Diabetic Ketoacidosis Management: Updates and Challenges for Specific Patient Population

Round 1

Reviewer 1 Report

Overall this is a useful review of DKA management in adults. In particular, the review of the literature for specific challenging populations is a helpful contribution to the literature. There are some slightly controversial statements within the paper that do not have adequate references to support them, which need to be addressed. 

Major comments:

The organization of the paper is excellent and it flows and reads well. 

It would be helpful to have a reference for the DKA diagnostic criteria (table 1, lines 58-61) given that different professional societies have had slightly different criteria. 

When discussion fluid resuscitation, it would be helpful in lines 107-109 to clarify the way that the two bag system is used, ie by changing the relative amounts of the two fluids to functionally change the dextrose concentration. There may be some readers who are unfamiliar with this system and it would be helpful to clarify.

In the insulin therapy section, lines 121-124 it is presented that this is the definitive way to manage DKA insulin infusion, and no reference is presented for those sentences. Not every hospital uses the same protocol and if this is presented as the definitive way to manage insulin in DKA there should be a reference or explanation as to why these titration criteria are the best option. 

It is bold and somewhat controversial to state that "loss of kidney function is often associated with improved glycemic control." That statement needs a specific reference if it is kept. In particular, in my experience the loss of glycosuria as a mechanism for decreasing blood glucose in severe hyperglycemia as well as changes in insulin sensitivity around dialysis lead this population to have more labile blood glucose trends. 

There are numerous grammatical errors and difficult-to-read sentences throughout the paper. It would benefit from significant editing. 

Minor comments:

In line 35, I would specify that it is hormone-sensitive lipase which is activated as lipoprotein lipase is inhibited by insulin deficiency.

The figures are very helpful in understanding the issues at play, especially figure 2, but have low image quality and are pixelated. This should be addressed. Also, the word "pancreas" is misspelled in both figure 1 and figure 3.

I would spell out the word units in insulin infusion rates (units/kg/hr rather than u/kg/hr) 

In section 3, make the subsection titles consistent (ie include "DKA in" for every subsection or for none of the subsections)

There is an error in lines 203-204. SGLT inhibitors actually increase reabsorption of ketone bodies which leads to decreased urinary excretion of ketone bodies.

Author Response

Reviewer-1

Overall, this is a useful review of DKA management in adults. In particular, the review of the literature for specific challenging populations is a helpful contribution to the literature. The organization of the paper is excellent and it flows and reads well. There are some slightly controversial statements within the paper that do not have adequate references to support them, which need to be addressed. 

I would like to thank the reviewer for the positive feedback and critiques. Please see below point by point response/ clarification to the specific comments. The changes are highlighted in yellow in the revised manuscript.

 

Major comments:

1. It would be helpful to have a reference for the DKA diagnostic criteria (table 1, lines 58-61) given that different professional societies have had slightly different criteria. Thank you for pointing this out and this section is revised and a reference is added.

 

2. When discussing fluid resuscitation, it would be helpful in lines 107-109 to clarify the way that the two bag system is used, ie by changing the relative amounts of the two fluids to functionally change the dextrose concentration. There may be some readers who are unfamiliar with this system and it would be helpful to clarify. This point is well taken and this section was revised as suggested.

 

3. In the insulin therapy section, lines 121-124 it is presented that this is the definitive way to manage DKA insulin infusion, and no reference is presented for those sentences. Not every hospital uses the same protocol and if this is presented as the definitive way to manage insulin in DKA there should be a reference or explanation as to why these titration criteria are the best option. This section is updated as suggested and the references are updated.

 

4. It is bold and somewhat controversial to state that "loss of kidney function is often associated with improved glycemic control." That statement needs a specific reference if it is kept. In particular, in my experience, the loss of glycosuria as a mechanism for decreasing blood glucose in severe hyperglycemia as well as changes in insulin sensitivity around dialysis lead this population to have more labile blood glucose trends. This point is well taken and this section is revised as suggested.

 

5. There are numerous grammatical errors and difficult-to-read sentences throughout the paper.

The manuscript is thoroughly revised and edited. 

 

Minor comments:

1. In line 35, I would specify that it is hormone-sensitive lipase which is activated as lipoprotein lipase is inhibited by insulin deficiency. Corrected as suggested
2. The figures are very helpful in understanding the issues at play, especially figure 2, but have low image quality. Also, the word "pancreas" is misspelled in both figure 1 and figure 3. Corrected as suggested.
3. I would spell out the word units in insulin infusion (units/kg rather than u/kg). Corrected as suggested.
4. In section 3, make the subsection titles consistent (ie include "DKA in" for every subsection or for none of the subsections). Corrected as suggested.
5. There is an error in lines 203-204. SGLT inhibitors actually increase reabsorption of ketone bodies which leads to decreased urinary excretion of ketone bodies. Apology for the typo and corrected it as suggested.

 

Reviewer 2 Report

Please find minor comments attached 

Comments for author File: Comments.docx

Author Response

Reviewer-2

I thank the journal for giving me an opportunity to evaluate the article titled “Diabetic ketoacidosis management: Updates and challenges for specific patient population” by Azza El-Remessy. Overall, the review is comprehensive and detailed, focusing on DKA and its management in special populations. There are some minor suggestions that the author is requested to consider before this paper can be accepted for publication.

I would like to thank the reviewer for the positive feedback and critiques. Please see below point by point response/ clarification to the specific comments. The changes are highlighted in yellow in the revised manuscript.

 Figure 1: More clarity is needed. Is this image taken from some book/article? If yes, references are needed. The image resolution must be better. “Pancrease” spelling, hyphen between “aminoacids”. Is “vasc” vascular? The resolution of the figure is enhanced and corrected as suggested.

3. Table 1: references are needed, where did the author refer this table from? This section is updated as suggested and the references are updated.
4. Lines 100-101: Reference for sentence ”Traditionally, hyperglycemia is corrected ” Ref is inserted.
5. Lines 105-110: More references needed for this paragraph. This section is revised and updated.
6. Lines 195-199: Please include references (35352682) for these statements This section is revised and updated.
7. Some information on DKA in a setting of transplantation (whole pancreas or auto/allo-islets) related to pancreas pathologies (autoimmune T1D/T2D/pancreatitis) may be useful for the readers (for example – PMID: 30541144) A new section is added “3.3 DKA in acute pancreatitis and transplants”.

 

7. Please include a section on conclusions and future perspectives for the review. A new section (4. Conclusion) is added.

Reviewer 3 Report

This review article addresses the classic concepts of diagnosis and treatment of diabetic ketoacidosis (DKA) with focus on specific patient populations including the latest concepts of SGLT2-inubitor induced euglycemic DKA as well as DKA associated with SARSCoV-2 infection. The length and number of references are appropriate for an overview of DKA. The content is based on well-established literature as available. The manuscript is well written, and the topic is relevant to all clinicians managing patients with diabetes.

Specific comments:

Figures

Fig 1 and 2 have blurred images, is it possible to have a higher resolution

Figure 3: Recommend replacing the words “secretion” to excretion for glucose and sodium under the kidney image. Also, it is unclear what the symbol next to “insulin secretion” means?

Line 65: Is there a reference for this statement

Line 101: Repetitive word “to”

Line 172: Incomplete sentence and inappropriate punctuation, please review

Line 211-219: Please clarify if the STICH and STOP DKA protocols are for inpatient or outpatient DKA maangment. If they are for outpatient, please comment on the use of the traditional DKA protocol in SGLT2-I associated DKA and any changes that are appropriate

Section 3.2 for Renal Replacement and Section 3.4 for CHF- please comment on any modifications that would be needed in insulin, fluid, and/or potassium replacement in these specific disease states. Alternatively, you can add this to the treatment section 2.3 and 2.4

Please add a brief conclusion paragraph

Author Response

Reviewer-3

This review article addresses the classic concepts of diagnosis and treatment of diabetic ketoacidosis (DKA) with focus on specific patient populations including the latest concepts of SGLT2-inubitor induced euglycemic DKA as well as DKA associated with SARSCoV-2 infection. The length and number of references are appropriate for an overview of DKA. The content is based on well-established literature as available. The manuscript is well written, and the topic is relevant to all clinicians managing patients with diabetes.

I would like to thank the reviewer for the positive feedback and critiques. Please see below point by point response/ clarification to the specific comments. The changes are highlighted in yellow in the revised manuscript.

 Specific comments:

• Fig 1 and 2 have blurred images, is it possible to have a higher resolution. The resolution of the figure is enhanced and corrected as suggested.

 

• Figure 3: Recommend replacing the words “secretion” to excretion for glucose and sodium under the kidney image. corrected as suggested

Also, it is unclear what the symbol next to “insulin secretion” means? It means inhibit and it is now changed to an arrow to describe the action of SGLT inhibitors of decreasing insulin secretion.

• Line 65: Is there a reference for this statement. A reference is now cited “Tzamaloukas et al 2005”.
• Line 101: Repetitive word “to”. removed
• Line 172: Incomplete sentence and inappropriate punctuation, please review. That section is revised.
• Line 211-219: Please clarify if the STICH and STOP DKA protocols are for inpatient or outpatient DKA-management. The text is updated to reflect outpatient education and management.

If they are for outpatient, please comment on the use of the traditional DKA protocol in SGLT2-I associated DKA and any changes that are appropriate. This section is revised and updated.

•  

Section 3.2 for Renal Replacement and Section 3.4 for CHF- please comment on any modifications that would be needed in insulin, fluid, and/or potassium replacement in these specific disease states. 3.2 section is revised and updated.

• Please add a brief conclusion paragraph

A new section (4. Conclusion) is added.

 

Round 2

Reviewer 1 Report

Major comments: 

Great job incorporating feedback, the paper is now stronger and reads more clearly. This will make an excellent addition to the literature

Minor comments:

- Page 4 line 118-121: I don't know that this sentence giving examples of different fluid percentages is really necessary, I would remove it. In the prior sentence you may want to also specifically mention that the change in percentages of fluids changes the sodium concentration as well.

- Page 7 line 224: typo, I think you meant "severe" not "sever"

- Page 11 line 375: would change "Diabetic patients" to "Patients with diabetes"

Author Response

Great job incorporating feedback, the paper is now stronger and reads more clearly. This will make an excellent addition to the literature.

Thank you and greatly appreciated!

Minor comments:

- Page 4 line 118-121: I don't know that this sentence giving examples of different fluid percentages is really necessary, I would remove it.

A clarification with detailed example of fluid percentage will be helpful for readers that are not familiar with the 2-bag system, hence it is kept.

In the prior sentence you may want to also specifically mention that the change in percentages of fluids changes the sodium concentration as well. Added as suggested

- Page 7 line 224: typo, I think you meant "severe" not "sever". Corrected to severe.

- Page 11 line 375: would change "Diabetic patients" to "Patients with diabetes" Corrected as suggested.