Title: The Efficacy and Safety of Itopride in Feeding Intolerance of Critically ill Patients
Receiving Enteral Nutrition: A Randomized, Double-Blind study.
Version: 1 Date: 31 Dec 2020
Reviewer's report:
• Methodology comments
• There is the misuse of the word diet and meals throughout. If these patients are intubated I’m
assuming you are referring to enteral nutrition. This term should be used consistently
• 250mls is used as GRV cut off. Why was 500mls not used as per current international practice
and recommendations?
• Confusion throughout the methods sections in terms of the methods used for GRV’s. It is not
clear if all measures are done by gastric ultrasound or only one the patient is included in the study
• Inclusion – GRV’s > 250mls- one would assume this is done by the nurses at the bedside using
a syringe ? This needs to be clearer
• Interventions
• Was the intervention blinded? If not state why not and include in the study limitations
• Were the drugs given IV or via the enteral route? This is fundamental to be stated. If not IV
need to justify why not (as this is a per the ESPEN guidelines / current literature)
• States the drugs were given three times a day before meals. As previously mentioned patients
wouldn’t be eating. Need more details
• Therapy failure was 2 or more high GRV’s – how were these measures- USS or bedside
aspiration?
• Feeding protocol – lacks important details. Were commercial feeds not used? I’m not sure what
the ‘hospital blended enteral formula’ was. Was this food or commercial sterile enteral feed?
This will make a difference to the generalizability of the findings and also GI tolerance.
• Need to know the volumes of feed patients were provided with and also the calories and protein
• Was the enteral feeding given continuously via a pump or via a bolus syringed? Again
necessary to know. Route will influence GI tolerance and also the generalizability of results as
the majority of international ICU patients are fed continuously via a pump
• Primary outcome – using USS to measure GRV’s is not a standard technique used in clinical
practice. There needs to be more discussion over why this methods was utilized and its
advantages / disadvantages over bedside GRV aspirations.  Reference 28 used to support the
statement that radiological assessment of gastric emptying is widely used, doesn’t use gastic
USS.
• GRV data were collected at 3 time points- baseline, midpoint and at the end – I would like to
see the actual timelines for this. I.e were all measures done at the same time for each participant
i.e. day 1, 5, 7?
• How was GI tolerance determined on the days that USS measures weren’t undertaken. If a
different method was used, why use 2 different methods in the study?
• Secondary outcomes – Need to know the volumes, kcals and protein targets and what was
delivered
Results / discussions
• The intervention is statistically significant but is the reduction from 145 to 102 mls really
clinically meaningful?
• Table 3 – it would be useful to know the calorie and protein targets and what was delivered
• The % delivery is very high in both groups > 80% of target volume before the intervention.
It is internationally known that the mean delivery is 50-60% of energy and protein targets for
ICU patients, so how have you managed to achieve 80% before intervention? Is this because
the targets are very low in the first place, therefore affecting the generalizability to the wider
community
• The majority of the discussion is focused around the side effects, which isn’t actually the
primary outcome. Need to include more about the points I’ve already raised above that are
missing
• There are many limitations to this study which haven’t been included and need to be e.g.
o Single centre
o Lack on details on enteral feeding methods
o The volume of GRV decreased but is this clinically meaningful
o Using gastric USS is not routinely used in clinical practice
o Both group ‘appear’ to be very well fed even before the intervention. This is not usual – why
is this ?
o Need a statement about the generalizability of the results
o I don’t think all the sources of bias have been identified and accounted for e.g. malnutrition,
age, cardiovascular support, sepsis, sedation, paralysis to name a few
o Many patient groups were excluded and these are the ones that commonly experience
problems.
Title: The Efficacy and Safety of Itopride in Feeding Intolerance of Critically ill Patients
Receiving Enteral Nutrition: A Randomized, Double-Blind study.
Version: 1 Date: 31 Dec 2020
Reviewer's report:
• Methodology comments
• There is the misuse of the word diet and meals throughout. If these patients are intubated I’m
assuming you are referring to enteral nutrition. This term should be used consistently
• 250mls is used as GRV cut off. Why was 500mls not used as per current international practice
and recommendations?
• Confusion throughout the methods sections in terms of the methods used for GRV’s. It is not
clear if all measures are done by gastric ultrasound or only one the patient is included in the study
• Inclusion – GRV’s > 250mls- one would assume this is done by the nurses at the bedside using
a syringe ? This needs to be clearer
• Interventions
• Was the intervention blinded? If not state why not and include in the study limitations
• Were the drugs given IV or via the enteral route? This is fundamental to be stated. If not IV
need to justify why not (as this is a per the ESPEN guidelines / current literature)
• States the drugs were given three times a day before meals. As previously mentioned patients
wouldn’t be eating. Need more details
• Therapy failure was 2 or more high GRV’s – how were these measures- USS or bedside
aspiration?
• Feeding protocol – lacks important details. Were commercial feeds not used? I’m not sure what
the ‘hospital blended enteral formula’ was. Was this food or commercial sterile enteral feed?
This will make a difference to the generalizability of the findings and also GI tolerance.
• Need to know the volumes of feed patients were provided with and also the calories and protein
• Was the enteral feeding given continuously via a pump or via a bolus syringed? Again
necessary to know. Route will influence GI tolerance and also the generalizability of results as
the majority of international ICU patients are fed continuously via a pump
• Primary outcome – using USS to measure GRV’s is not a standard technique used in clinical
practice. There needs to be more discussion over why this methods was utilized and its
advantages / disadvantages over bedside GRV aspirations.  Reference 28 used to support the
statement that radiological assessment of gastric emptying is widely used, doesn’t use gastic
USS.
• GRV data were collected at 3 time points- baseline, midpoint and at the end – I would like to
see the actual timelines for this. I.e were all measures done at the same time for each participant
i.e. day 1, 5, 7?
• How was GI tolerance determined on the days that USS measures weren’t undertaken. If a
different method was used, why use 2 different methods in the study?
• Secondary outcomes – Need to know the volumes, kcals and protein targets and what was
delivered
Results / discussions
• The intervention is statistically significant but is the reduction from 145 to 102 mls really
clinically meaningful?
• Table 3 – it would be useful to know the calorie and protein targets and what was delivered
• The % delivery is very high in both groups > 80% of target volume before the intervention.
It is internationally known that the mean delivery is 50-60% of energy and protein targets for
ICU patients, so how have you managed to achieve 80% before intervention? Is this because
the targets are very low in the first place, therefore affecting the generalizability to the wider
community
• The majority of the discussion is focused around the side effects, which isn’t actually the
primary outcome. Need to include more about the points I’ve already raised above that are
missing
• There are many limitations to this study which haven’t been included and need to be e.g.
o Single centre
o Lack on details on enteral feeding methods
o The volume of GRV decreased but is this clinically meaningful
o Using gastric USS is not routinely used in clinical practice
o Both group ‘appear’ to be very well fed even before the intervention. This is not usual – why
is this ?
o Need a statement about the generalizability of the results
o I don’t think all the sources of bias have been identified and accounted for e.g. malnutrition,
age, cardiovascular support, sepsis, sedation, paralysis to name a few
o Many patient groups were excluded and these are the ones that commonly experience
problems.
Please review this paper.
user
Title: The Efficacy and Safety of Itopride in Feeding Intolerance of Critically ill Patients
Receiving Enteral Nutrition: A Randomized, Double-Blind study.
Version: 1 Date: 31 Dec 2020
Reviewer's report:
• Methodology comments
• There is the misuse of the word diet and meals throughout. If these patients are intubated I’m
assuming you are referring to enteral nutrition. This term should be used consistently
• 250mls is used as GRV cut off. Why was 500mls not used as per current international practice
and recommendations?
• Confusion throughout the methods sections in terms of the methods used for GRV’s. It is not
clear if all measures are done by gastric ultrasound or only one the patient is included in the study
• Inclusion – GRV’s > 250mls- one would assume this is done by the nurses at the bedside using
a syringe ? This needs to be clearer
• Interventions
• Was the intervention blinded? If not state why not and include in the study limitations
• Were the drugs given IV or via the enteral route? This is fundamental to be stated. If not IV
need to justify why not (as this is a per the ESPEN guidelines / current literature)
• States the drugs were given three times a day before meals. As previously mentioned patients
wouldn’t be eating. Need more details
• Therapy failure was 2 or more high GRV’s – how were these measures- USS or bedside
aspiration?
• Feeding protocol – lacks important details. Were commercial feeds not used? I’m not sure what
the ‘hospital blended enteral formula’ was. Was this food or commercial sterile enteral feed?
This will make a difference to the generalizability of the findings and also GI tolerance.
• Need to know the volumes of feed patients were provided with and also the calories and protein
• Was the enteral feeding given continuously via a pump or via a bolus syringed? Again
necessary to know. Route will influence GI tolerance and also the generalizability of results as
the majority of international ICU patients are fed continuously via a pump
• Primary outcome – using USS to measure GRV’s is not a standard technique used in clinical
practice. There needs to be more discussion over why this methods was utilized and its
advantages / disadvantages over bedside GRV aspirations.  Reference 28 used to support the
statement that radiological assessment of gastric emptying is widely used, doesn’t use gastic
USS.
• GRV data were collected at 3 time points- baseline, midpoint and at the end – I would like to
see the actual timelines for this. I.e were all measures done at the same time for each participant
i.e. day 1, 5, 7?
• How was GI tolerance determined on the days that USS measures weren’t undertaken. If a
different method was used, why use 2 different methods in the study?
• Secondary outcomes – Need to know the volumes, kcals and protein targets and what was
delivered
Results / discussions
• The intervention is statistically significant but is the reduction from 145 to 102 mls really
clinically meaningful?
• Table 3 – it would be useful to know the calorie and protein targets and what was delivered
• The % delivery is very high in both groups > 80% of target volume before the intervention.
It is internationally known that the mean delivery is 50-60% of energy and protein targets for
ICU patients, so how have you managed to achieve 80% before intervention? Is this because
the targets are very low in the first place, therefore affecting the generalizability to the wider
community
• The majority of the discussion is focused around the side effects, which isn’t actually the
primary outcome. Need to include more about the points I’ve already raised above that are
missing
• There are many limitations to this study which haven’t been included and need to be e.g.
o Single centre
o Lack on details on enteral feeding methods
o The volume of GRV decreased but is this clinically meaningful
o Using gastric USS is not routinely used in clinical practice
o Both group ‘appear’ to be very well fed even before the intervention. This is not usual – why
is this ?
o Need a statement about the generalizability of the results
o I don’t think all the sources of bias have been identified and accounted for e.g. malnutrition,
age, cardiovascular support, sepsis, sedation, paralysis to name a few
o Many patient groups were excluded and these are the ones that commonly experience
problems.
assistant