PEER REVIEW HISTORY ... · study is meant to determine the optimum dose of local anesthesia for spinal anesthesia for caesarean delivery, this really isn’t the case. To determine

PEER REVIEW HISTORY

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ARTICLE DETAILS

TITLE (PROVISIONAL) A height based dosing algorithm of bupivacaine in spinal

anesthesia for decreasing maternal hypotension in caesarean

section without prophylactic fluid pre-loading and vasopressors:

study protocol for a randomized controlled non-inferiority trial

AUTHORS Huang, Bowan; Huang, Qiang; Hai, Chao; Zheng, Zihao; Li, Yali;

Zhang, Zhongjun

VERSION 1 - REVIEW

REVIEWER Albert Moore

Royal Victoria Hospital, Canada

REVIEW RETURNED 11-Jul-2018

GENERAL COMMENTS Thank you for giving me the opportunity to review this protocol, and provide my comments. Although the title and description of the protocol suggest that this study is meant to determine the optimum dose of local anesthesia for spinal anesthesia for caesarean delivery, this really isn’t the case. To determine the optimum dose, some type of dose finding study should be performed. The protocol as presented is really a comparison of two methods of dosing local anesthesia for spinal. The authors hypothesize that using a height based dosing algorithm without prophylactic vasopressor will not be inferior with regards to maternal hypotension when compared to a conventional dose spinal anesthetic that is combined with a prophylactic vasopressor infusion. The manuscript and protocol would be easier to understand and more impactful if the authors chose to alter their title and description to reflect the fact that this is a randomized controlled non-inferiority trial for a height based dosing algorithm. Although the authors suggest that the holy grail of spinal hypotension has not been found, this is somewhat controversial. The advent of vasopressor infusions has greatly decreased the rates of caesarean hypotension, and some believe that the holy grail has been found. Although there are risks with fluid and vasopressor therapies, the authors have perhaps inflated the perception of the risks of these treatments, which are used quite safely thousands of times a day throughout the world. The use of a height algorithm results in a dose reduction for patients. The use of dose limitation for caesarean hypotension has been studied extensively, and a meta-analysis of the so called “mini-dose” spinal anesthesia has been published, which demonstrates decrease maternal hypotension, but increased anesthesia failure with this technique. However, the use of a height based adjustment to dosage is novel, and could perhaps provide each patient with the dose that they actually require. For

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this reason, the study does have merit, although the authors may have difficulty convincing future reviewers that any treatment other than prophylactic vasopressors is justified in this population. The protocol as described does have a high possibility for the introduction of bias, and further elaboration of the protocol would be required to ensure that this risk is minimized, and to ensure that the results are truly due to the height based algorithm. To start with, the randomization, and allocation masking are poorly described. More detail about who will perform the randomization, and what sizes of blocks the patients will be randomized into would be helpful- is the randomization performed in blocks of 2, which is what is implied by 1:1 blocks. If this is true then it will be easy to guess what the next patient in the block will be randomized to. The masking of the allocation is not well described- how hard will it be to guess the assignment of the next patient? The next major issue is the difficulty in blinding of this study. There should be a much more explicit, step by step description of how blinding will be performed. Many of the outcomes are open to interpretation (eg quality of anesthesia), and there are treatments that can be altered slightly (eg degree of wedging) between groups, which could lead to bias if blinding is not strictly enforced. How will the patient, the treating anesthesiologist, the surgeon, and the person recording the observations not know which group the patient is in? There is also the risk for significant loss to followup, which could also lead to bias. The patients in the height based group will have a higher risk of requiring epidural top ups, which could increase their rates of hypotension. However, if these patients are not included in the analysis the rates of hypotension may be underestimated in this group. The authors do not state whether this will be analysed as intention to treat or per protocol, and this should be explicitly stated. Although there is justification for the sample size, it is missing some information, including the power (?0.8) and acceptance for type one error (?0.05) The cited reference may not apply to this study, due to both the Asian population, and different definitions of hypotension, and this should be considered. Although generally understandable, the manuscript would benefit from editing by a native English speaker. Specific comments: The citation used to support the statement that fluid loading leads to heart failure does not seem to discuss the link between fluid loading for spinal anesthesia and developing heart failure. The risk for developing heart failure is most likely extremely low from fluid administration fpr spinal anesthesia in healthy parturients, and this statement should be rephrased, or supported with a citation relevant to spinal anesthesia. “Therefore, avoiding prophylactic fluid pre-loading and vasopressors is important” This statement is perhaps too drastic. Avoiding these treatments is not important, they are used routinely thousands of times a day across the world. However, they do carry some slight risks.



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Should exclude pre-eclampsia patients as well. A step by step description of the randomization procedure and how it will be masked, and all blinding procedures should be provided. These are important parts of a study such as this, and need to be completely described when writing the final mansucript. Measuring the blood pressure in the operating room will give a falsely elevated initial blood pressure, due to the anxiety/stress. A more representative blood pressure would probably be measured outside the operating room. The intervention itself may need some more technical description. Specifically, the difference between doses in the height based group is 0.05 ml. Most syringes have markings for 0.1 or 0.2 ml, making the measurement of 0.05ml quite difficult. Can the authors be more explicit in how they will ensure that each patient receives exactly the assigned dose. In addition, the presence of fluid or air in the epidural space can affect spinal blockade. The authors should describe how they will control for this. The fluid management should be more fully described- at what rate will the fluid be administered before the spinal, and at what rate after. If the authors are not using pumps to ensure consistent infusion rates and volumes, they should state this. In addition, the fasting status of the patient should be considered. Sample size: the definition of hypotension in this protocol (70% of baseline or SBP less than 90 mmHg) differs from that of the cited article, (only if SBP less than 90mmHg). This may affect the power of the study. Also, the cited study involves a European population, which may have a very different rate of hypotension than the population in this study. Also, the authors use uncited evidence from their own practice, which is unverifiable. The method used to measure block height should be more adequately supported. Are the authors able to provide a reference that supports their contention that hypoalgesia is superior to other methods of blockade measurement. Certainly in this reviewer’s experience the loss of sensation to ice is the method least sensitive to observer bias- the sensation does not depend on the amount of pressure applied, or the amount of alchohol that evaporates for alcohol cold sensation. Protocol amendments should be reviewed by the ethics committee, as they could have ethical implications.

REVIEWER Karim Nasseri

Associate Professor, Department of Anesthesiology, Kurdistan

University of Medical Siences.

REVIEW RETURNED 28-Jul-2018

GENERAL COMMENTS Bowan et al. designed a study protocol about optimal dose of bupivacaine in spinal anesthesia for caesarean section .They believe that the optimal dose of local anesthetics in spinal anesthesia is unclear, while there are already



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a lot of studies similar to the current designed research(1-2). So, it seems that originality of this study is weak. Authors of this protocol did not clearly describe the rationale of the dose selection for bupivacaine (1.8 ml) as standard dose. It is not clear that, the patients remain fasted during preoperative period or not? If yes , for what time? In "Strengths and limitations of this study" authors mentioned that study will be carried out without prophylactic fluid pre-loading but in intervention they used 1000 ml fluid , what is the name of this fluid(pre-load or maintenance)? Method: Authors should specify size and type of epidural needle. Also , it isn't clear that spinal needle introduced trough epidural needle or separately via another space . if needle through needle will be used spinal 25G is a thick needle and local anesthetic may be distribute from epidural to spinal space via spinal hole. They mentioned that" Immediately after the intrathecal injection, the infusion of Ringer’s lactate will be increased to the maximum rate" , without specifying target and maximum rate should be . is not clear. After delivery Choice of drug used for contraction of uterus during surgery may affect BP and HR , So author should consider the drug used for this purpose as a variable ,and be aware that these drugs could be a sours of bias. Is 15 ml target total volume for epidural anesthesia enough for all patients? In case of failure to reach to T8 sensory block during procedure, what do you do? Is T8 an Ideal sensory level for C-section ? It seems that T4/5 is a recommended level, though T8 is the lowest required level (4). Ousley et al. suggested median (IQR [range]) block height of T5 (T4–T6 [C7–L1]) for pinprick as satisfactory block level for cesarean section.In method the baricity of 0.5% bopivacaine as well as name of company should be determined. Refrences: 1.Korean J Anesthesiol. 2016 Apr; 69(2): 143–148 , 2. Int J Obstet Anesth. 2017 May;31:68-73. 3. scielo.br/pdf/rba/v59n6/en_v59n6a03 4. Editorial: Assessing the block for caesarean section 5. Assessment of block height for satisfactory spinal anaesthesia for

VERSION 1 – AUTHOR RESPONSE

Reviewer(s)' Comments to Author:

Reviewer: 1

Reviewer Name: Albert Moore

Institution and Country: Royal Victoria Hospital, Canada

Please state any competing interests or state ‘None declared’: None declared

Please leave your comments for the authors below

Thank you for giving me the opportunity to review this protocol, and provide my comments.

Although the title and description of the protocol suggest that this study is meant to determine the

optimum dose of local anesthesia for spinal anesthesia for caesarean delivery, this really isn’t the

case. To determine the optimum dose, some type of dose finding study should be performed. The



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protocol as presented is really a comparison of two methods of dosing local anesthesia for spinal.

The authors hypothesize that using a height based dosing algorithm without prophylactic vasopressor

will not be inferior with regards to maternal hypotension when compared to a conventional dose spinal

anesthetic that is combined with a prophylactic vasopressor infusion. The manuscript and protocol

would be easier to understand and more impactful if the authors chose to alter their title and

description to reflect the fact that this is a randomized controlled non-inferiority trial for a height based

dosing algorithm.

Response: We have changed the title as “A height based dosing algorithm of bupivacaine in spinal

anesthesia for decreasing maternal hypotension in caesarean section without prophylactic fluid pre-

loading and vasopressors: study protocol for a randomized controlled non-inferiority trial”. (Page 1,

line 2)

Although the authors suggest that the holy grail of spinal hypotension has not been found, this is

somewhat controversial. The advent of vasopressor infusions has greatly decreased the rates of

caesarean hypotension, and some believe that the holy grail has been found. Although there are

risks with fluid and vasopressor therapies, the authors have perhaps inflated the perception of the

risks of these treatments, which are used quite safely thousands of times a day throughout the world.

Response: We have changed “Therefore, avoiding prophylactic fluid pre-loading and vasopressors is

important” as “Therefore, avoiding prophylactic fluid pre-loading and vasopressors should be better”.

(Page 5, line 16)

The use of a height algorithm results in a dose reduction for patients. The use of dose limitation for

caesarean hypotension has been studied extensively, and a meta-analysis of the so called “mini-

dose” spinal anesthesia has been published, which demonstrates decrease maternal hypotension, but

increased anesthesia failure with this technique. However, the use of a height based adjustment to

dosage is novel, and could perhaps provide each patient with the dose that they actually require. For

this reason, the study does have merit, although the authors may have difficulty convincing future

reviewers that any treatment other than prophylactic vasopressors is justified in this population.

Response: Our preliminary data (n=23) showed that this height based dosing algorithm is feasible.

The protocol as described does have a high possibility for the introduction of bias, and further

elaboration of the protocol would be required to ensure that this risk is minimized, and to ensure that

the results are truly due to the height based algorithm.

To start with, the randomization, and allocation masking are poorly described. More detail about who

will perform the randomization, and what sizes of blocks （区组）the patients will be randomized into

would be helpful- is the randomization performed in blocks of 2, which is what is implied by 1:1 blocks.

If this is true then it will be easy to guess what the next patient in the block will be randomized to. The

masking of the allocation is not well described- how hard will it be to guess the assignment of the next

patient?

Response: We have detailedly described blocked randomization in the article. (Page 7, line 11)

The next major issue is the difficulty in blinding of this study. There should be a much more explicit,

step by step description of how blinding will be performed. Many of the outcomes are open to

interpretation (eg quality of anesthesia), and there are treatments that can be altered slightly (eg

degree of wedging) between groups, which could lead to bias if blinding is not strictly enforced. How

will the patient, the treating anesthesiologist, the surgeon, and the person recording the observations

not know which group the patient is in?



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Response: A research assistant will perform the randomization, and prepare and inject the study

drugs (bupivacaine, phenylephrine and normal saline), which will not participate outcome

assessments and statistical analyses. The parturients, outcomes assessors and surgical team will be

blinded to the information concerning randomization, group allocation and study drug preparation

(Page 7, line 18). After spinal anesthesia, all subjects will be immediately placed the supine position

with a left lateral tilt (15°). (Page 8, line 18)

There is also the risk for significant loss to followup, which could also lead to bias. The patients in the

height based group will have a higher risk of requiring epidural top ups, which could increase their

rates of hypotension. However, if these patients are not included in the analysis the rates of

hypotension may be underestimated in this group. The authors do not state whether this will be

analysed as intention to treat or per protocol, and this should be explicitly stated.

Response: Those patients required epidural top ups will not be included for analyzing the rates of

hypotension. (Page 10, line 9) In our practice, for those patients required epidural top ups, the rates of

hypotension seems to be very low. Omitting those patients may not influence our conclusion. We

have made changes in the manuscript.

Although there is justification for the sample size, it is missing some information, including the power

(?0.8) and acceptance for type one error (?0.05) The cited reference may not apply to this study, due

to both the Asian population, and different definitions of hypotension, and this should be considered.

Response: We have inserted the power (0.8) and acceptance for type one error (0.05) into the article.

Because it is very difficult to find a cited reference with similar study protocol, after consulting with the

statistician, the Pt and Pc according to our practice are used to estimate the sample size. (Page 15,

line 9)

Although generally understandable, the manuscript would benefit from editing by a native English

speaker.

Response: The manuscript has been edited by the American Journal Experts (AJE).

Specific comments:

The citation used to support the statement that fluid loading leads to heart failure does not seem to

discuss the link between fluid loading for spinal anesthesia and developing heart failure. The risk for

developing heart failure is most likely extremely low from fluid administration fpr spinal anesthesia in

healthy parturients, and this statement should be rephrased, or supported with a citation relevant to

spinal anesthesia.

Response: We have changed “increasing the risk of heart failure” as “which may increase the risk of

heart failure”, and deleted this citation. (Page 5, line 13)

“Therefore, avoiding prophylactic fluid pre-loading and vasopressors is important” This statement is

perhaps too drastic. Avoiding these treatments is not important, they are used routinely thousands of

times a day across the world. However, they do carry some slight risks.

Response: We have changed “Therefore, avoiding prophylactic fluid pre-loading and vasopressors is

important” as “Therefore, avoiding prophylactic fluid pre-loading and vasopressors should be better”.

(Page 5, line 16)

Should exclude pre-eclampsia patients as well.

Response: We are sorry to omit the pre-eclampsia patients in the exclusion criteria. The pre-

eclampsia patients will be excluded from the study. We have made changes in the manuscript and

Figure2. (Page 7, line 7)



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A step by step description of the randomization procedure and how it will be masked, and all blinding

procedures should be provided. These are important parts of a study such as this, and need to be

completely described when writing the final mansucript.

Response: We have made changes in the manuscript. (Page 7, line 11)

Measuring the blood pressure in the operating room will give a falsely elevated initial blood pressure,

due to the anxiety/stress. A more representative blood pressure would probably be measured outside

the operating room.

Response: We have changed “Measuring the blood pressure in the operating room” as “Measuring

the blood pressure before entering the operation room” in the article. (Page 8, line 5)

The intervention itself may need some more technical description. Specifically, the difference

between doses in the height based group is 0.05 ml. Most syringes have markings for 0.1 or 0.2 ml,

making the measurement of 0.05ml quite difficult. Can the authors be more explicit in how they will

ensure that each patient receives exactly the assigned dose. In addition, the presence of fluid or air

in the epidural space can affect spinal blockade. The authors should describe how they will control

for this.

Response: Our syringes have markings for 0.05 ml. For controling the effect of fluid or air in the

epidural space on spinal blockade, what we can do is only test loss-of-resistance with identical air

volume to decrease the bias. We have made changes in the manuscript. (Page 8, line 15)

The fluid management should be more fully described- at what rate will the fluid be administered

before the spinal, and at what rate after. If the authors are not using pumps to ensure consistent

infusion rates and volumes, they should state this. In addition, the fasting status of the patient should

be considered.

Response: Before spinal anesthesia, 2 ml/kg/h fluid will be administered (Page 8, line 11). After spinal

anesthesia, 10 ml/kg/h fluid will be administered (Page 9, line 2). The patients will fast for ten hours

(Page 7, line 3). We have made changes in the manuscript.

Sample size: the definition of hypotension in this protocol (70% of baseline or SBP less than 90

mmHg) differs from that of the cited article, (only if SBP less than 90mmHg). This may affect the

power of the study. Also, the cited study involves a European population, which may have a very

different rate of hypotension than the population in this study. Also, the authors use uncited evidence

from their own practice, which is unverifiable.

Response: We have deleted the cited article. Because it is very difficult to find a cited reference with

similar study protocol, after consulting with the statistician, the Pt and Pc according to our practice are

used to estimate the sample size. (Page 15, line 8)

The method used to measure block height should be more adequately supported. Are the authors

able to provide a reference that supports their contention that hypoalgesia is superior to other

methods of blockade measurement. Certainly in this reviewer’s experience the loss of sensation to

ice is the method least sensitive to observer bias- the sensation does not depend on the amount of

pressure applied, or the amount of alchohol that evaporates for alcohol cold sensation.

Response: We regret that we can not provide a reference, which supports that hypoalgesia is superior

to other methods of blockade measurement. However, in our practice, hypoalgesia seems to be

superior to other methods of blockade measurement. We have not used the loss of sensation to ice to

measure block height. We do not know whether the loss of sensation to ice is superior to hypoalgesia.



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Protocol amendments should be reviewed by the ethics committee, as they could have ethical

implications.

Response: The amended protocol has been approved by the Ethics Committee of Shenzhen People’s

Hospital of Jinan University.

Reviewer: 2

Reviewer Name: Karim Nasseri

Institution and Country: Associate Professor , Department of Anesthesiology, Kurdistan University of

Medical Siences .

Please state any competing interests or state ‘None declared’: none


Bowan et al. designed a study protocol about optimal dose of bupivacaine in spinal anesthesia for

caesarean section .They believe that the optimal dose of local anesthetics in spinal anesthesia is

unclear, while there are already a lot of studies similar to the current designed research(1-2). So, it

seems that originality of this study is weak.

Response: In your mentioned article, prophylactic fluid pre-loading were carried out. However, in our

study, prophylactic fluid pre-loading will be unnecessary. Therefore, we consider that originality of this

study is not weak.

Authors of this protocol did not clearly describe the rationale of the dose selection for bupivacaine (1.8

ml) as standard dose. It is not clear that, the patients remain fasted during preoperative period or not?

If yes , for what time?

Response: The conventional dose of bupivacaine (1.8 ml) is based on our practice and the article

(Teoh WH, Thomas E, Tan HM. Ultra-low dose combined spinal-epidural anesthesia with intrathecal

bupivacaine 3.75 mg for cesarean delivery: a randomized controlled trial. International journal of

obstetric anesthesia 2006;15(4):273-8.). The patients will fast for ten hours (Page 7, line 3).

In "Strengths and limitations of this study" authors mentioned that study will be carried out without

prophylactic fluid pre-loading but in intervention they used 1000 ml fluid , what is the name of this

fluid(pre-load or maintenance)?

Response: The name of this fluid is Ringer’s lactate, which is used for maintenance. (Page 8, line 11)

Method: Authors should specify size and type of epidural needle. Also , it isn't clear that spinal needle

introduced trough epidural needle or separately via another space . if needle through needle will be

used spinal 25G is a thick needle and local anesthetic may be distribute from epidural to spinal space

via spinal hole.

Response: The size and type of epidural needle is a 16-gauge Tuohy needle (Page 8, line 13). a 27-

gauge pencil-point spinal needle introduced trough epidural needle (Page 8, line 16). We have made

changes in the manuscript.

They mentioned that" Immediately after the intrathecal injection, the infusion of Ringer’s lactate will be

increased to the maximum rate" , without specifying target and maximum rate should be . is not clear.

Response: The maximum rate is 10 ml/kg/h. We have made changes in the manuscript. (Page 9, line

2)



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After delivery Choice of drug used for contraction of uterus during surgery may affect BP and HR , So

author should consider the drug used for this purpose as a variable ,and be aware that these drugs

could be a sours of bias.

Response: Because the BP after delivery is influenced by many factor (e.g., blood loss), we only

record the incidence of maternal hypotension during time from anesthesia initiation to delivery. (Page

11, line 12)

Is 15 ml target total volume for epidural anesthesia enough for all patients? In case of failure to reach

to T8 sensory block during procedure, what do you do?

Response: In our practice, 15 ml target total volume is usually enough for chinese women. If the

sensory block level can not reach to T8, the anesthetic technique will be changed into general

anesthesia. (Page 10, line 12)

Is T8 an Ideal sensory level for C-section ? It seems that T4/5 is a recommended level, though T8 is

the lowest required level (4). Ousley et al. suggested median (IQR [range]) block height of T5 (T4–T6

[C7–L1]) for pinprick as satisfactory block level for cesarean section.In method the baricity of 0.5%

bopivacaine as well as name of company should be determined.

Response: In our practice, T8 seems to be enough for most women. In addition, T8 is also based on

other articles (1.Guo R, Xue Q, Qian Y, et al. The Effects of Ephedrine and Phenylephrine on

Placental Vascular Resistance During Cesarean Section Under Epidual Anesthesia. Cell biochemistry

and biophysics 2015;73(3):687-93.2. 2.Quan Z, Tian M, Chi P, et al. Combined use of hyperbaric and

hypobaric ropivacaine significantly improves hemodynamic characteristics in spinal anesthesia for

caesarean section: a prospective, double-blind, randomized, controlled study. PloS one

2015;10(5):e0125014.). 0.5% bopivacaine is isobaric (Page 8, line 19) and from ChaoHui drug

company, ShangHai, China (Page 8, line 19). We have made changes in the manuscript.

Refrences:

1.Korean J Anesthesiol. 2016 Apr; 69(2): 143–148 ,

2. Int J Obstet Anesth. 2017 May;31:68-73.

3. scielo.br/pdf/rba/v59n6/en_v59n6a03

4. Editorial: Assessing the block for caesarean section

5. Assessment of block height for satisfactory spinal anaesthesia for

VERSION 2 – REVIEW


Mcgill University Canada

REVIEW RETURNED 18-Sep-2018

GENERAL COMMENTS Thank you for allowing me to review the resubmission for this study. The authors have used many of the suggestions to improve the presentation of the manuscript. Specific comments 1. The introduction could be shorter, with less focus on fluids, and more on the height based dosage.



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2. The risks of fluid overload are still overstated. It might be better to say something like “in rare occurrences fluid therapy might cause heart failure” and support with an appropriate reference. 3. The phrase “Therefore, avoiding prophylactic fluid pre-loading and vasopressors should be better.” does not make sense in English and should be revised. 4. The randomization procedure is much better described which is very much appreciated. Could the authors further describe if the randomization will take place all at the same time, with the entire patient assignment schedule placed in sealed envelopes? Also, who will be responsible for opening the envelopes, and when it will be opened? 5. For the blinding procedures more description is required. The actual steps taken to ensure that the anesthesiologist, surgeon, and patient are blinded are not described. Will the research assistant perform the study procedures while the surgeon and anesthesiologist are out of the room? Will the research assistant prepare the drugs somewhere where the anesthesiologist and surgeon won’t see? What other capacity will the research assistant play? Will that same research assistant be performing the block level checking? A more explicit description of the blinding procedures will allow future readers to assess how successful the blinding will be. 6. It may be useful to record at which level the CSE is performed, as this could play a role, especially for the height based dosing 7. It would be useful to know the sensory block characteristics from the start to finish of the anesthesia. Checking the sensory level every minute until 10 minutes, and then every 10 or 15 minutes until the block has receded will be useful information for anybody interested in this technique, and could be different between groups. 8. The Bromage score as classically described is a score from 1 to 4. Please review how you are measuring motor blockade, preferably utilizing a published reference for its support. 9. Please provide an example of the wording you will use to judge the patients intraoperative comfort, as this could be impacted by many factors, including the nausea, cold sensation etc, and not be impacted by the quality of the spinal blockade. 10. The sample size is based on unpublished results, and therefore cannot be verified. It will be up to the authors to be able to justify the sample size when the results of this study are published. 11. “metering data” is not a term usually encountered in the literature. Please consider the use of “continuous data.” 12. Please devise a plan for multiple measurements- either correct using some sort of Bonferonni correction, or plan that any secondary outcomes are hypothesis generating comparisons.


Kurdistan University of Medical Sciences , Kurdistan , Iran

REVIEW RETURNED 19-Sep-2018

GENERAL COMMENTS The authors have solved all my concerns. I have not any more

comment.



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Reviewer: 1


Institution and Country: Mcgill University, Canada

Please state any competing interests or state ‘None declared’: None Declared


Thank you for allowing me to review the resubmission for this study. The authors have used many of

the suggestions to improve the presentation of the manuscript.

Specific comments

1. The introduction could be shorter, with less focus on fluids, and more on the height based dosage.

Response: We have deleted the phrase “fluid therapy may increase the risk of heart failure” (Page 5,

line 13) and increased the text about the height based dosage (Page 5, line 20).

2. The risks of fluid overload are still overstated. It might be better to say something like “in rare

occurrences fluid therapy might cause heart failure” and support with an appropriate reference.

Response: We are sorry not to find an appropriate reference to support the statement that fluid

loading leads to heart failure in healthy parturient. We have deleted the phrase “fluid therapy may

increase the risk of heart failure” (Page 5, line 13).

3. The phrase “Therefore, avoiding prophylactic fluid pre-loading and vasopressors should be better.”

does not make sense in English and should be revised.

Response: We have changed “Therefore, avoiding prophylactic fluid pre-loading and vasopressors

should be better.” as “Therefore, avoiding prophylactic fluid pre-loading and vasopressors may be

advantageous to the parturient or fetus”. (Page 5, line 16)

4. The randomization procedure is much better described which is very much appreciated. Could the

authors further describe if the randomization will take place all at the same time, with the entire patient

assignment schedule placed in sealed envelopes? Also, who will be responsible for opening the

envelopes, and when it will be opened?

Response: The randomization will take place all at the same time (i.e., before conducting this study)

(Page 7, line 22). The random serial numbers of each subject will be placed in a sealed envelope

(Page 7, line 21). After recruiting a new subject, the research assistant who performs the

randomization will open the sealed envelope, and allocate a random serial number to a new recruited

subject (Page 7, line 22).

5. For the blinding procedures more description is required. The actual steps taken to ensure that the

anesthesiologist, surgeon, and patient are blinded are not described. Will the research assistant

perform the study procedures while the surgeon and anesthesiologist are out of the room? Will the

research assistant prepare the drugs somewhere where the anesthesiologist and surgeon won’t see?

What other capacity will the research assistant play? Will that same research assistant be performing



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the block level checking? A more explicit description of the blinding procedures will allow future

readers to assess how successful the blinding will be.

Response: A research assistant open the sealed envelope, and allocate a random serial number to a

new recruited subject, then prepare the study drugs out of the operation room (OR) without presence

of other persons (parturients, outcomes assessors and surgical team), but will not participate outcome

assessments and statistical analyses. The block level checking will be performed by anesthesiologists

and another research assistant (Page 8, line 1).

6. It may be useful to record at which level the CSE is performed, as this could play a role, especially

for the height based dosing

Response: The CSE is performed at the L3-4 interspace (Page 8, line 18).

7. It would be useful to know the sensory block characteristics from the start to finish of the

anesthesia. Checking the sensory level every minute until 10 minutes, and then every 10 or 15

minutes until the block has receded will be useful information for anybody interested in this technique,

and could be different between groups.

Response: Thank you for your advice. We have made changes in the manuscript (Page 11, line 12).

8. The Bromage score as classically described is a score from 1 to 4. Please review how you are

measuring motor blockade, preferably utilizing a published reference for its support.

Response: We have made changes in the manuscript and cited a supportive reference (Page 11, line

14).

9. Please provide an example of the wording you will use to judge the patients intraoperative comfort,

as this could be impacted by many factors, including the nausea, cold sensation etc, and not be

impacted by the quality of the spinal blockade.

Response: The patients intraoperative comfort is the subjective general feeling of subjects during

operation. The subjects will be required to make a choice from four options (excellent, good, fair or

poor) after asking how you feels during operation (Page 12, line 1).

10. The sample size is based on unpublished results, and therefore cannot be verified. It will be up to

the authors to be able to justify the sample size when the results of this study are published.

Response: We have chosed the other method for sample size calculation (Page 16, line 4).

11. “metering data” is not a term usually encountered in the literature. Please consider the use of

“continuous data.”

Response: We have changed “metering data” as “continuous data” (Page 16, line 13 and 16).

12. Please devise a plan for multiple measurements- either correct using some sort of Bonferonni

correction, or plan that any secondary outcomes are hypothesis generating comparisons.

Response: We have made changes in the manuscript (Page 16, line 15).

Reviewer: 2


Institution and Country: Kurdistan University of Medical Sciences , Kurdistan , Iran



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Please state any competing interests or state ‘None declared’: None


The authors have solved all my concerns. I have not any more comment.



Mcgill University Canada

REVIEW RETURNED 23-Oct-2018

GENERAL COMMENTS Thank you for allowing me to further revise this manuscript. The authors have improved the presentation of the project, and made it easier to interpret the risks of bias. Page 8 line 4- “participate IN outcome assessments” Page 8 line 18- how will the L3-4 interspace be determined- clinically, or by ultrasound? If clinically, this could lead to unintentional higher (or lower) injection sites Who is giving the bolus phenylephrine? The treating team, or the research assisitant? The sample size has been changed quite significantly. It is unclear if the authors are now powered for non-inferiority with the new calculation. Using the provided numbers and a non-inferiority design, I am not able to replicate the numbers found by the authors. Instead, I am finding that they need around 260 patients in each group, not total. This calculation should be reviewed by a statistician. There may be further typographical and grammatical errors that require attention.


Department of anesthesiology , faculty of medicine , Kurdistan

University of Medical Sciences , Iran.

REVIEW RETURNED 05-Dec-2018

GENERAL COMMENTS As previously mentioned, authors resolved my concerns in first round of review, so study protocol should be published after minor revision. Specific comments: P 7 – L 6: fasting for ten hour has not scientific bases. Fasting for 2-3 hour for nonparticulat liquids, and 6-8 hour for non-fatty solids are enough. P11_ L6-`11: how you solve the interfere between investigator and surgeon during measurement of sensory and motor block? Do you stop surgery until completion of your evaluation? In both abstract and discussion imply to baricity of bupivacaine (isobaric) is necessary.

REVIEWER Jonas Ranstam

Lund University, Sweden

REVIEW RETURNED 04-Dec-2018



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GENERAL COMMENTS The manuscript presents a study protocol for a non-inferiority trial of a treatment, using a height based dosing algorithm of bupivacaine in spinal anaesthesia, for decreasing maternal hypotension in caesarean section without prophylactic fluid pre-loading and vasopressors. The trial is approved by an ethics committee and registered in a public trial register. I have a few, mainly methodological, comments on the manuscript. 1. It is described on page 7 that written informed consent will be obtained from the patients, but it is not clear if the trial will be performed in compliance with ICH-GCP and the Helsinki Declaration. 2. The primary outcome is "the incidence of maternal hypotension". I assume that this refers to cumulative incidence. 3. It is written on page 6 that "However, several studies have reported no correlation between height and block level, indicating that it is unnecessary to adjust the dose of the local anaesthetic according to height". How was it determined that there was "no correlation"? If "no correlation" just reflects statistical nonsignificance, was the sample size sufficient to exclude clinically relevant correlation coefficients? And how would such a correlation be defined? 4. The sample size calculation is presented on page 16. However, the description is unclear and the presented sample size seems insufficient. Please define the non-inferiority margin clearly. Second, describe how the sample size calculation was performed. Explain why a two-sided test is used? Specify the test function and underlying assumptions. Clarify whether the calculations have been performed for a non-inferiority trial or for superiority trial. In the latter case, further explanation would be necessary. Clarify also if the calculations have been performed by hand or if a computer program was used. 5. The randomisation procedure is described on page 7-8, but the description is unclear and unnecessarily difficult to follow. Please describe more clearly the sequence generation, the allocation concealment mechanism, and the implementation. 6. The statistical tests to be used are described on page 17: "Unpaired t test (Normally distributed data) or 2 Independent Samples Tests (Non-normally distributed data)". Please describe the tests more specifically and in generic terms (e.g. Student's t-test). 7. Non-inferiority trials are based on one-sided testing and usually evaluated using the upper limit of a one-sided 97.5% confidence interval or equivalently a 95% two-sided confidence interval. How are the evaluation of non-inferiority and the presentation of results planned? 8. What endpoints will be evaluated for non-inferiority and what endpoints will be tested for superiority? If more than the primary endpoint will be evaluated for non-inferiority, has the relevant non-inferiority margins been presented?



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9. What endpoints will be tested confirmatory and what endpoints will be tested exploratory? Will a strategy for addressing multiplicity issues be necessary?



Reviewer: 1


Institution and Country: Mcgill University

Canada



Thank you for allowing me to further revise this manuscript. The authors have improved the

presentation of the project, and made it easier to interpret the risks of bias.

Page 8 line 4- “participate IN outcome assessments”

Response:

We have inserted “in” in the manuscript (Page 8, line 5).

Page 8 line 18- how will the L3-4 interspace be determined- clinically, or by ultrasound? If clinically,

this could lead to unintentional higher (or lower) injection sites

Response:

We have not ultrasonic equipment for intraspinal puncture at present. L3-4 interspace is clinically

determined.. It is inevitable that unintentional higher (or lower) injection sites may occur in part

parturients.

Most chinese parturients are thin and the spinous process is easily touched. We consider that the

location of L3-4 interspace is accurate in most chinese parturients, unless special parturients (e.g.,

sacralization of the fifth lumbar vertebra or lumbarization of the first sacral vertebra). Although

ultrasound can increase the accuracy of location of L3-4 interspace, For those parturients with

sacralization of the fifth lumbar vertebra or lumbarization of the first sacral vertebra, can ultrasound

accurately locate the L3-4 interspace?

Who is giving the bolus phenylephrine? The treating team, or the research assisitant?

Response:

The bolus phenylephrine is given by the outcomes assessors (Page 10, line 6).

The sample size has been changed quite significantly. It is unclear if the authors are now powered for

non-inferiority with the new calculation. Using the provided numbers and a non-inferiority design, I am

not able to replicate the numbers found by the authors. Instead, I am finding that they need around

260 patients in each group, not total. This calculation should be reviewed by a statistician.



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Response:

Thank you for careful review. After consulting with a statistician, with this equation ( ) for sample size

calculation, each group actually requires 130 subjects (Page 16, line 20).

There may be further typographical and grammatical errors that require attention.

Response:

We have renewedly examined the manuscript, and made some changes in the manuscript (Page 7,

line 15 and 20) (Page 8, line 5) (Page 13, line 18).

Reviewer: 3

Reviewer Name: Jonas Ranstam

Institution and Country: Lund University, Sweden



The manuscript presents a study protocol for a non-inferiority trial of a treatment, using a height based

dosing algorithm of bupivacaine in spinal anaesthesia, for decreasing maternal hypotension in

caesarean section without prophylactic fluid pre-loading and vasopressors. The trial is approved by an

ethics committee and registered in a public trial register. I have a few, mainly methodological,

comments on the manuscript.

1. It is described on page 7 that written informed consent will be obtained from the patients, but it is

not clear if the trial will be performed in compliance with ICH-GCP and the Helsinki Declaration.

Response:

It is certain that the trial will be performed in compliance with ICH-GCP and the Helsinki Declaration

(Page 6, line 15).

2. The primary outcome is "the incidence of maternal hypotension". I assume that this refers to

cumulative incidence.

Response:

The SBP < 90 mmHg or 70% of baseline value will be defined as maternal hypotension. During time

from anesthesia initiation to delivery, if the SBP is less than 90 mmHg or 70% of baseline value at any

time point, this parturient will be defined as a parturient with hypotension (Page 10, line 3).

3. It is written on page 6 that "However, several studies have reported no correlation between height

and block level, indicating that it is unnecessary to adjust the dose of the local anaesthetic according

to height". How was it determined that there was "no correlation"? If "no correlation" just reflects

statistical nonsignificance, was the sample size sufficient to exclude clinically relevant correlation

coefficients? And how would such a correlation be defined?

Response:

The conclusion of "no correlation" is determined via Spearman's test or linear regression analysis for

height and block level in other references. There is not sample size calculation in these references.



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We do not know whether the sample size is sufficient in these references. a correlation is defined by

the “P > 0.05” after Spearman's test or linear regression analysis for height and block level.

4. The sample size calculation is presented on page 16. However, the description is unclear and the

presented sample size seems insufficient. Please define the non-inferiority margin clearly. Second,

describe how the sample size calculation was performed. Explain why a two-sided test is used?

Specify the test function and underlying assumptions. Clarify whether the calculations have been

performed for a non-inferiority trial or for superiority trial. In the latter case, further explanation would

be necessary. Clarify also if the calculations have been performed by hand or if a computer program

was used.

Response:

We have made change in the manuscript (Page 16, line 15).

5. The randomisation procedure is described on page 7-8, but the description is unclear and

unnecessarily difficult to follow. Please describe more clearly the sequence generation, the allocation

concealment mechanism, and the implementation.

Response:

Thank you for your advice. After consulting with a statistician, the randomisation procedure (Page 7,

line 22), allocation concealment mechanism, and implementation (Page 8, line 5) seem to be clear.

6. The statistical tests to be used are described on page 17: "Unpaired t test (Normally distributed

data) or 2 Independent Samples Tests (Non-normally distributed data)". Please describe the tests

more specifically and in generic terms (e.g. Student's t-test).

Response:


7. Non-inferiority trials are based on one-sided testing and usually evaluated using the upper limit of a

one-sided 97.5% confidence interval or equivalently a 95% two-sided confidence interval. How are the

evaluation of non-inferiority and the presentation of results planned?

Response:

We have explained the evaluation of non-inferiority (Page 16, line 15) and the presentation of results

planned (Page 17, line 3) in the manuscript.

8. What endpoints will be evaluated for non-inferiority and what endpoints will be tested for

superiority? If more than the primary endpoint will be evaluated for non-inferiority, has the relevant

non-inferiority margins been presented?

Response:

Only the primary endpoint will be evaluated for non-inferiority. The relevant non-inferiority margin is

10% (Page 16, line 14).

9. What endpoints will be tested confirmatory and what endpoints will be tested exploratory? Will a

strategy for addressing multiplicity issues be necessary?

Response:




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Reviewer: 2


Institution and Country: Department of anesthesiology , faculty of medicine , Kurdistan University of

Medical Sciences , Iran.



Specific comments:

P 7 – L 6: fasting for ten hour has not scientific bases. Fasting for 2-3 hour for nonparticulat liquids,

and 6-8 hour for non-fatty solids are enough.

Response:

For elective cesarean section, most parturients usually go to sleep at 10:00 PM and are be

transferred to operation room at 8:00 AM in the next day. In China, there are not special commercial

liquids for elective surgery patients. In order to avoid to eat unsuitable liquids and solids. The elective

surgery patients are usually informed that they can not eat liquids and solids after 10:00 PM at the

night before the surgery.

P11_ L6-`11: how you solve the interfere between investigator and surgeon during measurement of

sensory and motor block? Do you stop surgery until completion of your evaluation?

Response:

The measurement of sensory block can be carried out at the cephalic side of the patient by outcomes

assessors. The measurement of motor block can be carried out at the foot side of the patient under

surgical instrument table by outcomes assessors.The measurement of sensory and motor block seem

to not influence the surgery.

In both abstract and discussion imply to baricity of bupivacaine (isobaric) is necessary.

Response:

We have inserted “isobaric” in both abstract (Page 2, line 14) and discussion (Page 17, line 22).



McGill University, Canada

REVIEW RETURNED 25-Jan-2019

GENERAL COMMENTS Thank you for allowing me to review this revision. The manuscript has undergone a few changes to address other reviewers concerns. Although it could be edited for brevity and clarity, the manuscript would allow replication of this study. My largest concern about this project is still the sample size, which has not changed since the previous revision. Although there is a better explanation of the sample size calculation, there is no justification for the sample size formula provided, and no explanation for what each of the symbols represent. If I assume that the authors want



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ualpha+ubeta to represent the z value at the chosen alpha and beta, the π to be the proportion of hypotensive patients, and the sigma to be the inferiority margin, then this formula is similar to that found in: (Jones et al: Trials to assess equivalence: the importance of rigorous methods. BMJ 1996; 313 doi: https://doi.org/10.1136/bmj.313.7048.36). However, the formula in Jones et al includes a 2 in the numerator and is only for one treatment group. Using the formula from Jones et al, I still calculate that each group would require 260 patients for a total of 520. In order to avoid future criticism of an underpowered study, the authors should re-examine and provide robust justification for their sample size calculations.


Kurdistan University of Medical Sciences , Iran


GENERAL COMMENTS Authors improved their article in compare to first version, I have only some minor specific comments as follow; 1. Page 7 ,line 7 “ “All parturient will fast for ten hours “ this time is very long , because based on ASA guideline “ patients that scheduled for elective cesarean delivery may have moderate amounts of clear liquids up to 2 h before induction of anesthesia”. So, I recommend to reduce the fasting time. 2. Page 9 . line 1 : “epidural catheter will be inserted 4-6 cm. “ 4-6 cm is so long 4 cm is enough . 3. P9,L10: In the” Test group, by the research assistant who prepares study drugs, normal saline (2.5 ml/h) will be introduced” , introduced is not a good verb here, I recommend to change that . 4. Page 11.line 7: Please change verb “was” to “will be”

REVIEWER Jonas Ranstam

Lund University, Sweden


GENERAL COMMENTS I have a few remaining comments on the manuscript. The numbering refers to my earlier comments. 2. Please clarify if the primary outcome, "incidence of maternal hypotension", is measured in terms of cumulative incidence, i.e. risk or proportion. 3. Concluding "no correlation" from statistical nonsignificance is misleading because statistical significance is a measure of inferential uncertainty, not practical importance. 4. The description needs to be adjusted. How can a non-inferiority test be two-sided?



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Reviewer: 3

Reviewer Name: Jonas Ranstam

Institution and Country: Lund University, Sweden



I have a few remaining comments on the manuscript. The numbering refers to my earlier comments.

2. Please clarify if the primary outcome, "incidence of maternal hypotension", is measured in terms of

cumulative incidence, i.e. risk or proportion.

Response:

We have clarify that the "incidence of maternal hypotension" is cumulative incidence in the manuscript

(Page 12, line 11).

3. Concluding "no correlation" from statistical nonsignificance is misleading because statistical

significance is a measure of inferential uncertainty, not practical importance.

Response:

The conclusion of "no correlation" is from other studies. We only introduce other results in the

INTRODUCTION. Actually, we have some confusion about how to revise our manuscript according to

your comment. We have made little changes in the manuscript (Page 5, line 17). We hope to meet

your requirement.

4. The description needs to be adjusted. How can a non-inferiority test be two-sided?

Response:

We have calculated the sample size again (one-sided) (Page 16, line 18).

Reviewer: 1


Institution and Country: McGill University, Canada



Thank you for allowing me to review this revision.

The manuscript has undergone a few changes to address other reviewers concerns. Although it

could be edited for brevity and clarity, the manuscript would allow replication of this study. My largest

concern about this project is still the sample size, which has not changed since the previous revision.

Although there is a better explanation of the sample size calculation, there is no justification for the



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sample size formula provided, and no explanation for what each of the symbols represent. If I

assume that the authors want ualpha+ubeta to represent the z value at the chosen alpha and beta,

the π to be the proportion of hypotensive patients, and the sigma to be the inferiority margin, then this

formula is similar to that found in: (Jones et al: Trials to assess equivalence: the importance of

rigorous methods. BMJ 1996; 313 doi: https://doi.org/10.1136/bmj.313.7048.36). However, the

formula in Jones et al includes a 2 in the numerator and is only for one treatment group. Using the

formula from Jones et al, I still calculate that each group would require 260 patients for a total of 520.

In order to avoid future criticism of an underpowered study, the authors should re-examine and

provide robust justification for their sample size calculations.

Response:

We have calculated the sample size again with the new equation (Page 16, line 19; Page 7, line 15).

Reviewer: 2


Institution and Country: Kurdistan University of Medical Sciences , Iran



Authors improved their article in compare to first version, I have only some minor specific comments

as follow;

1. Page 7 ,line 7 “ “All parturient will fast for ten hours “ this time is very long , because based on ASA

guideline “ patients that scheduled for elective cesarean delivery may have moderate amounts of

clear liquids up to 2 h before induction of anesthesia”. So, I recommend to reduce the fasting time.

Response:


2. Page 9 . line 1 : “epidural catheter will be inserted 4-6 cm. “ 4-6 cm is so long 4 cm is enough .

Response:


3. P9,L10: In the” Test group, by the research assistant who prepares study drugs, normal saline (2.5

ml/h) will be introduced” , introduced is not a good verb here, I recommend to change that .

Response:

The “introduced” has been changed into “applied” (Page 9, line 11).

4. Page 11.line 7: Please change verb “was” to “will be”

Response:




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Documents

PEER REVIEW HISTORY ... · study is meant to determine the optimum dose of local anesthesia for spinal anesthesia for caesarean delivery, this really isn’t the case. To determine