the use o albumin. Tereore, cirrhotic patients at highrisk o circulatory dysunction during paracentesis shouldreceive albumin or an alternative plasma expander, andcirrhotic patients with sepsis or inection at high risk o renalimpairment or death should receive albumin.

Broadly, our ndings support the AASLD and EASLrecommendations or the management o large volume

paracentesis [, ]. Te use o other plasma expanders isnot supported as there is insufficient evidence according tothe guidelines. While albumin may cost more than plasmaexpanders, the use o albumin is justied as there is evidencethat there are ewer -day liver related events among thepatients treated with albumin []. Both guidelines supportthe use o albumin in spontaneous bacterial peritonitis [,]but there are currently no guidelines or non-SBP inections.

Tere are a number o potential explanationsor our nd-ings. Human albumin is a major plasma protein and acts asan intravascular volume expander. It is produced in the liverand its concentration is reduced with hepatic dysunction.It is responsible or % o the colloid osmotic pressure o

plasma; thereore, the intravenous administration o albuminis associated with a rapid increase in the circulating blood

volume. In the context o inection and sepsis, the acuteinammatory response has a vasodilatory effect. Tis leadsto circulatory collapse which is compounded by a lack oalbumin to maintain oncotic pressure in the intravascularcompartment. In addition, it has other physiological unc-tions such as transport o water insoluble endogenous andexogenous substances such as anti-inammatory mediators,hormones, and antibiotics in sepsis. It also acts as a circu-latory antioxidant which may prevent cellular injury romreactive oxygen species in sepsis and ischaemia.

Our review builds on the nding o the meta-analysis by

Bernardi et al. []. Similar to their ndings, we ound thatthe use o albumin reduces the risk o paracentesis-inducedcirculatory dysunction. However, we did not nd that therewasany signicant difference when albumin wascomparedtoother volume expanders. Teir study was limited to patientsreceiving paracentesis while our study also considers patientswith inection.

Our study has several advantages. All the studies includedwere prospective randomized trials. We were able to considercirrhotic patients in several different settings including thoserequiring paracentesis with tense ascites as well as those withSBP and non-SBP inection. In addition, we were able to con-sider a variety o outcomes including death, encephalopathy,


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Albumin No albuminStudy or subgroup

EventsWeight

TotalEventsTotal

1.1.1 Death

Choi 2002 3 21 2 19 6.1%

Guevara 2012 8 56 10 54 11.7%

Sort 1999 14 63 26 63 13.8%

Xue 2002 5 56 17 56 11.2%Subtotal (95% CI) 196 192 42.9%

Total events 30 55

Choi 2002 4 21 2 19 6.5%

Subtotal (95% CI) 21 19 6.5%

Total events 4 2

Heterogeneity: Not applicable

1.1.3 Inection resolution

Nazar 2009 55 56 50 54 4.9%

Sort 1999 62 63 59 63 5.0%

Subtotal (95% CI) 119 117 9.9%

Total events 117 109

1.1.4 Renal impairment

Choi 2002 3 21 1 19 4.5%

Guevara 2012 1 56 4 54 4.9%

Nazar 2009 3 56 4 54 8.0%

Sort 1999 6 63 21 63 12.0%

Xue 2002 5 56 19 56 11.3%

Subtotal (95% CI) 252 246 40.7%

Total events 18 49

Test or overall effect:Z = 2.46 (P = 0.01)




Heterogeneity: 2 = 0.00; 2 = 0.00, d= 1 (P = 0.98);I2 = 0%



Odds ratio Odds ratio

M-H, random, 95% CI M-H, random, 95% CI

1.42 [0.21, 9.55]

0.73 [0.27, 2.02]

0.41 [0.19, 0.88]

0.22 [0.08, 0.66]0.46 [0.25, 0.86]

2.00 [0.32, 12.41]

2.00 [0.32, 12.41]

4.40 [0.48, 40.70]

4.20 [0.46, 38.71]

4.30 [0.89, 20.70]

3.00 [0.28, 31.63]

0.23 [0.02, 2.10]

0.71 [0.15, 3.32]

0.21 [0.08, 0.57]

0.19 [0.07, 0.56]

0.34 [0.15, 0.75]

1.1.2 Hyponatraemia

0.01 0.1

Favours albumin

1 10 100

Favours no albumin

F : Albumin versus no albumin among cirrhotic patients with inections.

hyponatraemia, paracentesis-induced circulatory dysunc-tion, readmission renal impairment, gastrointestinal bleed,

inection resolution, and sepsis/severe inection.Tere are several limitations in this review. Te quality

o the studies is generally poor as blinding was not used.Furthermore, the sample size o the studies is small and onlya ew studies were included in each pooled analysis. Teduration o ollowup was also variable among the studies.

We would recommend three studies o albumin andplasma expanders which are in the context o paracentesis,non-SBP, and SBP inections. In addition to clinical outcomessuch as need or death, encephalopathy, hyponatraemia, GIbleeding, readmission, renal impairment, sepsis, and need orliver transplant, this study should urther consider the costimplications. Te most important o the possible studies is

that o albumin versus plasma expanders in inections (non-SBP and SBP) as these questions have not been answered.

In addition, a study o different doses o albumin could helpdetermine the dosing regimen that would lead to the bestclinical outcomes. We believe that the ideal trial would bean adequately powered multicentre double-blinded trial thathas ollowup o at least month and corrects or liver diseaseseverity.

5. Conclusions

In conclusion, the ndings o this meta-analysis support theuse o albumin or preventing paracentesis-induced circula-tory collapse and reducing the risk o death and renal ailurein cirrhotic patients with inections limited to SBP. More


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: Summary o results.

Outcome or subgroup Studies Participants Odds ratio (% condence interval)

Is albumin useful in paracentesis?

.. Death . (., .)

.. Encephalopathy . (., .)

.. Hyponatraemia . (., .).. Paracentesis-induced circulatory dysunction . (., .)

.. Readmission . (., .)

.. Renal impairment . (., .)

Is albumin better than other volume expander in paracentesis?

.. Death . (., .)

.. Encephalopathy . (., .)

.. Hyponatraemia . (., .)

.. Gastrointestinal bleeding . (., .)

.. Readmission . (., .)


.. Sepsis/severe inection . (., .)

Is albumin useful in infections overall?.. Death . (., .)

.. Hyponatraemia . (., .)

.. Inection resolution . (., .)


Is albumin useful in spontaneous bacterial peritonitis?

.. Death . (., .)



Is albumin useful in non-spontaneous bacterial peritonitis infections?

.. Death . (., .)



studies are needed to evaluate i albumin reduces adverseoutcomes among cirrhotic patients without paracentesis orinections. Tere is no evidence to support the use o albuminover other plasma expanders or paracentesis.

Conflict of Interests

Chun Shing Kwok, Lukasz Krupa, Ash Mahtani, DuncanKaye, Simon M. Rushbrook, Martin G. Phillips, and WilliamGelson have no conict o interests to declare. No undingwas received.

Authors Contribution

William Gelson conceptualised the review. Chun ShingKwok, Lukasz Krupa, and William Gelson developed theprotocol. Chun Shing Kwok, Duncan Kaye, and Ash Mahtaniabstracted the data. Chun Shing Kwok analysed the data. Allauthors were involved in writing the paper. William Gelsonwill act as the guarantor or the paper.

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