Reviewer's report
Title:Development of an invasively monitored porcine model of
acetaminophen-induced acute liver failure
Version: 1Date:3 February 2010
Reviewer: Humphrey Hodgson
Reviewer's report:
This study contains worthwhile data, which should help other researchers
intending to develop a large animal model for acute liver failure. It has some
important messages, but there are also some significant omissions and areas of
discussion need attention.
A key approach in this porcine model was to monitor acetaminophen levels and
thus (more-or-less) avoid methaemoglobinaemia (an event which if it occurs
confounds comparison with human acetaminophen toxicity acute liver failure
problem).
An important omission in the clinical detail is an account of the anaesthetic
strategy used to maintain the animals. In particular what fluids were infused? The
increased pulmonary resistance and dyspnoea observed in many of the pigs
would be unsurprising if these hypoproteinaemic animals received large volumes
of saline and died of pulmonary oedema. (Incidentally fig 4 appears to be
mislabelled as the rising pulmonary pressure terminally is seen in the control
group). The authors speculate on the nature of the lung pathophysiology, but
provide no histological evidence.
The authors maintain that these animals developed encephalopathy on the basis
of a reversal of Fisher’s ratio. Whiles this ratio is correlated with the development
of encephalopathy in some studies, it is certainly not evidence of
encephalopathy. This short-coming should be at least discussed.
There was a failure to develop increased intracranial pressure in this model
which is a significant deviation from human analogue. Many other models of
acute liver failure in pigs e.g. ischaemic, do achieve this within this time frame.
This discrepancy should be discussed further.
The authors state that this model would be useful for the assessment of artificial
liver devices, but they should discuss this further. Although ‘reproducible’ the
survival of the animals varied enormously from 8 - >28hrs, and a significant
number of animals with euthanased. The criteria for ‘death under anaesthesia’
are not defined. In view of this group’s experience it would be very helpful for
them to address this issue – would they aim to improve survival – and if so how
would they measure survival – or do they have another criterion for failure or for
parameters to be improved.
These are immensely complicated as well as costly experiments to do; although
there are obvious short-comings as outlined, it would be unreasonable to ask the
group to reassemble (many of them no longer work in the initial centre) to do
further experimental work, however, the discussion could usefully address the
issues raised.
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:Development of an invasively monitored porcine model of
acetaminophen-induced acute liver failure
Version: 1Date:3 February 2010
Reviewer: Humphrey Hodgson
Reviewer's report:
This study contains worthwhile data, which should help other researchers
intending to develop a large animal model for acute liver failure. It has some
important messages, but there are also some significant omissions and areas of
discussion need attention.
A key approach in this porcine model was to monitor acetaminophen levels and
thus (more-or-less) avoid methaemoglobinaemia (an event which if it occurs
confounds comparison with human acetaminophen toxicity acute liver failure
problem).
An important omission in the clinical detail is an account of the anaesthetic
strategy used to maintain the animals. In particular what fluids were infused? The
increased pulmonary resistance and dyspnoea observed in many of the pigs
would be unsurprising if these hypoproteinaemic animals received large volumes
of saline and died of pulmonary oedema. (Incidentally fig 4 appears to be
mislabelled as the rising pulmonary pressure terminally is seen in the control
group). The authors speculate on the nature of the lung pathophysiology, but
provide no histological evidence.
The authors maintain that these animals developed encephalopathy on the basis
of a reversal of Fisher’s ratio. Whiles this ratio is correlated with the development
of encephalopathy in some studies, it is certainly not evidence of
encephalopathy. This short-coming should be at least discussed.
There was a failure to develop increased intracranial pressure in this model
which is a significant deviation from human analogue. Many other models of
acute liver failure in pigs e.g. ischaemic, do achieve this within this time frame.
This discrepancy should be discussed further.
The authors state that this model would be useful for the assessment of artificial
liver devices, but they should discuss this further. Although ‘reproducible’ the
survival of the animals varied enormously from 8 - >28hrs, and a significant
number of animals with euthanased. The criteria for ‘death under anaesthesia’
are not defined. In view of this group’s experience it would be very helpful for
them to address this issue – would they aim to improve survival – and if so how
would they measure survival – or do they have another criterion for failure or for
parameters to be improved.
These are immensely complicated as well as costly experiments to do; although
there are obvious short-comings as outlined, it would be unreasonable to ask the
group to reassemble (many of them no longer work in the initial centre) to do
further experimental work, however, the discussion could usefully address the
issues raised.
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:Development of an invasively monitored porcine model of
acetaminophen-induced acute liver failure
Version: 1Date:3 February 2010
Reviewer: Humphrey Hodgson
Reviewer's report:
This study contains worthwhile data, which should help other researchers
intending to develop a large animal model for acute liver failure. It has some
important messages, but there are also some significant omissions and areas of
discussion need attention.
A key approach in this porcine model was to monitor acetaminophen levels and
thus (more-or-less) avoid methaemoglobinaemia (an event which if it occurs
confounds comparison with human acetaminophen toxicity acute liver failure
problem).
An important omission in the clinical detail is an account of the anaesthetic
strategy used to maintain the animals. In particular what fluids were infused? The
increased pulmonary resistance and dyspnoea observed in many of the pigs
would be unsurprising if these hypoproteinaemic animals received large volumes
of saline and died of pulmonary oedema. (Incidentally fig 4 appears to be
mislabelled as the rising pulmonary pressure terminally is seen in the control
group). The authors speculate on the nature of the lung pathophysiology, but
provide no histological evidence.
The authors maintain that these animals developed encephalopathy on the basis
of a reversal of Fisher’s ratio. Whiles this ratio is correlated with the development
of encephalopathy in some studies, it is certainly not evidence of
encephalopathy. This short-coming should be at least discussed.
There was a failure to develop increased intracranial pressure in this model
which is a significant deviation from human analogue. Many other models of
acute liver failure in pigs e.g. ischaemic, do achieve this within this time frame.
This discrepancy should be discussed further.
The authors state that this model would be useful for the assessment of artificial
liver devices, but they should discuss this further. Although ‘reproducible’ the
survival of the animals varied enormously from 8 - >28hrs, and a significant
number of animals with euthanased. The criteria for ‘death under anaesthesia’
are not defined. In view of this group’s experience it would be very helpful for
them to address this issue – would they aim to improve survival – and if so how
would they measure survival – or do they have another criterion for failure or for
parameters to be improved.
These are immensely complicated as well as costly experiments to do; although
there are obvious short-comings as outlined, it would be unreasonable to ask the
group to reassemble (many of them no longer work in the initial centre) to do
further experimental work, however, the discussion could usefully address the
issues raised.
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'
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