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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2016, Vol. 10 Issue (4) : 451-464     DOI: 10.1007/s11684-016-0474-7
RESEARCH ARTICLE |
Machine perfusion versus cold storage of livers: a meta-analysis
Sushun Liu,Qing Pang,Jingyao Zhang,Mimi Zhai,Sinan Liu,Chang Liu()
Department of Hepatobiliary Surgery, The First Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an 710061, China
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Abstract  

Different organ preservation methods are key factors influencing the results of liver transplantation. In this study, the outcomes of experimental models receiving donation after cardiac death (DCD) livers preserved through machine perfusion (MP) or static cold storage (CS) were compared by conducting a meta-analysis. Standardized mean difference (SMD) and 95% confidence interval (CI) were calculated to compare pooled data from two animal species. Twenty-four studies involving MP preservation were included in the meta-analysis. Compared with CS preservation, MP can reduce the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and hyaluronic acid (HA) and the changes in liver weight. By contrast, MP can enhance bile production and portal vein flow (PVF). Alkaline phosphatase (ALP) levels and histological changes significantly differed between the two preservation methods. In conclusion, MP of DCD livers is superior to CS in experimental animals.

Keywords machine perfusion      cold storage      DCD      meta-analysis     
Corresponding Authors: Chang Liu   
Just Accepted Date: 08 October 2016   Online First Date: 14 November 2016    Issue Date: 01 December 2016
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-016-0474-7     OR     http://academic.hep.com.cn/fmd/EN/Y2016/V10/I4/451
Author (year) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Quality score
Iwamoto et al. [16]
(2000)
+ + + + + + + + 8
Imber et al. [17]
(2002)
+ + + + + + + + + + + 11
Peter et al. [18]
(2002)
+ + + + + + + + 8
Jain et al. [19]
(2004)
+ + + + + + + 7
Guarrera et al. [20]
(2004)
+ + + + + + + + + + + + + + 14
Bessems et al. [21]
(2006)
+ + + + + + + + + + + + 12
Vekemans et al. [22]
(2007)
+ + + + + + + + + + + + + 13
Monbaliu et al. [23]
(2011)
+ + + + + + + + + + + + 12
Fondevila et al. [24]
(2012)
+ + + + + + + + + + + + 12
Nassar et al. [25]
(2014)
+ + + + + + + + + + + + + 13
Dries et al. [26]
(2014)
+ + + + + + + + + + + + + + 14
Lee et al. [27]
(2002)
+ + + + + + + + + 9
Charles et al. [28]
(2003)
+ + + + + + + 7
Xu et al. [29]
(2004)
+ + + + + + + + + 9
Bessems et al. [30]
(2005)
+ + + + + + + + + + + + + 13
Bessems et al. [31]
(2007)
+ + + + + + + + + 9
Vairetti et al [32]
(2007)
+ + + + + + + + + 9
Vairetti et al. [33]
(2008)
+ + + + + + + + + + 10
Ferrigno et al. [34]
(2009)
+ + + + + + + + + 9
Vairetti et al. [35]
(2009)
+ + + + + + + + + + 10
Olschewski et al. [36]
(2010)
+ + + + + + + + + 9
Boncompagni et al. [37]
(2011)
+ + + + + + + + + 9
Ferrigno et al. [38]
(2011)
+ + + + + + + + + + + 11
Carnevale et al. [39]
(2013)
+ + + + + + + + + + + + + 13
Tab.1  Study quality based on ARRIVE guidelines
Author (year) 1 2 3 4 5 6 7 Quality score
Iwamoto et al. [16]
(2000)
+ + 2
Imber et al. [17]
(2002)
+ + + 3
Peter et al. [18]
(2002)
+ + 2
Jain et al. [19]
(2004)
+ + 2
Guarrera et al. [20]
(2004)
+ + + 3
Bessems et al. [21]
(2006)
+ + + 3
Vekemans et al. [22]
(2007)
+ + + 4
Monbaliu et al. [23]
(2011)
+ + + 3
Fondevila et al. [24]
(2012)
+ + + 3
Nassar et al. [25]
(2014)
+ + + 3
Dries et al. [26]
(2014)
+ + + + + 5
Lee et al. [27]
(2002)
+ + + 3
Charles et al. [28]
(2003)
+ + + + 4
Xu et al. [29]
(2004)
+ + 2
Bessems et al. [30]
(2005)
+ + + 3
Bessems et al. [31]
(2007)
+ + + 3
Vairetti et al. [32]
(2007)
+ + 2
Vairetti et al. [33]
(2008)
+ + 2
Ferrigno et al. [34]
(2009)
+ + 2
Vairetti et al. [35]
(2009)
+ + 2
Olschewski et al. [36]
(2010)
+ 1
Boncompagni et al. [37]
(2011)
+ + 2
Ferrigno et al. [38]
(2011)
+ + + 3
Carnevale et al. [39]
(2013)
+ + + 3
Tab.2  Study quality report
Fig.1  Search criteria and studies selected for analysis. One search based on the search strategies initially identified 111 articles. After screening based on the inclusion and exclusion criteria, 24 studies involving MP preservation in two species (rats and pigs) were finally included in this meta-analysis.
Fig.2  Effect of MP vs. CS preservation on hepatocellular injury in DCD livers by using all available studies for comparison. (A) ALT. MP reduced the release of ALT, and the SMD of ALT was -2.22 units (95% CI, -3.01 to -1.43). (B) AST. MP reduced the level of AST, and the SMD was -1.56 units (95% CI, -2.02 to -1.11). (C) LDH. MP reduced the release of LDH, and the SMD was -1.71 units (95% CI, -2.58 to -0.84).
References Species Number
of CS
Time
of CS
Number
of MP
Time
of MP
Pressure of MP Outcomes
Iwamoto et al. [16]
(2000)
Pig 4 2 8 2 Not reported AST, LDH, HA, weight change of liver, fraction surviving
Imber et al. [17]
(2002)
Pig 5 24 5 24 Not reported ALT, ALP, bile production, histological changes, GGT, blood glucose, galactose elimination capacity, factor V, oxygen consumption, hemolysis
Peter et al. [18]
(2002)
Pig 4 24 4 24 Not reported ALT, bile production, PVF, blood glucose
Jain et al. [19]
(2004)
Pig 4 24 4 24 30 mmHg (hepatic artery)
10?12 mmHg (portal vein)
ALT, bile production, canaliculus secretion of ICG, oxygen consumption
Guarrera et al. [20]
(2004)
Pig 3 12 3 12 Not reported AST, total bilirubin
Bessems et al. [21]
(2006)
Pig 5 24 5 24 Not reported ALT, AST, LDH, weight change of liver, perfusate pH,intravascular resistance, ammonia clearance
Vekemans et al. [22]
(2007)
Pig 5 24 10 24 Not reported Histological changes, ATP
Monbaliu et al. [23]
(2011)
Pig 6 4 8 4 30 mmHg (hepatic artery)
7 mmHg (portal vein)
AST, LDH, HA, PNF, recipient survival, pH, lactate,
b-galactosidase, TNF-a
Fondevila et al. [24]
(2012)
Pig 6 4 5 4 30/20 mmHg(hepatic artery)
4 mmHg (portal vein)
AST, histological changes, HAF, pH, PO2, Na+ , K+ , bilirubin, bile salt, quick prothrombin time, IL-6 mRNA, IL-6, TNF mRNA, TNF, Survival
Nassar et al. [25]
(2014)
Pig 5 10 15 10 Not reported ALT, AST, LDH, ALP, bile production, PVF, weight change of liver, histological change
Dries et al. [26]
(2014)
Pig 9 4 9 4 30 mmHg (hepatic artery)
5 mmHg (portal vein)
AST, LDH, bile production, PVF, weight change of liver, histological changes, HAF, ATP, oxygenation, bile salt, phospholipid, BSEP, GGT, TBARS
Lee et al. [27]
(2002)
Rat Not reported 10 Not reported 10 Not reported LDH, bile production, PVF, histological changes, ICG secretion, intravital microscopy, wet/dry weight ratio
Charles et al. [28]
(2003)
Rat 7 5 6 5 Not reported ALT, LDH, histological changes, bilirubin, perfusate flow, survival
Xu et al. [29]
(2004)
Rat 6 24 7 24 Not reported LDH, bile production, HA, histological changes, ICG uptake, wet/dry weight
Bessems et al. [30]
(2005)
Rat 6 24 10 24 15 mmHg ALT, AST, bile production, PVF, histological changes, ATP, oxygen consumption, ammonia clearance, urea production, perfusate flow, dry/wet weight
Bessems et al. [31]
(2007)
Rat 7 24 7 24 16 mmHg AST, LDH, bile production, PVF, histological changes, ATP, α-GST, perfusate flow, dry/wet weight, triglyceride, ammonta clearance, urea production, oxygen consumption
Vairetti et al. [32]
(2007)
Rat 6 6 6 6 Not reported ALT, AST, LDH, GGT, ATP
Vairetti et al. [33]
(2008)
Rat Not reported 6 Not reported 6 Not reported AST, LDH, bile production, histological changes, ATP
Ferrigno et al. [34]
(2009)
Rat Not reported 6 Not reported 6 Not reported AST, LDH, bile production, PVF, histological changes, Nox level, ATP
Vairetti et al. [35]
(2009)
Rat Not reported Not reported Not reported 6 Not reported AST, LDH, bile production, histological changes, ATP/ADP ratio, Caps-3, NOx, GGT, TNF-a
Olschewski et al. [36]
(2010)
Rat Not reported 6 Not reported 6 Not reported ALT, LDH, bile production, portal venous resistance(PVR), oxygen consumption, endothelia damage
Boncompagni et al. [37]
(2011)
Rat 5 6 5 6 Not reported Histological changes, Caps-3, M30 antigen, Tunel,
perfusate flow
Ferrigno et al. [38]
(2011)
Rat 5 6 5 6 6–7 mmHg ALT, AST, LDH, ALP, histological changes, GGT, ATP, glutamate dehydrogenase enzyme, glycogen store
Carnevale et al. [39]
(2013)
rat 5 24 5 24 40 mmH2O AST, bile production, PVF, histological changes, intrahepatic resistance, oxygen consumption, glycogen content
Tab.3  Characteristics of the included studies
Fig.3  Effect of MP vs. CS preservation on biliary epithelial and sinusoidal endothelial injury in DCD livers by using all available studies for comparison. (A) ALP. The SMD of ALP was -0.17 units (95% CI, -0.96 to 0.61), and no statistically significant difference existed. (B) Bile production. MP increased bile production by a standardized mean (95% CI) difference of 1.10 (0.01 to 2.18) units. (C) HA. MP preservation experienced a lower HA level, and the SMD was -1.92 units (95% CI,-3.01 to -0.82).
Fig.4  Effect of MP vs. CS preservation on hemodynamics. The PVF increased in the MP group compared with the CS group by a standardized mean (95% CI) difference of 1.38 (0.38 to 2.38) units.
Fig.5  Effect of MP vs. CS preservation on general and histologic changes in DCD livers by using all available studies for comparison. (A) Weight change of liver. The SMD of weight change in liver was -1.74 units (95% CI, -3.23 to -0.24) (B) Histologic changes. The SMD was -1.04 units (95% CI, -3.13 to 1.04). No significant difference existed between the two preservation methods with regard to histologic changes.
Fig.6  Funnel plots of all experiments. A funnel plot is a scatterplot used as a visual aid to assess publication bias. The P value of Begg’s test was calculated, and P<0.05 is considered to represent statistically significant publication bias. (A) ALT (P = 0.057), (B) AST (0.177), (C) LDH (P = 0.052), (D) ALP (P = 1.00), (E) Bile production (P = 0.976), (F) HA (P = 0.930), (G) PVF (P = 0.090), (H) Weight change of liver (P = 0.465), (I) Histologic changes (P = 0.498). No evidence of publication bias was found in the selected indicators used to evaluate MP preservation.
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