Reviewer's report
Title:A simple dummy liver assist device prolongs anhepatic survival in a
porcine model of total hepatectomy by slight hypothermia.
Version: 1Date:1 May 2011
Reviewer: NIKOLAOS ARKADOPOULOS
Reviewer's report:
This is an interesting report that addresses an old debate on the mechanisms by
which extracorporeal liver support systems derive their clinical benefit. In the
search for allternative explanations-other than the presumed primary action of
the device, e.g detoxification provided by hepatocyte bioreactors-, hypothermia,
as well as dilutional effects are among the usual suspects. In fact, the concept
that hypothermia by itself can prolong survival in experimental models of
fulminant hepatic failure (FHF) is probably 30 years old.1,2 Limited clinical data
appear to validate this concept in FHF patients as well. If this is the case, one
could wonder what is really original about the present manuscript. In my view, the
new finding is the fact that a significant survival benefit of almost 24 hours, was
achieved with a combination of plasma separation with very mild periodic
hypothermia of only 1-1,5ºC. Otherwise, this is an observational study, with no
investigation of posssible mechanisms and-as the authors themselves admit-
lack of appropriate control groups, e.g. a group that would undergo normothermic
plasma separation and a group that would be subjected to hypothermia only,
without plasma separation. These limitations of the study should be clearly stated
in the manuscript.
Major revisions
1.The authors state in their introduction that previous studies with liver support
devices may have not been appropriately controlled for hypothermia. Although
this may be true for some studies, they should also acknowledge that in
numerous other experiments heating of the animals has been very rigorously
controlled in order to eliminate the hypothermia factor. This is especiallly true in
systems that use heat-exchangers connected or not with ooxygenators.3,4 For
example, in our recently published study4, we maintained tight temperature
control by means of heating pads, blankets, warming of infused fluids and use of
the extracorporeal oxygenator/heat-exchannger.
2.In order to take into account a possible dilutional effect the authors need to
inform us on extracorporeal volume of their system, the amount of fluid
administered in each group, and indices of volume load (e.g central venous
pressure or pulmonary capillary wedge pressure if they used pulmonary artery
catheterization).
3.The authors state in their Discussion (page 11) that the course of laboratory
parameters such as ammonia, lactate and creatinine was not altered by the
cyclic application of the dummy device. However, their results show significantly
lower values for blood lactate, creatinine and arterial ammonia in the dummy
device group. To be consistent, the authors need to coorrect their discussion and
also include-based on the available literature-possible explanations for their
findings regarding ammonia and lactate.
4.The conclusions need to be rephrased. Since they do not have appropriate
control groups, they cannot state that “episodes of slight hypothermia alone
produced a significant survival benefit”. In fact it is the combination of three
12-hour long plasma separation sessions, combined with slight hypothermia that
produced the observed effect.
References
1.Bernuaau J, Peignooux M, Benhamou JP. Dehepatization and body
temperature in pigs. Surgery 1982; 91:607-608.
2.Traber P, Dal Canto M, Ganger D, Blei AT. Effect of body tempperature on
brain edema and encephalopathy in the rat after hepatic devascularization.
Gastroenterology 1989;96:885-891.
3.Sosef MN, Abrahamse LSL, van de KKerkhove MPP, Hartman R, Chamuleau
RAFM, van Gulik T. Assessment of the AMC-bioaartificial liver in the annhepatic
pig. Transplantation 2002;73:204-209.
4.Arkadopoulos N, Kostopanaagiotou G, Nastos C et al. Reversal of
experimental posthepatectomy liver failure in pigs:a new application for
hepatocyte bioreactors. Artificial Organs 2010;35:29-36.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
Reviewer's report
Title:A simple dummy liver assist device prolongs anhepatic survival in a
porcine model of total hepatectomy by slight hypothermia.
Version: 1Date:1 May 2011
Reviewer: NIKOLAOS ARKADOPOULOS
Reviewer's report:
This is an interesting report that addresses an old debate on the mechanisms by
which extracorporeal liver support systems derive their clinical benefit. In the
search for allternative explanations-other than the presumed primary action of
the device, e.g detoxification provided by hepatocyte bioreactors-, hypothermia,
as well as dilutional effects are among the usual suspects. In fact, the concept
that hypothermia by itself can prolong survival in experimental models of
fulminant hepatic failure (FHF) is probably 30 years old.1,2 Limited clinical data
appear to validate this concept in FHF patients as well. If this is the case, one
could wonder what is really original about the present manuscript. In my view, the
new finding is the fact that a significant survival benefit of almost 24 hours, was
achieved with a combination of plasma separation with very mild periodic
hypothermia of only 1-1,5ºC. Otherwise, this is an observational study, with no
investigation of posssible mechanisms and-as the authors themselves admit-
lack of appropriate control groups, e.g. a group that would undergo normothermic
plasma separation and a group that would be subjected to hypothermia only,
without plasma separation. These limitations of the study should be clearly stated
in the manuscript.
Major revisions
1.The authors state in their introduction that previous studies with liver support
devices may have not been appropriately controlled for hypothermia. Although
this may be true for some studies, they should also acknowledge that in
numerous other experiments heating of the animals has been very rigorously
controlled in order to eliminate the hypothermia factor. This is especiallly true in
systems that use heat-exchangers connected or not with ooxygenators.3,4 For
example, in our recently published study4, we maintained tight temperature
control by means of heating pads, blankets, warming of infused fluids and use of
the extracorporeal oxygenator/heat-exchannger.
2.In order to take into account a possible dilutional effect the authors need to
inform us on extracorporeal volume of their system, the amount of fluid
administered in each group, and indices of volume load (e.g central venous
pressure or pulmonary capillary wedge pressure if they used pulmonary artery
catheterization).
3.The authors state in their Discussion (page 11) that the course of laboratory
parameters such as ammonia, lactate and creatinine was not altered by the
cyclic application of the dummy device. However, their results show significantly
lower values for blood lactate, creatinine and arterial ammonia in the dummy
device group. To be consistent, the authors need to coorrect their discussion and
also include-based on the available literature-possible explanations for their
findings regarding ammonia and lactate.
4.The conclusions need to be rephrased. Since they do not have appropriate
control groups, they cannot state that “episodes of slight hypothermia alone
produced a significant survival benefit”. In fact it is the combination of three
12-hour long plasma separation sessions, combined with slight hypothermia that
produced the observed effect.
References
1.Bernuaau J, Peignooux M, Benhamou JP. Dehepatization and body
temperature in pigs. Surgery 1982; 91:607-608.
2.Traber P, Dal Canto M, Ganger D, Blei AT. Effect of body tempperature on
brain edema and encephalopathy in the rat after hepatic devascularization.
Gastroenterology 1989;96:885-891.
3.Sosef MN, Abrahamse LSL, van de KKerkhove MPP, Hartman R, Chamuleau
RAFM, van Gulik T. Assessment of the AMC-bioaartificial liver in the annhepatic
pig. Transplantation 2002;73:204-209.
4.Arkadopoulos N, Kostopanaagiotou G, Nastos C et al. Reversal of
experimental posthepatectomy liver failure in pigs:a new application for
hepatocyte bioreactors. Artificial Organs 2010;35:29-36.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
Please review this paper.
user
Reviewer's report
Title:A simple dummy liver assist device prolongs anhepatic survival in a
porcine model of total hepatectomy by slight hypothermia.
Version: 1Date:1 May 2011
Reviewer: NIKOLAOS ARKADOPOULOS
Reviewer's report:
This is an interesting report that addresses an old debate on the mechanisms by
which extracorporeal liver support systems derive their clinical benefit. In the
search for allternative explanations-other than the presumed primary action of
the device, e.g detoxification provided by hepatocyte bioreactors-, hypothermia,
as well as dilutional effects are among the usual suspects. In fact, the concept
that hypothermia by itself can prolong survival in experimental models of
fulminant hepatic failure (FHF) is probably 30 years old.1,2 Limited clinical data
appear to validate this concept in FHF patients as well. If this is the case, one
could wonder what is really original about the present manuscript. In my view, the
new finding is the fact that a significant survival benefit of almost 24 hours, was
achieved with a combination of plasma separation with very mild periodic
hypothermia of only 1-1,5ºC. Otherwise, this is an observational study, with no
investigation of posssible mechanisms and-as the authors themselves admit-
lack of appropriate control groups, e.g. a group that would undergo normothermic
plasma separation and a group that would be subjected to hypothermia only,
without plasma separation. These limitations of the study should be clearly stated
in the manuscript.
Major revisions
1.The authors state in their introduction that previous studies with liver support
devices may have not been appropriately controlled for hypothermia. Although
this may be true for some studies, they should also acknowledge that in
numerous other experiments heating of the animals has been very rigorously
controlled in order to eliminate the hypothermia factor. This is especiallly true in
systems that use heat-exchangers connected or not with ooxygenators.3,4 For
example, in our recently published study4, we maintained tight temperature
control by means of heating pads, blankets, warming of infused fluids and use of
the extracorporeal oxygenator/heat-exchannger.
2.In order to take into account a possible dilutional effect the authors need to
inform us on extracorporeal volume of their system, the amount of fluid
administered in each group, and indices of volume load (e.g central venous
pressure or pulmonary capillary wedge pressure if they used pulmonary artery
catheterization).
3.The authors state in their Discussion (page 11) that the course of laboratory
parameters such as ammonia, lactate and creatinine was not altered by the
cyclic application of the dummy device. However, their results show significantly
lower values for blood lactate, creatinine and arterial ammonia in the dummy
device group. To be consistent, the authors need to coorrect their discussion and
also include-based on the available literature-possible explanations for their
findings regarding ammonia and lactate.
4.The conclusions need to be rephrased. Since they do not have appropriate
control groups, they cannot state that “episodes of slight hypothermia alone
produced a significant survival benefit”. In fact it is the combination of three
12-hour long plasma separation sessions, combined with slight hypothermia that
produced the observed effect.
References
1.Bernuaau J, Peignooux M, Benhamou JP. Dehepatization and body
temperature in pigs. Surgery 1982; 91:607-608.
2.Traber P, Dal Canto M, Ganger D, Blei AT. Effect of body tempperature on
brain edema and encephalopathy in the rat after hepatic devascularization.
Gastroenterology 1989;96:885-891.
3.Sosef MN, Abrahamse LSL, van de KKerkhove MPP, Hartman R, Chamuleau
RAFM, van Gulik T. Assessment of the AMC-bioaartificial liver in the annhepatic
pig. Transplantation 2002;73:204-209.
4.Arkadopoulos N, Kostopanaagiotou G, Nastos C et al. Reversal of
experimental posthepatectomy liver failure in pigs:a new application for
hepatocyte bioreactors. Artificial Organs 2010;35:29-36.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests
assistant