Intensive versus conservative glycemic control in patients undergoing coronary artery bypass graft surgery: A protocol for systematic review of randomised controlled trials.

INTRODUCTION: Hyperglycemia and hypoglycemia are common during coronary artery bypass graft (CABG) and are associated with a variety of postoperative outcomes. Therefore, the strategy of intraoperative glycemic control is an important issue for the patients undergoing CABG. This systematic review aims to evaluate the effect of different intraoperative glycemic control strategies on postoperative outcomes. METHODS AND ANALYSES: We will perform this systematic review of randomised controlled trials (RCTs) according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Relevant studies will be searched in Medline, Embase, Cochrane Library and Web of Science. Two independent reviewers will conduct study selection, data extraction, risk of bias and quality assessment. The primary outcome is postoperative mortality, and the secondary outcomes include the duration of mechanical ventilation in the intensive care unit (ICU), the incidence of postoperative myocardial infarction (MI), the incidence of postoperative atrial fibrillation (AF), the type and volume of blood product transfusion, the rate of rehospitalization, the rate of cerebrovascular accident, the rate of significant postoperative bleeding, the rate of infection, the incidence of acute kidney failure (AKF), hospital and ICU lengths of stay (LOS). ReviewManager 5.4 will be used for data management and statistical analysis. The Cochrane risk-of -bias tool 2.0 and GRADEpro will be applied for risk of bias and quality assessment of the evidence. DISCUSSION: There is no consensus that which strategy of glycemic control is better for improving postoperative complications of patients undergoing CABG. The results of our study might provide some evidence for the relationship between intraoperative glycemic control strategies and postoperative outcomes in patients undergoing CABG.

1. Introduction

Nowadays, coronary artery bypass graft (CABG) surgery has become the most common surgical procedure. Almost 400,000 patients accept CABG annually [1]. Previous studies have shown that hyperglycemia during cardiac surgery is associated with hospital complications including mortality, renal failure, wound infections and the duration of mechanical ventilation, if it is not well controlled [2-6]. Besides, hyperglycemia has also been thought to increase perioperative morbidity and mortality [7].

On the other hand, it has been suggested that there may be a significant reduction in early mortality in patients who accepted the intensive glycemic control strategy during CABG [8-11]. However, other evidence of severe hypoglycemia resulted from intensive glycemic control brings the safety and effectiveness of intraoperative glycemic control strategy into question [5, 7, 12]. Moreover, hypoglycemia has also been considered as an independent risk factor of undesired clinical outcomes and hospital mortality [13]. Several studies confirmed that the incidence of hypoglycemia was associated with the overall risk of hospital mortality and the increased risk of cardiovascular events in critically ill patients [5, 14–16].

However, the optimal glycemic control strategy for patients undergoing CABG surgery remains controversial. Therefore, we will perform this systematic review and meta-analysis of randomised controlled trials to investigate the different effects of conservative and intensive glycemic control strategies on postoperative short-term mortality and severe complications in patients undergoing CABG.

2. Methods and analyses

2.1 Protocol design and registration

Our study has been registered at PROSPERO international prospective register of systematic reviews (https://www.crd.york.ac.uk/PROSPERO/). The registration number is CRD42021240841. The protocol is performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) 2015 checklist [17]. The PRISMA-P 2015 checklist will be shown in S1 Checklist. We will conduct our systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 statement [18].

2.2 Inclusion and exclusion criteria

2.2.1 Study design

Randomised controlled trials (RCTs) will be strictly screened. Cross-over studies and quasi-randomised controlled trials will be excluded.

2.2.2 Population

Studies including patients undergoing CABG surgery who have accepted intraoperative glycemic control will be included. Studies including patients with incomplete information will be excluded.

2.2.3 Intervention and comparator groups

Studies with at least two glycemic control groups (intensive group and conservative group) will be included. In the systematic review, the group with a lower blood glucose target (≤160mg/dL) is defined as the ‘intensive group’, and the group with a higher blood glucose target (≤200mg/dL) is defined as the ‘conservative group’. Studies that did not measure blood glucose or did not have both groups above will be excluded.

2.2.4 Outcomes

Studies that evaluate any variable of the primary or secondary outcomes as endpoints will be included. The primary outcome is postoperative mortality. The secondary outcomes include the variables as follow: the duration of mechanical ventilation in the intensive care unit (ICU), the incidence of postoperative myocardial infarction (MI), the incidence of postoperative atrial fibrillation (AF), the type and volume of blood product transfusion, the rate of rehospitalization, the rate of cerebrovascular accident, the rate of significant postoperative bleeding, the rate of postoperative infection, the incidence of acute kidney failure (AKF), hospital and ICU lengths of stay (LOS). If the outcomes were reported on multiple time points, we will use the longest follow-up data.

All outcomes of our study are defined as follows:

Postoperative mortality: 30 days mortality after surgery or hospital mortality;

The duration of mechanical ventilation in ICU: from the time of admission to ICU to the time of tracheal extubation;

Postoperative MI: recognized by clinical features, including electrocardiographic (ECG) findings, elevated values of biochemical markers (biomarkers) of myocardial necrosis, and by imaging, or may be defined by pathology [19];

Postoperative AF: diagnosed with an electrocardiogram [20];

Blood product transfusion: the type and volume of blood products during the perioperative period;

Rehospitalization: re-admission due to postoperative complications of CABG;

Cerebrovascular accident: cerebrovascular accident within postoperative 30-day or during hospitalization;

Significant postoperative bleeding: postoperative bleeding ≥200 ml/h or ≥1000 ml in 24 hours, or massive bleeding needing reoperation;

Postoperative infection: any reported infection after surgery, such as pneumonia or wound infection;

AKF: new requirement for dialysis or an increase in serum creatinine > 2.0 mg/dl and double the most recent preoperative creatinine level;

ICU Length of stay (LOS): from ICU admission to transfer to the ward;

Hospital Length of stay (LOS): from hospital admission to the day of discharge.

2.2.5 Language

Studies reported in all types of languages will be included.

2.3 Search strategy

Two independent reviewers (YL and XXS) will perform the comprehensive search strategies in Medline, Embase, Cochrane Library and Web of Science. Records from the inception until the 9 August 2021 will be included. The search strategy will combine relevant Medical Subject Headings (MeSH) and keywords with synonyms and names of generic and brand names of the CABG and glycemic control. We will also check the reference lists of included RCTs and relevant reviews. In addition, a grey literature search will be performed on trial registry sites (such as WHO international clinical trial registry platform and NIH resources), regulatory agency databases for unpublished and ongoing studies. A manual search of citations and meeting reports will also be conducted. The details of search strategies of four databases were included in S1 File.

2.4 Study selection

Endnote X9 will be applied to manage relevant articles and remove duplicated. Two reviewers (YL and XXS) will assess the eligibility of the potentially relevant studies independently and in duplicate. Studies will be selected according to the predefined inclusion and exclusion criteria. The process will be conducted strictly in accordance with a study eligibility form (see S2 File). The detailed reasons for exclusion will be carefully documented. Any disagreement will be resolved by discussion or consulting a third reviewer (ML). If necessary, they will consult the methodological experts to reach consensus. The flow chart of study selection will be presented in S3 File.

2.5 Data extraction

The data will be extracted from eligible studies. A predefined data collection template will be used to collect the study data and will be tested on a few randomly selected studies. The data extraction template can be found in S1 Table. The author of study without insufficient information will be contacted for further information. Two investigators will perform data extraction independently and in duplicate. A third reviewer will be consulted to reach a consensus. Arm-level data (e.g., number of events) will be extracted whenever possible.

2.6 Risk of bias assessment

According to the Cochrane risk-of-bias tool 2.0 for the methodological quality of randomised trials [21], two investigators will independently perform the risk of bias of the included studies. The studies will be evaluated into three categories: low of risk, high of risk and some concerns. Bias of the following domains will be assessed: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), incomplete outcome data (attrition bias), selective reporting (reporting bias). In addition, we will reach an overall risk-of-bias judgement for the outcome based on the above assessments.

2.7 Measures of treatment effects

The level of blood glucose will be regarded as a binary variable. Each postoperative outcome will be estimated for intensive glycemic control group and conservative glycemic control group.

2.8 Assessment of heterogeneity

χ2 (Cochran’s Q) and I2 methods will be used to assess statistical heterogeneity among the eligible studies. According to the Cochrane Handbook for Systematic Reviews of Interventions, the I2 method will be used to category the heterogeneity into non-important (<30%), moderate (30%-60%) and substantial (>60%).

2.9 Data synthesis

Risk ratio (RR) will be used for both fixed and random effects models (weighting by inverse of variance). The primary outcome and secondary outcomes of dichotomous variables will be assessed using forest plots and presented as RR. Sensitivity analyses will be performed to confirm the robustness of the results in the meta-analyses by excluding each study. A funnel plots for meta-analyses will be used to assess publication bias. If required, the Begg’s and Egger’s tests will be used to quantify the publication bias. Statistical analyses will be performed using RevMan5.4 software (the Nordic Cochrane Centre, Copenhagen, Denmark). For continuous outcomes, weighted mean differences or standardized mean differences will be used according to different measurement scales. In our studies, the confidence interval (CI) will be established at 95%, and P value <0.05 will be considered to be statistically significant.

2.10 Subgroup analyses

To explore the sources of the heterogeneity of the included studies, subgroup analysis will be performed according to the primary and secondary outcomes. We will conduct subgroup analyses based on the following criteria:

with versus without the history of diabetes;

history of diabetes ≤5 years versus >5 years;

with versus without the history of hypertension;

with versus without the history of smoking;

different glycemic control strategy: insulin versus GIK;

off-pump CABG versus on-pump CABG.

2.11 Sensitivity analyses

To confirm the robustness of our findings, a sensitivity analysis will be conducted based on the different levels of bias of the included studies. To evaluate the internal validity of studies or treatment adequacy, we will subsequently remove studies of ‘high risk of bias’, studies of ‘some concerns’, and studies of ‘low risk of bias’. In addition, both random effect model and fixed effect model will be used for the synthesis of the primary and secondary outcomes.

2.12 Meta-bias

To determine whether reporting bias is present, we will explore whether the protocol of the studies included in this systematic review was published before recruitment of patients was started. The reporting bias will be further determined by funnel plots if there are more than 10 studies in this systematic review.

2.13 Confidence in cumulative estimate

In order to evaluate the quality of the treatment effect estimate, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach will be used. We will rate the quality of evidence by using the five GRADE categories: risk of bias, inconsistency, indirectness, imprecision and publication bias. In addition, we will categorize confidence in the estimate of the outcomes into four levels: high level, moderate level, low level and very low level [22]. The GRADEpro software will be applied to estimate the quality of evidence assessment (see S4 File).

2.14 Patient and public involvement

There will be no patients and/or the public involved in the design, or conduct, or reporting, or dissemination plans of this study.

3. Discussion

Intraoperative blood glucose level is considered as a significant factor of postoperative outcomes. However, there is no consensus that which strategy of glycemic control is more beneficial for improving postoperative complications of patients undergoing CABG. The aim of this systematic review is to explore the effects of different glycemic control strategies on postoperative outcomes of patients undergoing CABG.

In our study, we will conduct a comprehensive database search, select eligible studies, extract data, assess the risk of bias, perform data synthesis and assess the heterogeneity among included studies. Moreover, subgroup analysis will be conducted to explore the source of heterogeneity, and sensitivity analysis will be performed to ascertain the robustness of the results. All of above process will be achieved by two reviewers independently and in duplicate.

There are two limitations in our study. First, some perioperative complications of CABG only reported in few studies, which limits the meta-analysis for these complications. Second, some of the eligible studies included in our systematic review might be low quality. We will perform sensitivity analysis to ascertain the robustness of the results.

PRISMA-P 2015 checklist.

(DOCX)

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Draft of data extraction template.

(DOCX)

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Search strategies.

(DOCX)

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Study eligibility form.

(DOCX)

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PRISMA 2020 flow diagram.

(TIF)

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Assessment of evidence quality by GRADE approach.

(DOCX)

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19 Jul 2022

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Additional Editor Comments:

Reviewer#1:

The authors have proposed a protocol for a systematic review on intensive vs. conservative glycemic control in CABG patients. The methods have been well-described, and I hope the authors stick to all these elements, particularly critical appraisal and bias control. Although the review protocol has been already registered in PROSPERO, I suggest these comments be considered in the review:

1- Include the duration of the disease as a confounder in your meta-analysis.

2- I think you can add more variables to the secondary outcomes, such as the need for blood product transfusion, postoperative atrial fibrillation, and rehospitalization.

3- Subanalysis section: Please consider a better wording for "not accompanied of." That does not sound nice!

4- There are some typos and grammatical issues in the manuscript. So please have it checked by an expert.

Reviewer#2:

There are several points in this protocol that require further clarification, as follows:

Introduction:

- The authors clearly have described the condition, how glycemic control during cardiac surgery might affect postoperative outcomes, and how different glycemic control strategies might work.

- The purpose of the study has been explained in a very general way. The authors should specify exactly what research questions this review ultimately answers.

- Place the point after the closing bracket of the citations.

Methods:

- The authors should describe some items of eligibility criteria more clearly and in detail:

1) Regarding the target population, will you include all patients undergoing CABG surgery and intraoperative glycemic control, regardless of their demographic characteristics (e.g., age), background, and past medical history of diabetes mellitus?

2) Regarding types of interventions, please explain clearly what range of blood sugar control you consider to define “intensive” and “conservative” control.

3) Please specify the comparison group more clearly. Will you only include studies that considered high levels of glycemic control target (conservative group) as the comparison group?

4) Since you discussed the eligibility criteria based on the PICOS in the 2.2 subsection, and the outcomes are also one of its items, there is no need to describe the outcomes in a separate section. Please leave the explanation of subsection 2.3, which is about the outcomes, below in subsection 2.2.

5) The authors should describe the report characteristics of studies to be included, such as years considered, language, and publication status. If relevant studies published in all languages are to be included, how to deal with articles that have a language different from the language of the authors?

- Study selection, data synthesis, and risk of bias assessment have been described according to the PRISMA-P statement.

Other comments:

- The authors should arrange the order of the abstract sections according to the main text (Introduction/background, Methods, Discussion).

- The manuscript has some typing mistakes and grammatical errors that need to be corrected

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

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Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Partly

**********

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Reviewer #1: Yes

Reviewer #2: Partly

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #2: Yes

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Reviewer #1: The authors have proposed a protocol for a systematic review on intensive vs. conservative glycemic control in CABG patients. The methods have been well-described, and I hope the authors stick to all these elements, particularly critical appraisal and bias control. Although the review protocol has been already registered in PROSPERO, I suggest these comments be considered in the review:

1- Include the duration of the disease as a confounder in your meta-analysis.

2- I think you can add more variables to the secondary outcomes, such as the need for blood product transfusion, postoperative atrial fibrillation, and rehospitalization.

3- Subanalysis section: Please consider a better wording for "not accompanied of." That does not sound nice!

4- There are some typos and grammatical issues in the manuscript. So please have it checked by an expert.

Reviewer #2: In this protocol, the authors tried to describe the objectives, eligibility criteria, and planned methodology of their systematic review that will assess the effect of different intraoperative glycemic control strategies on postoperative outcomes. Evidence shows that poor intraoperative glycemic control is a risk factor for postoperative morbidity and mortality. Different strategies are used for intraoperative control of blood sugar, but their effect on postoperative outcomes has been conflicting across studies. Therefore, this systematic review aims to examine this crucial question and, more specifically, to determine the effect intensive glycemic control of blood sugar has on postoperative outcomes versus conservative control. The title is interesting and the protocol has been written according to the PRISMA-P statement. However, there are several points in this protocol that require further clarification, as follows:

Introduction:

- The authors clearly have described the condition, how glycemic control during cardiac surgery might affect postoperative outcomes, and how different glycemic control strategies might work.

- The purpose of the study has been explained in a very general way. The authors should specify exactly what research questions this review ultimately answers.

- Place the point after the closing bracket of the citations.

Methods:

- The authors should describe some items of eligibility criteria more clearly and in detail:

1) Regarding the target population, will you include all patients undergoing CABG surgery and intraoperative glycemic control, regardless of their demographic characteristics (e.g., age), background, and past medical history of diabetes mellitus?

2) Regarding types of interventions, please explain clearly what range of blood sugar control you consider to define “intensive” and “conservative” control.

3) Please specify the comparison group more clearly. Will you only include studies that considered high levels of glycemic control target (conservative group) as the comparison group?

4) Since you discussed the eligibility criteria based on the PICOS in the 2.2 subsection, and the outcomes are also one of its items, there is no need to describe the outcomes in a separate section. Please leave the explanation of subsection 2.3, which is about the outcomes, below in subsection 2.2.

5) The authors should describe the report characteristics of studies to be included, such as years considered, language, and publication status. If relevant studies published in all languages are to be included, how to deal with articles that have a language different from the language of the authors?

- Study selection, data synthesis, and risk of bias assessment have been described according to the PRISMA-P statement.

Other comments:

- The authors should arrange the order of the abstract sections according to the main text (Introduction/background, Methods, Discussion).

- The manuscript has some typing mistakes and grammatical errors that need to be corrected

**********

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Reviewer #1: Yes: Akbar Shafiee

Reviewer #2: Yes: Danesh Soltani

**********

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Submitted filename: Peer review.docx

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30 Aug 2022

Dear editor and reviewers,

Thanks for your letter and the reviewers’ comments concerning our manuscript entitled “Intensive versus conservative glycemic control in patients undergoing coronary artery bypass graft surgery: A protocol for systematic review of randomized controlled trials” (PONE-D-22-18985). The comments are very helpful and valuable for revising and improving our paper. We would like to thank you for allowing us to submit a revised copy of the manuscript, and we highly appreciate your time and consideration. We have read through those comments carefully and revised the manuscript accordingly. In addition to the response letter, a marked and clean version of our revised manuscript were uploaded based on the instructions provided in your letter. Revised portions are marked in red in the marked version of revised manuscript. Our point-by-point responses are detailed below.

Reviewer#1:

Q1. Include the duration of the disease as a confounder in your meta-analysis.

Response: We deeply appreciate the suggestion. According to the reviewer’s comment, we will include the duration of some diseases (e.g., the duration of diabetes mellitus, coronary heart disease and hypertension) as confounders. The characteristics of all patients in eligible literatures will be carefully extracted and recorded in detail for subsequent analyses. All items that need to be extracted were presented in the predefined table (see S1 table. Draft of data extraction template).

Q2. I think you can add more variables to the secondary outcomes, such as the need for blood product transfusion, postoperative atrial fibrillation, and rehospitalization.

Response: Thank you for your precious advice. It is of great interest to add more variables to the secondary outcomes. Therefore, we decide to add the type and volume of blood product transfusion, postoperative atrial fibrillation, rehospitalization, cerebrovascular accident, and significant postoperative bleeding as secondary outcomes. (Line 114, page 6)

Q3. Subanalysis section: Please consider a better wording for "not accompanied of." That does not sound nice!

Response: Thank you for your thoughtful suggestions. In the revised manuscript, we have replaced “not accompanied of” with the word “without”, and we have modified this expression throughout the text according to the reviewer’s comment. (Line 205, 207 and 208, page 11)

Q4. There are some typos and grammatical issues in the manuscript. So please have it checked by an expert.

Response: Thank you for your careful review. We have corrected the typos and grammatical issues. The revision portions were marked in red in the revised manuscript. In order to meet the standard of the journal, the manuscript has been checked by a professional polishing company named American journal expert (AJE, verification code 67E6-E5CE-98E4-68EB-5D9A).

Reviewer#2:

The part of introduction:

Q1. The authors clearly have described the condition, how glycemic control during cardiac surgery might affect postoperative outcomes, and how different glycemic control strategies might work.

Response: Thanks very much for taking your time to review our manuscript. The reviewer’s comments were highly insightful and enabled us to greatly improve the quality of our manuscript.

Q2. The purpose of the study has been explained in a very general way. The authors should specify exactly what research questions this review ultimately answers.

Response: Thank you very much for your precious suggestions. We will perform this systematic review and meta-analysis to investigate the effect of different glycemic control strategies on the postoperative outcomes in patients undergoing coronary artery bypass graft. To be more exact and in accordance with the reviewer’ comment, we have clearly demonstrated the purpose of this review in the revised manuscript. (Line 78-82, page 4-5)

Q3. Place the point after the closing bracket of the citations.

Response: We deeply appreciate the reviewer’s suggestions. According to the comments, we have placed the point after the citations and have carefully checked the entire manuscript.

The part of methods:

Q1. Regarding the target population, will you include all patients undergoing CABG surgery and intraoperative glycemic control, regardless of their demographic characteristics (e.g., age), background, and past medical history of diabetes mellitus?

Response: Thank you for the thoughtful comments. All patients undergoing CABG surgery and intraoperative glycemic control will be included in our study, regardless of their demographic characteristics (e.g., age and sex), the history and duration of diabetes mellitus, the duration of coronary artery disease, the history and duration of hypertension, and the history of smoking. The items that needed to be extracted had been presented in the predefined table (see S1 table. Draft of data extraction template). All detailed information would be extracted according to the draft when the protocol is implemented. Moreover, we will perform secondary analyses (e.g., subgroup analysis and sensitivity analysis) according to demographic characteristics and past medical history. (Line 205-208, page 11)

Q2. Regarding types of interventions, please explain clearly what range of blood sugar control you consider to define “intensive” and “conservative” control.

Response: Thank you for the reviewer’s suggestions. In this systematic review, the participants of the included studies were allocated into different groups based on the target blood glucose level. The group with a lower target blood glucose level (≤160mg/dL) was defined as the intensive group, while the other group with a higher target blood glucose level (≤200mg/dL) was defined as the conservative group. (Line 104-108, page 6)

Q3. Please specify the comparison group more clearly. Will you only include studies that considered high levels of glycemic control target (conservative group) as the comparison group?

Response: We deeply appreciate the reviewer’s careful review. All studies with at least two glycemic control group (intensive versus conservative group) will be included in our systematic review. (Line 104-105, page 6).

Q4. Since you discussed the eligibility criteria based on the PICOS in the 2.2 subsection, and the outcomes are also one of its items, there is no need to describe the outcomes in a separate section. Please leave the explanation of subsection 2.3, which is about the outcomes, below in subsection 2.2.

Response: Thank you very much for the reviewer’s valuable advice. We strongly agree with the comments and leave the explanation 2.3 below in subsection 2.2 in the revised manuscript (Line 111-140, page 6-7).

Q5. The authors should describe the report characteristics of studies to be included, such as years considered, language, and publication status. If relevant studies published in all languages are to be included, how to deal with articles that have a language different from the language of the authors?

Response: Thank you for your careful review and we strongly agree with your comment. There is no limitation on publication year, journal, first author, language, and publication status. The above literatures characteristics have been taken into account (see S1 table). If some literatures with languages different from the authors’ language, we would seek help on some translation software (e.g., Youdao Translator, Google Translator and Baidu Translator). Moreover, we would consult experts proficient in languages.

Other comments:

Q1. The authors should arrange the order of the abstract sections according to the main text (Introduction/background, Methods, Discussion).

Response: We are extremely grateful to the reviewer for pointing out this problem. In accordance with the reviewer’s comments, we would like to arrange the order of the abstract sections according to the main text consisting of three parts (introduction, methods and analyses, discussion).

Q2. The manuscript has some typing mistakes and grammatical errors that need to be corrected

Response: Thank you for your valuable suggestions. Following the reviewer’s suggestions, we carefully checked and corrected the mistakes and grammatical errors one by one. And the corrections were marked in red in the marked version.

Our deepest gratitude goes to you for your careful work and thoughtful suggestions that would help to improve this paper substantially. As the reviewers’ suggestions, we tried our best to improve the manuscript and made some changes in the manuscript. We appreciate for the editors and reviewers’ warm work earnestly, and hope that the corrections will meet with approval.

Once again, thank you very much for your efforts in reviewing our manuscript.

Your sincerely,

Meng Lv

Department of Anesthesiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Ji'nan, Shandong Province, 250014, China.

Telephone: +8615169105373

Email: qylvmeng@163.com

Submitted filename: Response to Reviewers.docx

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12 Sep 2022

Submitted filename: Peer review. R1.docx

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27 Sep 2022

Dear editor and reviewers,

Thanks for your letter and the reviewers’ comments concerning our manuscript entitled “Intensive versus conservative glycemic control in patients undergoing coronary artery bypass graft surgery: A protocol for systematic review of randomised controlled trials” (PONE-D-22-18985). The comments are very helpful and valuable for revising and improving our manuscript. We would like to thank you for allowing us to submit a revised copy of the manuscript, and we highly appreciate your time and consideration. We have read through those comments carefully and revised the manuscript accordingly. In addition to the response letter, a marked and clean version of our revised manuscript were uploaded based on the instructions provided in your letter. Revised portions are marked in red in the marked version of revised manuscript.

Reviewer#1:

The authors have well revised the manuscript; however, I can still see some errors in writing, particularly in using the articles (i.e., the). As an example from the abstract, it should be written: "the intensive care unit (ICU), the incidence of postoperative myocardial infarction), the incidence of ....". Or in discussion of the Abstract "There is no certain evidence that which strategy of glycemic...." is better to change "There is no certain evidence to clarify which strategy of glycemic....". Please double check the manuscript for these issues.

Response: Thank you for your valuable suggestions. Following the reviewer’s suggestions, we carefully corrected the mistakes and double checked the manuscript. And the corrections were marked in red in the marked version.

Once again, thank you very much for your efforts in reviewing our manuscript.

Your sincerely,

Meng Lv

Department of Anesthesiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Ji'nan, Shandong Province, 250014, China.

Telephone: +8615169105373

Email: qylvmeng@163.com

Submitted filename: Response to Reviewers.docx

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4 Oct 2022

Intensive versus conservative glycemic control in patients undergoing coronary artery bypass graft surgery: A protocol for systematic review of randomised controlled trials

PONE-D-22-18985R2

Dear Dr. Lv,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Ozra Tabatabaei-Malazy

Academic Editor

PLOS ONE

7 Oct 2022

PONE-D-22-18985R2

Intensive versus conservative glycemic control in patients undergoing coronary artery bypass graft surgery: A protocol for systematic review of Randomised controlled trials

Dear Dr. Lv:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Ozra Tabatabaei-Malazy

Academic Editor

PLOS ONE