The Impact of Critical Illness on the Outcomes of Cardiac Surgery in Patients with Acute Infective Endocarditis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Authors analyse and describe the impact of critical ilness status in post operative outcomes following surgery for acute endocarditis.
Major limitation of this paper is the unclear definition of critical ilness which authors consider as any reason for ITU admission.

Unfortunately, for the purpose of this study and to achieve meaningful relevance, critical illness needs to be better defined and clarified.

looking in the details:

Study Design:

a) Since the aim of the work is to evaluate the impact of critical state on the outcomes of patients with infective endocarditis, I would also include in the evaluation patients with infective endocarditis who did not undergo surgery.

b) In the tables relating to the study groups, 2 aspects must be specified, namely the indications for admission to the ITU (i.e. respiratory, haemodynamic, renal or cerebral) and the subsequent indications for surgical intervention. This is especially relevant in the 26% of patients who underwent elective surgery although they were admitted to the ITU. These aspects (indications for ITU admission and for surgery, according current guidelines for treatment of acute endocarditis) are in my mind mandatory to evaluate the real impact of critical ilness in the history of these patients .

c) the median time to surgery has also to be better clarified as, the current guidelines define different time to surgery according different clinical presentation (i.e high risk of embolization, persistent infective status, valve erosion etc etc).

d) the overall discussion has also to be targetted according 

Author Response

1. Authors analyse and describe the impact of critical illness status in post operative outcomes following surgery for acute endocarditis.
   Major limitation of this paper is the unclear definition of critical illness, which authors consider as any reason for ITU admission.

Unfortunately, for the purpose of this study and to achieve meaningful relevance, critical illness needs to be better defined and clarified.

*** Response

We concur that the definition of critical illness is not clear. There is no universal definition or criteria used to define critical illness or critically ill patients. Albeit the lack of consensus in the definition, critical illness is a term used in research, resource allocation and insurance claims. For the purposes of our study, we have referred to patients who were admitted to intensive care with a diagnosis of infective endocarditis for investigation, monitoring and organ support by any means with the aim of preventing deterioration prior to cardiac surgery for the infective endocarditis.  The comparators were patients with a primary diagnosis of infective endocarditis who were admitted to intensive care after cardiac surgery for infective endocarditis.

To provide some data to support the categorization of critical illness, we have now provided a list of reasons for these patients being admitted to ITU including diagnoses and invasive therapies. (Table 4)..

We have also extracted APACHE III score of all the patients to  define and compare critical illness severity.

2. Study Design:
3. a) Since the aim of the work is to evaluate the impact of critical state on the outcomes of patients with infective endocarditis, I would also include in the evaluation patients with infective endocarditis who did not undergo surgery.

***Response

It is true that the evaluation of patient who did not undergo cardiac surgery is important and interesting. However, in this study, we only wanted to compare the outcome of cardiac surgery in-patient who were critically ill compared to those who were not admitted to ICU. Patients who did not receive cardiac surgery are discussed elsewhere in a different paper. These patients were captured by a different database, which do not provide EUROSCOREs and other relevant comparable parameters.

Even more importantly, patients who did not have surgery for endocarditis were those who either had (a) less severe disease which could be managed medically or (b) life-limiting illnesses, severe comorbidities or advanced age which would have precluded them from undergoing surgery. These patients are inherently different to those who underwent surgery for endocarditis, and including these patients would result in an “apples and oranges” comparison.

1. b) In the tables relating to the study groups, 2 aspects must be specified, namely the indications for admission to the ITU (i.e. respiratory, haemodynamic, renal or cerebral) and the subsequent indications for surgical intervention. This is especially relevant in the 26% of patients who underwent elective surgery although they were admitted to the ITU. These aspects (indications for ITU admission and for surgery, according current guidelines for treatment of acute endocarditis) are in my mind mandatory to evaluate the real impact of critical illness in the history of these patients.

*** Response

This is very important and relevant information. This information is not captured by the database used in this study. The details for the indications for major organ support and the outcomes have now been discussed.

To provide some data to support the categorization of critical illness, we have now provided a list of reasons for these patients being admitted to ITU including diagnoses and invasive therapies. (Table 4).

 

1. c) The median time to surgery has also to be better clarified as, the current guidelines define different time to surgery according different clinical presentation (i.e. high risk of embolization, persistent infective status, valve erosion etc. etc.).

*** Response

The median time to surgery refers to the time from the cardiothoracic consultation to the timing of surgery. There is no universal definition of the right timing of surgery from guidelines.

The elective surgery patients who were admitted to ICU refers to the group of patients who had other acute or competing issues that required to be sought out before the cardiac surgery could proceed. An example is a patient who has a neurological complication who is prioritised for the neurosurgical procedure before the cardiothoracic surgery. The database does not provide the reason for the elective surgery, which is the limitation of a retrospective database analysis.

To our understanding, there is no current consensus as to the optimal timing of early surgery. The ESC guideline classifies surgical indications in IE as emergent (within 24 hours), urgent (within a few days), and elective (after 1-2 weeks of antibiotic therapy). The AHA/ACC guideline defines early surgery as occurring during the initial hospitalization and before completion of a full therapeutic course of antibiotics.

 

1. d) The overall discussion has also to be targeted according 

*** Response

Thank you. This has been taken into consideration and modifications made accordingly.

Reviewer 2 Report

Comments and Suggestions for Authors

Line 73: were there patients needing cardiac surgery, but who refused, or who were too sick to undergo surgery, while this was indicated? What would be the effect of their inclusion?

How many patients had a preoperative need for (mechanical) ventilation or a preoperative acute renal injury? What was the effect of these confounders on the outcome? 

Were there patients with prosthetic valve endocarditis, with cardiac abscesses, AV blocks and fistulae?

the number of closures of fistulae, abscesses and aortic root replacements should be specified. 

 

 

 

 

 

Author Response

1. Line 73: were there patients needing cardiac surgery, but who refused, or who were too sick to undergo surgery, while this was indicated? What would be the effect of their inclusion?

*** Response

The study is investigating patients who were diagnosed with infective endocarditis, who are admitted to ICU for the management of the complications of surgery and the impact of those complications on the outcome of cardiac surgery. The patients who did not undergo cardiac surgery cannot be included in the outcomes of surgery as they have not undergone the procedure.

Additionally, patients who did not have surgery for endocarditis were those who either had (a) less severe disease which could be managed medically or (b) life-limiting illnesses, severe comorbidities or advanced age which would have precluded them from undergoing surgery. These patients are inherently different to those who underwent surgery for endocarditis, and including these patients would result in an “apples and oranges” comparison.

Patients who were offered surgery but refused are a separate group worthy of consideration. We did not have this data available for our study.

2. How many patients had a preoperative need for (mechanical) ventilation or a preoperative acute renal injury? What was the effect of these confounders on the outcome? 

*** Response

This is an important and relevant question. We have included the characteristics of the critically ill patient to highlight the need for ICU admission. Thank you

To provide some data to support the categorization of critical illness, we have now provided a list of reasons for these patients being admitted to ITU including diagnoses and invasive therapies. (Table 4)..

 

3. INDICATIONS for ICU admission:

***Response

This has been addressed and added to Table 4.

To provide some data to support the categorization of critical illness, we have now provided a list of reasons for these patients being admitted to ITU including diagnoses and invasive therapies. (Table 4)..

 

Were there patients with prosthetic valve endocarditis, with cardiac abscesses, AV blocks and fistulae?

*** Response

We reviewed the database and have included the information for the valves involved (native, prosthetic, and aortic root).  The ANZCTS database lacks the data on the sizes of vegetations  involved. This is a limitation of the retrospective study and the design of the database. We agree the number of closures of fistulae, abscesses and aortic root replacements should be specified. This is the detail, which will be included in the prospective trial or infective endocarditis registry which we are currently developing.

Reviewer 3 Report

Comments and Suggestions for Authors

In the abstract, it is essential to clearly define what is meant by “Illness.” If there are constraints regarding word count, I suggest omitting the description of the database, as this is already well-detailed in the Methods section. However, it is inappropriate for the reader to go through the abstract without understanding the criteria used to distinguish between the two patient populations.

There is a notable discrepancy between the study results and the conclusions drawn by the authors. The only reported outcomes are 30-day mortality, bleeding, and length of hospital stay. Of these, the first two appear to be comparable between the “illness” and “non-illness” populations. Why, then, is it stated that the “illness” group had poorer outcomes? Lines 31-32

A major limitation of the study is the exclusion of patients who did not undergo surgery. This introduces a significant selection bias, rendering the statement in lines 230–232 inaccurate: the low mortality rate observed is likely due to the exclusion of high-risk patients who were not deemed operable.

The definition of “illness” relies on the decision to admit a patient to the ICU prior to surgery. However, in the absence of objective criteria (such as Swan-Ganz measurements, anuria, malignant arrhythmias, or extreme severe valvular disease), this decision appears to be highly subjective. This is underscored by the presence of patients who underwent elective surgery despite being admitted to the ICU preoperatively (line 136). I would argue that this is less “interesting” than it is paradoxical.

I fully agree with the statement in lines 97–98. However, the subsequent reference to several endocarditis-specific scoring systems (lines 212–223) lacks clear purpose. The authors should have selected one of these scores and compared it directly with the EuroSCORE.

Regarding Table 1: EuroSCORE is classically stratified into low (<4%), intermediate (4–8%), and high (>8%) risk categories, based on studies in aortic valve stenosis. Additionally, the rest of the table lacks sufficient detail. It does not indicate which valve was affected by endocarditis, whether multiple valves were involved, or whether the valve was native or prosthetic. These omissions substantially limit the interpretability of the findings.

There are repetitions in lines 123–124 and 128–129, which should be addressed for clarity and conciseness.

Line 151 raises another point requiring elaboration: were the patients undergoing CABG also affected by acute endocarditis? The wording suggests a chronic process. Moreover, the mention of TAVI in the context of endocarditis is completely off-label; such a patient should be excluded from the analysis without hesitation. As for “other cardiac surgeries,” these should be clearly defined and described.

In lines 205–207, regarding surgical timing, the authors should acknowledge the limitations of current clinical guidelines. I recommend reviewing and potentially citing the recent study “The Surgical Dilemma” which offers valuable considerations regarding acute aortic endocarditis.

Finally, lines 264–267, which conclude the Discussion, should have contained the mot compelling insights of the manuscript. The authors ought to elaborate on how clinical practice could benefit from, or be influenced by, the findings of this study.

Author Response

1. In the abstract, it is essential to clearly define what is meant by “Illness.” If there are constraints regarding word count, I suggest omitting the description of the database, as this is already well detailed in the Methods section. However, it is inappropriate for the reader to go through the abstract without understanding the criteria used to distinguish between the two patient populations.

*** Response

Thank you for the question. As per the current description. Admission to intensive care is considered critical illness. We understand the definition of critical unwellness/illness is a point of contention, however for the purpose of the study, endocarditis for investigation, monitoring and organ support by any means with the aim of preventing deterioration prior to cardiac surgery for the infective endocarditis.  The comparator were patients with a primary diagnosis of infective endocarditis who were admitted to intensive care after cardiac surgery for infective endocarditis. As per other reviewers, definition of critical illness has been revised. We have updated the abstract accordingly so that readers will immediately understand what we mean by critical illness.

 

2. There is a notable discrepancy between the study results and the conclusions drawn by the authors. -1) The only reported outcomes are 30-day mortality, bleeding, and length of hospital stay. Of these, the first two appear to be comparable between the “illness” and “non-illness” populations. Why, then, is it stated that the “illness” group had poorer outcomes? Lines 31-32

***Response

Thank you for the comments and review. The manuscript has been corrected accordingly to reflect that. Additionally, the comparator is “critical illness” which has a specific meaning now clarified in the abstract and methods sections. It is not accurate to state that the group of patients who did not have pre-operative critical illness did not have any illness. They simply did not require invasive monitoring or organ support prior to surgery.

3. A major limitation of the study is the exclusion of patients who did not undergo surgery. This introduces a significant selection bias, rendering the statement in lines 230–232 inaccurate: the low mortality rate observed is likely due to the exclusion of high-risk patients who were not deemed operable.

***Response

It is true that the evaluation of patient who did not undergo cardiac surgery is important and interesting. However, in this study, we only wanted to compare the outcome of cardiac surgery in-patient who were critically ill compared to those who were not admitted to ICU. We agree the exclusion of the patients who did not undergo surgery may introduce a selection bias. However, working with the limitations of the database, we had to investigate the impact of critical illness and infective endocarditis on cardiac surgery. It would be interesting to see the outcomes of those who did not undergo surgery and there are discussed elsewhere.

4. The definition of “illness” relies on the decision to admit a patient to the ICU prior to surgery. However, in the absence of objective criteria (such as Swan-Ganz measurements, anuria, malignant arrhythmias, or extreme severe valvular disease), this decision appears to be highly subjective. This is underscored by the presence of patients who underwent elective surgery despite being admitted to the ICU preoperatively (line 136). I would argue that this is less “interesting” than it is paradoxical.

**** Response

Thank you very much for the question. Unfortunately there is no universal description or objective measure of critical illness. There is no objective criteria for critical illness. For the purposes of the study, we had to choose a standard or reference point. That standard is defined as a state of being so unwell to require intensive care. Understandably this standard may not be accurate and we accept that as a limitation of the study.

 

5. I fully agree with the statement in lines 97–98. However, the subsequent reference to several endocarditis-specific scoring systems (lines 212–223) lacks clear purpose. The authors should have selected one of these scores and compared it directly with the EuroSCORE.

****Response

Thank you once again for an interesting observation. The inclusion of the several endocarditis specific scoring systems is for reader to be aware of and to highlight that the idea is already being thought elsewhere. It illustrates the complexity of the illness and the current ongoing interest with no current validated scoring system. One of the reviewers has requested a commentary on the EndoSCORE of which we have happily obliged We couldn’t compare our finding because it lacked the parameters required for the comparing IE specific Scoring systems.

We are unable to compare the EuroSCORE II  to the suggested Infective Endocarditis score because this is labour intensive.  This can only be achieved on a prospective study with the appropriate parameters used.

.

6. Regarding Table 1: EuroSCORE II is classically stratified into low (<4%), intermediate (4–8%), and high (>8%) risk categories, based on studies in aortic valve stenosis. Additionally, the rest of the table lacks sufficient detail. It does not indicate which valve was affected by endocarditis, whether multiple valves were involved, or whether the valve was native or prosthetic. These omissions substantially limit the interpretability of the findings.

***Response

We can only provide and interpret data to the limits of the database. We have acknowledged the weakness of the study being based on a database and the retrospective nature of the study overall.

7. There are repetitions in lines 123–124 and 128–129, which should be addressed for clarity and conciseness.

***Response

The repetitions have been deleted and clarified. Thank you.

8. Line 151 raises another point requiring elaboration: were the patients undergoing CABG also affected by acute endocarditis? The wording suggests a chronic process. Moreover, the mention of TAVI in the context of endocarditis is completely off-label; such a patient should be excluded from the analysis without hesitation. As for “other cardiac surgeries,” these should be clearly defined and described.

***Response

1. This is a good question. We have interrogated the database. The CABG surgery were opportunistic  for the patients who were found to have infective endocarditis. Following revisions and interrogation of the database we   excluded 33 non-critically ill patients and 3 non critically ill patient. 
2. We excluded patients who had a historic diagnosis of infective endocarditis who were subsequently admitted for an unrelated surgery.

 

1. We excluded the TAVI patient. Thank you.

 

 

9. In lines 205–207, regarding surgical timing, the authors should acknowledge the limitations of current clinical guidelines. I recommend reviewing and potentially citing the recent study “The Surgical Dilemma” which offers valuable considerations regarding acute aortic endocarditis.

***Response

Thank you. We have acknowledged the limitations of clinical guidelines regarding the timing of cardiac surgery.

 

We may not have referred to the “surgical dilemma” however, we have acknowledged the limitations of guidelines on timing of surgery for the critically ill patients. We have refered to both the ESC and AHA/ACA guidleines.

10. Finally, lines 264–267, which conclude the Discussion, should have contained the most compelling insights of the manuscript. The authors ought to elaborate on how clinical practice could benefit from, or be influenced by, the findings of this study.

***Response:

The commented is noted and the discussion and conclusion has been revised to highlight the benefits of the study.

Thank you. We acknowledge the limitations of the study, especially the small size and retrospective design which prohibit generazability and clinical application. The study can be used to inform design of infective endocarditis databases and registries to better understand and manage patients with infective endocarditis.

Reviewer 4 Report

Comments and Suggestions for Authors

I read the paper by Matebele et al. "The impact of critical illness on the outcomes of cardiac surgery in patients with acute infective endocarditis".

The manuscript is well written and can be clearly read throughout the whole text. The limitations are correctly stated, but should also consider adding the small sample size (critically ill) may limit the detection of possible significant differences.

As concluded quite agreeably by the Authors, while the originality of the findings is definitely intriguing, the weakness of the study is strongly related to its retrospective nature and limited sample size. For example, the primary endpoint was more than double in the "critically ill" group, but did not reach significance.

The manuscript could benefit from the following additional comments:

Methods

- The definition of “critically ill” requires clarification. Were there cases of patients admitted to the ICU post cardiac surgery that were more “critical” (like required mechanical circulatory support, maximal doses of inotropes, etc.)? There may be a possible selection bias in the current definition.

- The primary outcome needs clarification. Despite being related, in-hospital and 30-day mortality are different. In-hospital mortality refers to deaths that occur during the same hospital admission—regardless of how long the patient stays. If someone is admitted and dies 5 days or 50 days later before discharge, it’s counted as in-hospital mortality; 30-day mortality refers to any death that occurs within 30 days of a specific event, such as a procedure or admission—regardless of whether the patient is still in the hospital or has been discharged. It captures both in-hospital and post-discharge deaths.

 

Statistical analysis

- Lines 106-108. You first mention that data is presented as median (IQR), and then that it is expressed either as mean (SD) or median (IQR). This is quite confusing and should be revised.

- You mention that 5 parameters were utilized for multivariable analysis. However, it seems that the statistical power to perform such analysis is low. Was the power tested? As a rule of thumb a variables should be added every 10 events. According to your Results there were 20 deaths, i.e., no more than 2 variables should be utilized. Despite this, the confidence interval of the regression analysis is reasonable and not excessively large.

 

Results

- Surprisingly enough the EuroSCORE II was not significantly different between the two groups. Even though the critically ill patients had a larger IQR (up to 9.8), the “critical preoperative state” is one of the parameters utilized to calculate the score and includes situations that are very frequent to patients admitted to the ICU (i.e., preoperative ventilation, preoperative inotropic support, etc.). Can the Authors comment in addition to the paragraph in the Discussion?

- Line 127, correct the mistypo of the EuroSCORE II “92.2”.

- You repeat twice the significant difference in age and IVDU in the Results section. Remove one of the two to avoid redundancy.

- Also the whole paragraph regarding the surgical procedures is duplicated. Please stick to only one of the two.

- Table 4 and Supplementary Table 1 are not mentioned in the text. They should also be briefly described in the Result section.

 

Discussion

- Lines 212-223. It seems the reference for this paragraph should be Gatti et al. (30), not related to REF 29 on bleeding.

- I suggest adding and discussing also the EndoSCORE (Int J Cardiol. 2017 Aug 15:241:97-102.).

 

Text

- Lines 38-39, “octagenarians” should be spelt “octogenarians”.

- Line 70. The “none” should be corrected.

- Line 227. It seems a reference is missing “(x)”.

 

Author Response

I read the paper by Matebele et al. "The impact of critical illness on the outcomes of cardiac surgery in patients with acute infective endocarditis".

1. The manuscript is well written and can be clearly read throughout the whole text. The limitations are correctly stated but should also consider adding the small sample size (critically ill) may limit the detection of possible significant differences.
2. You mention that 5 parameters were utilized for multivariable analysis. However, it seems that the statistical power to perform such analysis is low. Was the power tested? As a rule of thumb, a variables should be added every 10 events. According to your Results there were 20 deaths, i.e., no more than 2 variables should be utilized. Despite this, the confidence interval of the regression analysis is reasonable and not excessively large.

***Response:

Thank you for the detailed review of the statistical analysis. ***Response

Thank you for rightfully pointing out the limitations of multivariable analysis with small sample sizes. However, to pick only 2 variables as suggested would inherently introduce selection bias by the investigators. The investigators instead included all the 5 parameters for the purposes of highlighting important associations that could inform future study hypothesis investigating causality. Importantly, these 5 variables did not show significant collinearity which would have justified pairing. The variance inflation factor (VIF) to assess for collinearity between the ICU length of stay and hospital length of stay was 2.18 (VIF values below 5 are generally acceptable for presentation as separate variables)

2. As concluded quite agreeably by the Authors, while the originality of the findings is definitely intriguing, the weakness of the study is strongly related to its retrospective nature and limited sample size. For example, the primary endpoint was more than double in the "critically ill" group, but did not reach significance.
   
   The manuscript could benefit from the following additional comments:

Methods

- The definition of “critically ill” requires clarification. Were there cases of patients admitted to the ICU post cardiac surgery that were more “critical” (like required mechanical circulatory support, maximal doses of inotropes, etc.)? There may be a possible selection bias in the current definition.

- The primary outcome needs clarification. Despite being related, in-hospital and 30-day mortality are different. In-hospital mortality refers to deaths that occur during the same hospital admission—regardless of how long the patient stays. If someone is admitted and dies 5 days or 50 days later before discharge, it’s counted as in-hospital mortality; 30-day mortality refers to any death that occurs within 30 days of a specific event, such as a procedure or admission—regardless of whether the patient is still in the hospital or has been discharged. It captures both in-hospital and post-discharge deaths.

***Response

This has been clarified.

1. a) Critical illness has been defined to our best ability. We concur that the definition of critical illness is not clear. There is no universal definition or criteria used to define critical illness or critically ill patients. There is no objective measurement of critical illness. Albeit the lack of consensus in the definition, critical illness is a term used in research, resource allocation and insurance claims. For the purposes of our study, we have referred to patients who were admitted to intensive care with a diagnosis of infective endocarditis for investigation, monitoring and organ support by any means with the aim of preventing deterioration prior to cardiac surgery for the infective endocarditis. The comparators were patients with a primary diagnosis of infective endocarditis who were admitted to intensive care after cardiac surgery for infective endocarditis.

We acknowledge that patients can be classified as critically ill after cardiac surgery, however, for the simplicity of the definition, the above definition has been chosen.

 The correct outcome is 30-day mortality and has been used in the manuscript.

 

Statistical analysis

3. Lines 106-108. You first mention that data is presented as median (IQR), and then that it is expressed either as mean (SD) or median (IQR). This is quite confusing and should be revised.

***Response

The data is summarised and presented as means (SD) if normally distributed or medians (IDR) if the distribution is skewed.

4. Results

Surprisingly enough the EuroSCORE II was not significantly different between the two groups. Even though the critically ill patients had a larger IQR (up to 9.8), the “critical preoperative state” is one of the parameters utilized to calculate the score and includes situations that are very frequent to patients admitted to the ICU (i.e., preoperative ventilation, preoperative inotropic support, etc.). Can the Authors comment in addition to the paragraph in the Discussion?

****Response

Unfortunately this important information regarding the preoperative status for the critically ill patients is not available. We agree that this information is very important and crucial to the interpretation of the results and outcome measures.

 

5. Line 127, correct the mistypo of the EuroSCORE II “92.2”.

*** This has been corrected. The correct EuroSCORE II has been discussed.

6. You repeat twice the significant difference in age and IVDU in the Results section. Remove one of the two to avoid redundancy.

Also the whole paragraph regarding the surgical procedures is duplicated. Please stick to only one of the two.

**** Response

This has been corrected. The repeated text has been deleted.

7. Table 4 and Supplementary Table 1 are not mentioned in the text. They should also be briefly described in the Result section.

***Response

Supplementary Table 1 has been removed and Table 4 referred to in the text. Thank you for picking this up.

8. Discussion

Lines 212-223. It seems the reference for this paragraph should be Gatti et al. (30), not related to REF 29 on bleeding.

***Response

This has been corrected. The correct reference is Gatti et al (29)

9. I suggest adding and discussing also the EndoSCORE (Int J Cardiol. 2017 Aug 15:241:97-102.).

***Response:

The EndoSCORE has been discussed as suggested in the manuscript.

10. Text

Lines 38-39, “octagenarians” should be spelt “octogenarians”.

*** Response

This has been corrected to “Octogenarians”

11. Line 70. The “none” should be corrected.

*** Response

This has been corrected to non-critically ill patients

12. Line 227. It seems a reference is missing “(x)”.

*** Response

This has been corrected. Reference X has been inserted: The reference is as follows:

Ahtela E, Oksi J, Porela P, et al. Trends in occurrence and 30-day mortality of infective endocarditis in adults: population-based registry study in Finland BMJ Open 2019;9:e026811. doi:10.1136/bmjopen-2018-026811

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

I appreciate the authors' efforts to revise the manuscript and to address the comments raised in the previous round. However, several substantial concerns remain:

1. It is still unclear what contribution this study offers to everyday clinical practice. I am afraid the answer might be: none.

2. The limitations, as acknowledged by the authors themselves, are numerous and, in my opinion, insurmountable. As a result, the scientific robustness of the study remains highly questionable.

3. The lack of a clear definition of "illness" significantly undermines the credibility of the study design. It raises serious concerns about potential selection bias, to the point that the overall structure and reliability of the study might be compromised.

Author Response

I appreciate the authors' efforts to revise the manuscript and to address the comments raised in the previous round. However, several substantial concerns remain:

1. It is still unclear what contribution this study offers to everyday clinical practice. I am afraid the answer might be: none.

Response

Thank you for a second review and appraisal of the study. This study informs development of a prospective registry for infective endocarditis The study has highlighted some data points which can be explored further in prospective studies to understand the impact of critical illness better. Everyday practice can only be answered by randomised controlled trials which we will design using the registry data to inform the development of hypotheses. This study can be used to determine exactly what data points to incorporate into a prospective registry.

2. The limitations, as acknowledged by the authors themselves, are numerous and, in my opinion, insurmountable. As a result, the scientific robustness of the study remains highly questionable.

Response

Thank you very much for the review and quest for clarity. The limitations of the study have been highlighted and acknowledged. A better-designed infective endocarditis registry which has been informed by this study will identify the appropriate clinical and meaningful parameters to explore and capture critically ill patients with infective endocarditis. This cycle can only be achieved through audit cycle which is what this study has been able to achieve.

3. The lack of a clear definition of "illness" significantly undermines the credibility of the study design. It raises serious concerns about potential selection bias, to the point that the overall structure and reliability of the study might be compromised.

Response:

Thank you for raising these important concerns and inquiries. We acknowledge the inherent complexity and variability in defining the term "illness." One of the strengths of scientific inquiry is its capacity to embrace diverse perspectives and promote constructive dialogue. In our study, we addressed this challenge by referencing existing scoping studies that have attempted to define critical illness, and by incorporating validated ICU severity scoring systems (APACHE III and ANZROD). These tools provide a structured and clinically meaningful framework for characterizing critical illness within our study population.

The design of the study is clearly defined: it exclusively includes patients who were admitted to a cardiac center with a diagnosis of infective endocarditis and who subsequently underwent cardiac surgery for this condition. The study then compares outcomes between patients who were critically ill and those who were not, providing a focused analysis of the impact of critical illness in this specific surgical cohort.

The overall study has an inherent bias due to selection of patients who were only admitted to a cardiothoracic referral centre. Despite its limitations of a small sample size and missing data, the study has been able to evaluate important patient characteristics and the impact of critically illness on the outcomes of patients with infective endocarditis following cardiac surgery. It is important to recognise that infective endocarditis (IE) is a rare condition, and the proportion of patients requiring intensive care due to critical illness is even smaller. This study is therefore unique in presenting the largest single-cohort analysis focused specifically on the impact of critical illness on outcomes in patients undergoing cardiac surgery for IE. Currently, critical illness is not addressed in existing clinical guidelines, and these patients often present complex challenges regarding the decision of operating, optimal timing of surgical intervention and the knowledge of surgical outcomes. Identifying key factors associated with mortality in this population can inform future prospective studies and generate hypotheses for targeted interventional research. For instance, a prospective study could be designed to explore the underlying causes of increased bleeding rates observed in patients with IE. Additionally, the available data points, along with the identification of key missing variables, will contribute to the development of a comprehensive registry aimed at improving the understanding and management of infective endocarditis.

Reviewer 4 Report

Comments and Suggestions for Authors

Thank you for addressing my comments. The revised versions has been improved. However, this new version is characterized my a large amount of mistakes in reporting the numbers between tables and main text. This shows lack of precision and must be thoroughly checked.
Please see my comments below for guidance:

Abstract

- Line 23, correct the IQR for age 49 [42-56].

- Line 31, the p-value for ICU LOS and all values for hospital LOS differ from Table 2.

- Line 32, the p-value for RRT differs from Table 2.

 

Introduction

- Line 44-45, correct “octagenarian” to “octogenarian”

 

Methods

- Line 179, Table 3 doesn’t not present the reasons for ICU admission, it’s Table 4.

 

Results

- Lines 388-389, I would suggest using “isolated” aortic valve, considering that there were also combination of locations that included the aortic valve. Numbers would not sum up in this case.

- Line 390, same as above regarding “isolated” mitral valve.

- Line 409-412, the p-value for ICU LOS and ICU LOS surgery do not match Table 2.

- Line 416, the p-value for RRT does not match Table 2.

- Line 579, the % of cardiovascular issues does not match Table 4.

- Line 582, 34% is not near to “about half”, it would be more correct to “about a third”.

 

Discussion

- Line 594, female sex % of the critically ill does not match Table 1.

- Lines 650-654, the European and American guidelines need a reference.

- Line 675, the IQR for the ANZROD does not match Table 1.

- Line 697, the p-value for ICU LOS does not match Table 2.

- Line 700, the p-value for ICU LOS surgery does not match Table 2.

- Line 717, the p-value for RRT does not match Table 2.

Author Response

Thank you for addressing my comments. The revised versions have been improved. However, this new version is characterized by a large amount of mistakes in reporting the numbers between tables and main text. This shows lack of precision and must be thoroughly checked.

 

We apologise for these. They have been addressed as below.

Please see my comments below for guidance:

Abstract

- Line 23, correct the IQR for age 49 [42-56]. Corrected

- Line 31, the p-value for ICU LOS and all values for hospital LOS differ from Table 2.-Corrected

- Line 32, the p-value for RRT differs from Table 2.Corrected

 

Introduction

- Line 44-45, correct “octagenarian” to “octogenarian”-Corrected (autocorrection reverts it to the former. Apologies)

 

Methods

- Line 179, Table 3 doesn’t not present the reasons for ICU admission, it’s Table 4. Corrected

 

Results

- Lines 388-389, I would suggest using “isolated” aortic valve, considering that there were also combination of locations that included the aortic valve. Numbers would not sum up in this case. Corrected

- Line 390, same as above regarding “isolated” mitral valve.-Corrected

- Line 409-412, the p-value for ICU LOS and ICU LOS surgery do not match Table 2.-Corrected

- Line 416, the p-value for RRT does not match Table 2.-Corrected

- Line 579, the % of cardiovascular issues does not match Table 4.-Corrected

- Line 582, 34% is not near to “about half”, it would be more correct to “about a third”. Corrected

 

Discussion

- Line 594, female sex % of the critically ill does not match Table 1.Corrected

- Lines 650-654, the European and American guidelines need a reference. Corrected

- Line 675, the IQR for the ANZROD does not match Table 1. Corrected

- Line 697, the p-value for ICU LOS does not match Table 2. Corrected

- Line 700, the p-value for ICU LOS surgery does not match Table 2. Corrected

- Line 717, the p-value for RRT does not match Table 2.  Corrected