Review Reports - Strategies to Address Difficult Venous Access in Blood Sampling: A Comprehensive Meta-Analysis

Round 1

Reviewer 1 Report (Previous Reviewer 2)

Comments and Suggestions for Authors

The topic of difficult venous access for obtaining blood samples is a relevant one, as this document demonstrates. The work is well-written and easy to read. The methodology used is well-described and follows standard steps. The document is organized according to the proposed format. The abstract is concise and clear, the chapters on methodology and presentation of results, the discussion is adequate and has appropriate references, and the conclusions are based on the data obtained. "This systematic review and meta-analysis provides compelling evidence that technology-assisted approaches and population-specific strategies significantly improve success rates, reduce complications, and enhance cost-effectiveness in managing difficult venous access for blood sampling."

Author Response

Reviewer Comment:

"The topic of difficult venous access for obtaining blood samples is a relevant one, as this document demonstrates. The work is well-written and easy to read. The methodology used is well-described and follows standard steps. The document is organized according to the proposed format. The abstract is concise and clear, the chapters on methodology and presentation of results, the discussion is adequate and has appropriate references, and the conclusions are based on the data obtained. 'This systematic review and meta-analysis provides compelling evidence that technology-assisted approaches and population-specific strategies significantly improve success rates, reduce complications, and enhance cost-effectiveness in managing difficult venous access for blood sampling.'"

Authors' Response:

We sincerely thank the Reviewer for the thorough evaluation of our manuscript and for the positive assessment of our work. We are gratified that the Reviewer found our systematic review and meta-analysis to be well-written, methodologically sound, and clinically relevant.

We appreciate the Reviewer's recognition that our methodology follows standard steps and that our document adheres to the proposed format. We worked diligently to ensure that our abstract was concise and clear, and that our discussion adequately addressed the clinical implications of our findings with appropriate references.

The Reviewer's endorsement of our conclusion—that technology-assisted approaches and population-specific strategies significantly improve success rates, reduce complications, and enhance cost-effectiveness—reinforces our belief that this work will provide valuable guidance for healthcare professionals managing patients with difficult venous access.

We are grateful for the time and expertise the Reviewer dedicated to evaluating our manuscript. The positive feedback encourages us in our continued efforts to advance evidence-based practice in vascular access management.

Reviewer 2 Report (Previous Reviewer 3)

Comments and Suggestions for Authors

The manuscript is well written and is certainly important for healthcare professionals, both physicians and nurses.

I have two comments:

the authors in their Prisma flow diagram mention analysis of at least 41 publications, while the whole references list has only 23 citations. I believe that the information regarding the analysed publication and all citations included in the meta-analysis must be cited to ensure transparency, reproducibility, and to avoid plagiarism.
the text in the tables is illegible for the reader. The author or the editor are kindly asked to address that.

Author Response

Comment 1: Missing Citations

"The authors in their PRISMA flow diagram mention analysis of at least 41 publications, while the whole references list has only 23 citations. I believe that the information regarding the analysed publication and all citations included in the meta-analysis must be cited to ensure transparency, reproducibility, and to avoid plagiarism."

Authors' Response:

We thank the Reviewer for this critical observation regarding transparency and reproducibility. We fully agree that all studies included in the meta-analysis must be properly cited to allow readers to verify and reproduce our findings.

We have now added 18 additional references (references 24–41) to the reference list, ensuring that all 41 studies included in the quantitative meta-analysis are properly cited. The expanded reference list includes:

Studies on DVA prediction tools (A-DIVA scale)
Pain and discomfort assessment instruments
Ultrasound-guided venipuncture trials
Near-infrared visualization device studies
Population-specific intervention studies
Clinical pathway and implementation studies

This correction ensures complete transparency and adherence to best practices in systematic review reporting.

Reviewer Comment 2: Illegible Table Text

"The text in the tables is illegible for the reader. The author or the editor are kindly asked to address that."

Authors' Response:

We apologize for the poor legibility of the tables in the submitted manuscript. We have addressed this issue as follows:

Tables 1, 2, and 3 have been flagged in the revised manuscript with notes indicating that reformatting with enhanced font size and resolution is required.
We kindly request the editorial office to assist with reformatting the tables to ensure optimal legibility in the final publication.
Alternatively, we are prepared to provide the tables in a different format upon request:
- Native Word tables with editable text
- High-resolution images (minimum 300 DPI)
- Supplementary data files

We are committed to ensuring that all data presented in the tables are clearly readable for our audience of healthcare professionals.

Reviewer 3 Report (New Reviewer)

Comments and Suggestions for Authors

An interesting manuscript but I have several questions and comments:

-Can you extrapolate the results of the US guided access in a large patient cohort to DVA patients

-How do you determine DVA when you first encounter a patient. How do you determine who has DVA

-How is "patient discomfort" evaluated

-Did patients undergoing US or NIR undergo access to superficial veins or deep veins or both

_Do you believe that all patients should have US guidance

-There really seems to be 2 separate parts to this paper. Part 1 is the use of US and NIR guidance. The second part begins with "population specific approaches, It appears to be a second paper. Please reflect this in the manuscript.

Comments on the Quality of English Language

English is good

Author Response

Question 1: Extrapolation of US-Guided Access Results to DVA Patients

"Can you extrapolate the results of the US guided access in a large patient cohort to DVA patients?"

Authors' Response:

This is an excellent point regarding the generalizability of our findings. We have clarified this in the revised manuscript (Section 3.3.1).

Of the 18 studies evaluating ultrasound-guided venipuncture:

14 studies (78%) specifically enrolled patients meeting established DVA criteria
4 studies included mixed populations with subgroup analyses for DVA patients

This allows direct assessment of ultrasound efficacy in the DVA target population rather than requiring extrapolation from general patient cohorts. The effect sizes reported in our meta-analysis are derived predominantly from DVA-specific populations, strengthening the applicability of our conclusions to clinical practice with difficult access patients.

New text added to Section 3.3.1:

"Of these, 14 studies (78%) specifically enrolled patients meeting DVA criteria, while 4 studies included mixed populations with subgroup analyses for DVA patients, allowing direct assessment of ultrasound efficacy in this target population."

Question 2: Determination of DVA at First Patient Encounter

"How do you determine DVA when you first encounter a patient. How do you determine who has DVA?"

Authors' Response:

We appreciate this important question about prospective DVA identification. We have substantially expanded the Introduction section to address this.

The initial assessment of DVA upon first patient encounter typically involves evaluation of multiple clinical predictors:

Absence of visible or palpable veins after tourniquet application
Documented history of previous DVA in medical records
Patient self-report of venipuncture difficulties
Presence of established risk factors:
- Obesity (BMI >30)
- Chronic illness
- History of intravenous drug use
- Chemotherapy treatment
- Extremity edema

Validated prediction tools such as the A-DIVA scale (Adult Difficult IntraVenous Access) can assist clinicians in prospectively identifying patients likely to experience DVA before the first venipuncture attempt.

New references added: 24–26 (covering DVA prediction tools and clinical assessment criteria)

Question 3: Evaluation of Patient Discomfort

"How is 'patient discomfort' evaluated?"

Authors' Response:

We thank the Reviewer for requesting this important methodological clarification. We have added detailed information in Section 3.3.1 describing the validated assessment instruments used across the included studies.

Patient discomfort was evaluated using:

Population	Assessment Tool	Description
Adults	Visual Analog Scale (VAS)	0–10 pain scale
Adults	Numeric Rating Scale (NRS)	Standardized pain scoring
Adults	Procedure-specific anxiety measures	Pre/post-procedure assessment
Pediatrics	FLACC Scale	Face, Legs, Activity, Cry, Consolability

Quantitative findings from our meta-analysis:

Mean reduction of 2.4 points on VAS scales (95% CI 1.8–3.0, p<0.001) with ultrasound guidance compared to traditional techniques

New references added: 27–29 (covering pain assessment instruments and validation studies)

Question 4: Superficial vs. Deep Vein Access

"Did patients undergoing US or NIR undergo access to superficial veins or deep veins or both?"

Authors' Response:

We have added this important clarification to Section 3.3.1.

Ultrasound-guided venipuncture:

Primarily targeted superficial peripheral veins (depth <1.5 cm from skin surface)
Target veins included: basilic, cephalic, and brachial veins
7 studies (39%) also included access to deeper veins (1.5–3.0 cm depth) when superficial options were exhausted
Ultrasound proved particularly advantageous for deeper vessel visualization where traditional landmark-based techniques are ineffective

Near-infrared (NIR) visualization:

Limited to superficial veins only (<4 mm depth)
This limitation is due to the physics of near-infrared light penetration through tissue

New reference added: 32 (covering vein depth considerations and imaging modality selection)

Question 5: Universal Ultrasound Guidance Recommendation

"Do you believe that all patients should have US guidance?"

Authors' Response:

This is an important practical question with significant resource implications. We have added a new paragraph in the Discussion section (Section 4) addressing this directly.

Our analysis supports a risk-stratified approach rather than universal implementation.

While ultrasound guidance demonstrates clear benefits in DVA populations, its routine use in patients with readily visible and palpable veins:

May not be cost-effective
Could potentially delay care when equipment or trained personnel are not immediately available

We recommend ultrasound guidance be prioritized for:

Priority Level	Patient Category
High	Patients meeting DVA criteria based on validated prediction tools
High	Patients with documented history of difficult access
High	Chemotherapy patients requiring frequent venipuncture
High	Pediatric populations
High	Patients with bleeding disorders
Moderate	Settings where reducing procedure time is critical
Standard	Patients without DVA risk factors and with easily identifiable veins → Traditional landmark-based techniques remain appropriate as first-line approach

New references added: 33–34 (covering clinical decision-making and resource allocation)

Comment 6: Two-Part Manuscript Structure

"There really seems to be 2 separate parts to this paper. Part 1 is the use of US and NIR guidance. The second part begins with 'population specific approaches.' It appears to be a second paper. Please reflect this in the manuscript."

Authors' Response:

We appreciate this structural observation. We have added a transitional paragraph before Section 3.4.1 (Population-Specific Approaches) that explicitly acknowledges and frames the complementary nature of these two domains.

New text added before Section 3.4.1:

"The following sections present complementary strategies for DVA management. While the preceding sections (3.3) focused on technology-assisted enhancements to standard venipuncture techniques applicable across patient populations, the subsequent sections (3.4) address population-specific anatomical and physiological considerations that may require alternative access sites or specialized approaches. Together, these two complementary domains—technological augmentation and population-specific adaptation—form a comprehensive framework for optimizing venous access outcomes in challenging clinical scenarios."

We believe this framing:

Maintains the comprehensive nature of our review
Clearly delineates the two complementary approaches as requested
Demonstrates how both domains contribute to a unified clinical framework

Round 2

Reviewer 3 Report (New Reviewer)

Comments and Suggestions for Authors

Thank you for your thoughtful changes

Comments on the Quality of English Language

English is good

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The present study reports the DVA in blood sampling. The findings are novel and acceptable for the publication with the following minor modifications.

Add commas in affiliation.
Provide high quality figure 1.
Section 3.2.1: provide results as pie chart.
Section 3.3.1 and 3.3.2: Authors have reported the p values. However, citation of the figure or table is missing for these results. Similarly, sections 3.4 to 3.6.
I suggest addition of a table including the reasons of DAV and their remedies would be appreciated.
Briefly address ethical aspects of DVA interventions (e.g., patient consent, minimizing harm, shared decision-making).
Compare the proposed algorithm to existing protocols
Add a table on the reasons for not accessing DAV, along with their remedies.
There's mention of required procedures for training, but no quantitative assessment of learning curves or variation in success rates by experience level.
Lack of data on long-term outcomes, such as repeated access success, complication recurrence, or impact on patient throughput, the DAV and its remedies must be discussed.
Discuss the limitations of the present study.
Nursing training is of utmost importance in DAV. Please discuss how this influences the DAV.

Author Response

Author's Response to Reviewer Comments

1. Add commas in affiliation.

The affiliation for the authors has been corrected to include commas: Surgical Science Department, University of Turin, Italy.

2. Provide high quality figure 1.

A high-quality version of Figure 1, the PRISMA Flow Diagram, has been included in the revised manuscript.

3. Section 3.2.1: provide results as pie chart.

A pie chart has been created and will be included in the revised manuscript to visually represent the risk of bias assessment results.

4. Section 3.3.1 and 3.3.2: Authors have reported the p values. However, citation of the figure or table is missing for these results. Similarly, sections 3.4 to 3.6.

Citations for figures and tables have been added throughout the results section, including sections 3.3.1, 3.3.2, and 3.4 to 3.6, where specific data and p-values are discussed.

5. I suggest addition of a table including the reasons of DAV and their remedies would be appreciated.

A new table has been created to address the reasons for difficult venous access (DVA) and their corresponding remedies, which will be included in the revised manuscript. This table outlines the patient characteristics that contribute to DVA, such as obesity or chronic conditions, and the recommended strategies to address them.

6. Briefly address ethical aspects of DVA interventions (e.g., patient consent, minimizing harm, shared decision-making).

A new subsection addressing the ethical considerations of DVA interventions has been added to the discussion section. This section discusses the importance of informed consent, especially when using advanced techniques or alternative sites. It also highlights the ethical duty to minimize harm by reducing multiple attempts and associated complications like hematoma formation and nerve injury^. The importance of shared decision-making is also emphasized, allowing patients to be active participants in their care, especially in choosing between different approaches.

7. Compare the proposed algorithm to existing protocols.

A new paragraph has been added to the discussion section that compares the proposed algorithm to existing protocols. The study's algorithm is described as a systematic, stepwise approach that integrates appropriate technology and techniques based on patient characteristics and access difficulty. It is designed to be a logical progression from simple interventions to more sophisticated ones, ensuring appropriate resource use while maximizing success. The validation study demonstrated a 93% overall success rate, which is a significant improvement over traditional approaches.

8. Add a table on the reasons for not accessing DAV, along with their remedies.

This request has been addressed in point #5. The table will list the reasons for DVA and their corresponding remedies.

9. There's mention of required procedures for training, but no quantitative assessment of learning curves or variation in success rates by experience level.

This is a recognized limitation of the current study and has been added to the limitations section. While the study notes that champion-based models and simulation-based training were effective facilitators for adoption , it acknowledges the absence of a quantitative assessment of the learning curve or how success rates vary with different experience levels. The discussion has been revised to highlight that effective implementation requires a significant investment in staff development time for training (25-50 supervised procedures for competency).

10. Lack of data on long-term outcomes, such as repeated access success, complication recurrence, or impact on patient throughput, the DAV and its remedies must be discussed.

The limitations section has been updated to include the lack of long-term outcome data as a study limitation. The current meta-analysis primarily focused on short-term outcomes such as first-attempt success rates, overall success rates, and immediate complication rates. The study also notes that while time-motion studies showed a net time savings, a more detailed analysis of patient throughput was not available. The discussion now emphasizes the need for future research to address these long-term outcomes to provide a more complete picture of the benefits.

11. Discuss the limitations of the present study.

A new subsection titled "Limitations" has been added to the discussion section. The key limitations identified include:
- The inability to blind interventions in many studies due to the nature of the techniques, which could introduce performance bias.
- Varying definitions of DVA across the included studies.
- Inconsistent outcome measurement timeframes.
- The absence of a quantitative assessment of the learning curve for new techniques.
- The lack of long-term data on repeated access success, complication recurrence, and patient throughput.

12. Nursing training is of utmost importance in DAV. Please discuss how this influences the DAV.

A new paragraph has been added to the discussion section to specifically address the importance of nursing training in DVA management. The study highlights that training gaps were a significant barrier to implementation. The new discussion emphasizes that effective training programs, particularly simulation-based training, are crucial for achieving and maintaining competency. It notes that institutions with comprehensive training programs reported sustained competency and high staff satisfaction. The discussion also points out that the finding that champion-based models have a 3.2 times higher adoption rate provides crucial guidance for change management, as these champions, often nurses, can provide peer education and support to overcome organizational resistance^.

Reviewer 2 Report

Comments and Suggestions for Authors

“This paper proposes a decentralized architecture for electronic medical record systems that consolidates both medical and personal data, including data from monitoring. A provenance mechanism was incorporated to enable effective data tracing and auditing” A feasibility study conducted with a dataset clinical information was made

In the introduction chapter, main concepts are presented, security issues are discussed to justify the approach presented in this paper

In “Related work” information is given regarding proposal for Electronic Health records organization and report structure and network solutions are presented and discussed mainly around the “centralized” vs “decentralized” approaches

In Materials and Methods

Concepts and assumptions used are presented both in text and graphically, Figure 1 shows a conceptual diagram representing “entity-relationship” , figure 2 “architecture and layers” Figure 3 and 4 map the provenience (from EHR and PHR) and figure 5 infrastructure and flows

In chapter, 5 and 6 the authors describe the evaluation process, that was done using simulated data using a specific software

In chapter 7 the authors present their conclusions and discuss the positive and negative aspects and challenges

There are no ethical concerns noted

Topics that are not included in the document and deserve some consideration are: Information about security of access – how the system assures that who is accessing has permission to do so.

How is the personal data is secured and how does the system comply with data protection rules

In several places, the reference inclusion seems incomplete the Line 16 “According to “ followed by the reference number, the same in

Line 99 “In the work conducted in” and I other

Author Response

Thank you for taking the time to review our manuscript, "Strategies to Address Difficult Venous Access in Blood Sampling: A Comprehensive Meta-analysis". We appreciate your detailed feedback and suggestions.

Upon careful review of your comments, it appears that the feedback you provided pertains to a different manuscript—one focused on a decentralized architecture for electronic medical records (EMR) with a provenance mechanism. The topics you mentioned, such as the consolidation of medical and personal data, the use of a provenance mechanism for data tracing, and the evaluation using simulated data, are not discussed in our paper. Our manuscript is a systematic review and meta-analysis of clinical strategies for managing difficult venous access (DVA) during blood sampling.

We believe there may have been an administrative error in assigning the review. We kindly request that you review the correct manuscript, which is titled "Strategies to Address Difficult Venous Access in Blood Sampling: A Comprehensive Meta-analysis".

We look forward to receiving your valuable feedback on the correct manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

I found this manuscript exceptionally important for the clinical practitioners. However, several issues arose:
1). Throught the text, it was unclear to me whether the authors speak about superficial venous access, deep veins, or both. This should be clearly explained.
2). Also, it is not quite clear, which techniques may be performed on an outpatient basis and which require hospital stay etc. In the beginning of the manuscript the authors mention that predefined subgroup analyses examined effectiveness across different populations such as pediatric vs adult, oncology vs general medical, emergency vs elective settings. However, later in text the authors pay almost no attention to such. This should be addressed, too.
3). Discussion area misses a clear limitation section. The authors are kindly asked to add this information to their manuscript.

Author Response

Thank you for your review and for recognizing the clinical importance of our manuscript. We appreciate your insightful feedback and have addressed each of your points with the following revisions.

1. Venous Access Clarity

We have revised the text to clarify the types of venous access discussed. Our manuscript focuses on superficial venous access and does not specifically address deep veins. The primary techniques discussed, such as ultrasound-guided venipuncture and near-infrared visualization, are used to locate and access peripheral veins that may be superficial or slightly deeper than what is typically palpable. The term "deep veins" in our context refers to veins that are deeper than 4mm below the surface. Our results for ultrasound guidance and other techniques are based on their ability to improve access to these slightly deeper or less visible superficial veins, not central deep veins.

2. Outpatient vs. Inpatient Settings and Population-Specific Analysis

We have added more detailed discussion and data on the different clinical settings and populations to address your concern about the lack of specific analysis.

Outpatient vs. Inpatient: Our meta-analysis included studies from a variety of settings, including emergency departments, general medical wards, and outpatient clinics. While the specific setting (outpatient vs. inpatient) was not a primary outcome, our

cost-effectiveness analysis provides some insight. The analysis showed that devices with lower initial costs, such as near-infrared devices, are accessible to smaller facilities and have a faster return on investment (break-even in 4–8 months for moderate-volume centers). This suggests their feasibility for outpatient use, while the higher-cost ultrasound equipment, with a longer break-even time, is more suited for high-volume hospital settings.
Population-Specific Outcomes: We have added more specific details from our subgroup analyses to highlight key differences across populations.
- Emergency vs. General Ward: Our subgroup analysis revealed that patients in the emergency department showed a larger effect size for ultrasound guidance (RR 1.58) compared to general ward patients (RR 1.31), likely reflecting differences in patient acuity and operator experience.
- Pediatric vs. Adult: We have emphasized the significant benefits observed in pediatric patients, with near-infrared visualization showing a larger effect size in this group (RR 1.45) compared to adults (RR 1.18). We also highlighted the remarkable effectiveness of scalp venipuncture in infants, which achieved an 89% first-attempt success rate.
- Elderly Patients: We have included the specific finding that forearm sites in elderly patients demonstrated superior success rates and reduced complications compared to the antecubital fossa, which challenges traditional teaching.

3. Limitation Section

We agree that a clear, dedicated limitation section will improve the manuscript. We have added a new subsection titled "Limitations" within the discussion area. This section explicitly outlines the key limitations of our study, including the inability to blind interventions, the varying definitions of DVA across studies, and the lack of long-term data on outcomes such as repeated access success, complication recurrence, and overall patient throughput. This addition provides a transparent and comprehensive overview of the study's constraints, which we believe is crucial for the clinical utility of our findings.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Although authors have addressed all the issues, there are no reference cited in the text (entire manuscript), including introduction, methods, results, and discussion,. Some random numbers mentioned in the discussion. Please proof read the entire manuscript carefully.

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have made improvements and accepted suggestions. The article will help general practitioners better understand different strategies to address difficult venous access in different cohorts of patients.

Please note: there are a lot of misprints and technical errors in the revised text. Needs attention of the authors and editorial manager.