Protective Treatments against Endothelial Glycocalyx Degradation in Surgery: A Systematic Review and Meta-Analysis

Round 1

Reviewer 1 Report

Report on review paper "Protective treatments against endothelial glycocalyx degradation in surgery: a systematic review and meta-analysis"

The authors report on a systematic review of works focusing on the endothelial glycocalyx (EG) degradation in surgery, and comparisons with inflammatory response, and extravasation. Biomarkers for glycocalyx degradation (syndecan-1, heparan sulphate), inflammatory markers (CRP) and capillary leakage are particularly investigated.
They show that plasma syndecan-1 is an important post operative marker. Methylprednisolone is a promising drug playing a role on the transient increase of syndecan-1. Other studies (hydrocortisone for ex.) are not so sound or remain isolated, but may suggest to study correlations with cytokines, fluid maintenance, and albumin extravasation.

Altogether, these results, lacking sometimes data on large populations, are important for finding EG treatments in surgery. Therefore the review is important and deserves publication. Below are listed minor corrections

Abstract 
- RCT (Randomised Control Trials) and UTI (Urinary Tract Infections) should be defined.

Introduction 
- 4000-7000m. Not clear ! Are we talking about nanometers (nm) ?
- What is the thickness of the glycocalyx layer ?
- Figure 1: what do the authors mean by "loss of fluid" ?

Materials and methods
- Khan H should (H.K.)
- Table 1: patients age is unclear e.g. 0.37 (0.15-1.36) ??
- Endothelial glycocalyx is used a lot and should abbreviated properly as EC (like in Fig2 where it is not defined yet)

page 9: hyluronan, please correct

Author Response

Dear Reviewer,

Thank you for taking the time to analyse our research. Below are the revisions we have made;

Abstract

• We have defined the terms RCT (randomised controlled trials) and UTI (ulinastatin).

Introduction

• ‘m’ is an error. It should be meters squared. This has been corrected to ‘m²’.
• The thickness of the EG has been added (0.5µm in capillaries to 4.5µm in the carotid artery).
• ‘Loss of fluid’ refers to the extravasation as a result of the EG degradation. Endothelial dysfunction causes albumin, followed with fluid, to leak out of the vascular wall. This has been explained on page 3.

Materials and Methods

• ‘Khan H’ has been corrected to ‘H.K.’
• One of the RCTs of Pesonen’s study had investigated on neonates. Hence, the age was shown in decimal places such as ‘0.37 (0.15-1.36)’. Patients included in this RCT were under the age of 1 year-old. The figures have been directly lifted from the published article.
• All references to ‘endothelial glycocalyx’ have been abbreviated to ‘EG’.

Page 9

• Hyluronan has been corrected

Thank you for your comments. 

Kind Regards

Hasnain

Reviewer 2 Report

In the present study the Authors investigate protective treatments against endothelial glycocalyx degradation in surgery, reviewing the pooled data from 385 patients in 8 randomized clinical trials (RCTs). Moreover, the Authors propose suggestions for improved uniformity and enhanced confidence for future RCTs.  

Overall the review is well conducted and has interesting results. Comments for minor revision:

1. The introduction is too long; I would advise on shortening.
2. Please note that abbreviations must be written out in full the first time they are mentioned in the abstract and the text, and used thereafter except at the beginning of a sentence. For example, in the abstract, RCTs and UTI were not written out in full.
3. Please provide a brief comment about the role of pro-inflammatory cytokines and increased oxidative stress in endothelial glycocalyx damage (Diagnostics (Basel). 2021 May 30;11(6):993, Basic Res Cardiol. 2021 Feb 6;116(1):9, Food Chem Toxicol. 2020 Nov;145:111694).
4. The Kim study included patients undergoing off-pump coronary artery bypass graft (CABG) surgery, whereas in the other 4 clinical trials patients underwent on-pump conventional CABG. The surgical technique is important, as it has been shown that avoiding cardiopulmonary bypass and cardioplegic arrest during off-pump CABG lead to differences in the profile of syndecan-1 and heparin sulfate concentrations in the plasma (J Thorac Cardiovasc Surg. 2009 Dec;138(6):1445-7). The Authors should mention this issue.
5. Given that the RCTs included in the systematic review show variability in patients age and comorbid conditions, the Authors should state that endothelial shedding products in plasma, such as syndecan-1, are dependent on kidney function (Clin Hemorheol Microcirc. 2019;72(2):161-168).
6. Page 14 “Conclusions”, line 4: “Reviewing the pooled data from 385 patients and 7 RCTs”, please correct to “…and 8 RCTs”.

Author Response

Dear Reviewer,

Thank you for taking the time to analyse our research. Below are the revisions we have made;

Abstract

• We have defined the terms RCT (randomised controlled trials) and UTI (ulinastatin).

Introduction

I have slightly shortened my introduction by reducing the explanation of the Johanssen study and the mechanism of mechanotransduction.

Points 3-5

• I have added a brief explanation for each point using references 11, 29 and 42 respectively.

Point 6

• I have corrected ‘7 RCTs’ to ‘8 RCTs’

Thank you for your comments

Kind Regards

Hasnain