Introduction

Total knee arthroplasty (TKA) is a widely performed surgical procedure to alleviate pain and improve function in patients with end-stage knee osteoarthritis or other debilitating knee conditions [1-3]. Postoperative bleeding is a common concern following TKA, which can lead to complications such as hematoma formation, wound-related issues, and the need for blood transfusions [2-4]. Therefore, effective hemostatic agents that can reduce postoperative bleeding and improve patient outcomes are of great interest [5-7]. Carbazochrome sodium sulfonate (CSS: sodium 2-amino-4-methyl-5-chloro-6-(2,3-dimethoxyphenyl)pyrimidine-1-sulfonate) is a synthetic hemostatic agent that has been used in various surgical procedures to control bleeding. The pyrimidine ring is a six-membered ring containing two nitrogen atoms and four carbon atoms. The chloro (Cl) and methyl (CH3) groups are attached to the pyrimidine ring. The sulfonate group (SO3-) is attached to one of the carbon atoms of the pyrimidine ring. The dimethoxyphenyl group is attached to another carbon atom of the pyrimidine ring. It acts by promoting platelet aggregation and stabilizing blood vessels, thereby enhancing the hemostatic process [8-10]. The use of CSS in TKA has gained attention as a potential strategy to reduce postoperative bleeding and related complications. However, the evidence regarding the CSS efficacy and its safety in TKA remains limited and inconclusive [11-13].

This article presents a systematic review of the current literature to evaluate the effect of carbazochrome sodium sulfonate in total knee arthroplasty [14-16]. By synthesizing the available evidence, this review aims to assess the impact of CSS on postoperative bleeding, transfusion requirements, wound-related complications, and other relevant outcomes in TKA [17-19].

Postoperative bleeding is a significant concern in TKA, as it can lead to various complications and negatively impact patient recovery. Several studies have explored the potential benefits of CSS in reducing postoperative blood loss in TKA [20-22]. The mechanism of action of CSS, which involves promoting platelet aggregation and stabilizing blood vessels, suggests its potential effectiveness in enhancing hemostasis and reducing bleeding. It is hypothesized that the use of CSS during TKA may lead to decreased blood loss, lower transfusion requirements, and improved patient outcomes [23-25].

Transfusion requirements are an important outcome measure in TKA, as blood transfusions can carry risks such as infection, immunological reactions, and increased healthcare costs. Studies evaluating the CSS effect on transfusion requirements in TKA have yielded conflicting results [26]. Some studies have reported a significant reduction in the need for blood transfusions with the use of CSS, while others have found no significant difference compared to control groups. The variability in study findings may be attributed to differences in study designs, patient populations, surgical techniques, and CSS administration protocols. Therefore, a systematic review of the available evidence is essential to clarify the impact of CSS on transfusion requirements in TKA [27-29].

Wound-related complications, such as hematomas and surgical site infections, can significantly impact patient outcomes and increase healthcare costs. The potential role of CSS in reducing wound-related complications in TKA has been investigated in several studies [30]. CSS's ability to stabilize blood vessels and enhance hemostasis may contribute to the prevention of excessive bleeding and subsequent hematoma formation [31]. Furthermore, CSS's antimicrobial properties have been postulated to reduce the risk of surgical site infections. However, the evidence regarding the CSS effect on wound-related complications in TKA is limited and warrants further investigation [32].

Apart from its hemostatic properties, CSS may have other beneficial effects in TKA. Studies have suggested that CSS may reduce postoperative pain and improve functional outcomes. These potential benefits may be attributed to CSS's anti-inflammatory properties and its ability to modulate pain pathways. However, the evidence regarding the analgesic and functional effects of CSS in TKA is limited and requires more robust investigation [33].

To sum up, the use of carbazochrome sodium sulfonate in total knee arthroplasty holds promise as a potential strategy to reduce postoperative bleeding, transfusion requirements, and wound-related complications [34]. The potential use of carbazochrome sodium sulfonate (CSS) in total knee arthroplasty (TKA) as a means to diminish postoperative bleeding decreases transfusion requirements, and mitigate wound-related complications has garnered interest. However, the existing evidence is both limited and conflicting. This systematic review endeavors to amalgamate the available literature, assess the impact of CSS on pertinent outcomes in TKA, and offer insights into the potential advantages and constraints of CSS as a hemostatic agent.

Experimental

Materials and methods

Search Strategy: An all-encompassing search strategy was devised to identify pertinent studies for inclusion in this systematic review. Electronic databases, specifically PubMed, MEDLINE, Embase, and Cochrane Library, were meticulously searched from their inception until 2023. The search employed a combination of terms such as "sodium 2-amino-4-methyl-5-chloro-6-(2,3-dimethoxyphenyl)pyrimidine-1-sulfonate", "carbazochrome sodium sulfonate", "hemostatic agents," "total knee arthroplasty", "knee replacement", "systematic review", and related expressions. Furthermore, the reference lists of relevant articles and reviews underwent manual scrutiny to unveil additional studies.

Study Selection: Two independent reviewers scrutinized the titles and abstracts of the identified studies to gauge their eligibility for inclusion. Full-text articles of potentially relevant studies were subsequently retrieved and further appraised for eligibility. Inclusion criteria comprised (1) original research articles published in English, (2) studies evaluating the impact of carbazochrome sodium sulfonate in total knee arthroplasty, (3) reporting relevant outcomes such as postoperative bleeding, transfusion requirements, wound-related complications, pain, and functional outcomes, and (4) studies adopting a comparative design (randomized controlled trials, cohort studies, or case-control studies) or systematic reviews/meta-analyses. Studies failing to meet these criteria or those identified as duplicate publications were excluded.

Data Extraction: Data from the included studies were extracted using a standardized data extraction form. Information collected encompassed study characteristics (author, year of publication, and study design), patient characteristics (sample size, age, and sex), surgical details (procedure type and CSS administration protocol), and outcome measures (postoperative bleeding, transfusion requirements, wound-related complications, pain, and functional outcomes). Any disparities in data extraction underwent resolution through discussion and consensus among the reviewers.

Quality Assessment: The quality and risk of bias in the included studies were evaluated using appropriate tools corresponding to their study design. Randomized controlled trials underwent assessment using the Cochrane Collaboration's tool for gauging the risk of bias, while observational studies were evaluated using the Newcastle-Ottawa Scale. Two independent reviewers conducted the quality assessment, and discrepancies were resolved through discussion or consultation with a third reviewer when necessary

Data Synthesis and Analysis: Given the anticipated heterogeneity among the included studies, a meta-analysis was planned contingent on the availability of a sufficient number of studies with comparable outcomes. If deemed feasible, pooled effect estimates and their 95% confidence intervals would be computed using appropriate statistical methods (e.g., fixed-effects or random-effects models). Subgroup analyses and sensitivity analyses would be carried out to delve into potential sources of heterogeneity and assess the robustness of the findings.

Data Interpretation and Reporting: The results of this systematic review would be amalgamated and presented in a narrative format. The findings would be interpreted, taking into consideration the strengths and limitations of the included studies, the quality of evidence, and potential biases. The implications of the results for clinical practice and future research would be thoroughly discussed.

Ethical Considerations: Ethical approval was deemed unnecessary for this systematic review, as it entailed the analysis of existing published data. The review adhered to ethical guidelines and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for transparent reporting.

Results

A comprehensive systematic review was executed to assess the impact of carbazochrome sodium sulfonate (CSS) in total knee arthroplasty (TKA). Twelve studies met the inclusion criteria and were incorporated into the review, comprising six randomized controlled trials (RCTs) and six observational studies. The characteristics of the included studies are presented in Table 1.

Effect of CSS on postoperative bleeding

The assessment of CSS's effect on postoperative bleeding was conducted across all studies included in the analysis. The majority of these studies indicated a noteworthy decrease in postoperative blood loss when CSS was employed in comparison to control groups. The collective analysis of the randomized controlled trials (RCTs) underscored a statistically significant reduction in postoperative bleeding among patients receiving CSS (p<0.001). Nevertheless, some heterogeneity among the studies was observed, potentially stemming from differences in CSS administration protocols and surgical techniques.

Effect of CSS on transfusion requirements

Eight studies scrutinized transfusion requirements. The results were varied, with certain studies noting a marked decrease in transfusion rates with CSS, while others detected no significant difference compared to control groups. The amalgamated analysis of RCTs failed to disclose a statistically significant disparity in transfusion requirements between the CSS-receiving group and the control group (p=0.124). Subgroup analyses, categorized by CSS dosage and surgical techniques, did not reveal any significant impact on transfusion requirements. (Fig 1).

Effect of CSS on wound-related complications

Wound-related complications, including hematomas and surgical site infections, were investigated in six studies. The use of CSS was associated with a reduced incidence of hematomas in several studies, although the results were not consistently significant across all studies. The CSS effect on surgical site infections was inconclusive, with some studies reporting a lower infection rate in the CSS group and others showing no significant difference compared to controls.

Effect of CSS on pain and functional outcomes

Pain and functional outcomes were assessed in seven studies. The majority of the studies reported improved pain scores and functional outcomes in patients receiving CSS compared to controls. However, due to variations in outcome measures and reporting methods, a meta-analysis could not be conducted. Nevertheless, the overall trend suggested a potential benefit of CSS in reducing postoperative pain and improving functional recovery in TKA patients (fig 2).

Quality assessment of included studies

The evaluation of the quality of the studies included in this review uncovered certain limitations, such as potential selection bias, a lack of blinding, and insufficient sample sizes in specific studies. Generally, randomized controlled trials (RCTs) exhibited a lower risk of bias compared to observational studies. The overall quality of evidence was deemed moderate, emphasizing the necessity for additional high-quality studies in this domain.

Discussion

This systematic review aimed to assess the impact of carbazochrome sodium sulfonate (CSS) in total knee arthroplasty (TKA) based on the findings from 12 included studies. The outcomes of this review offer insights into the potential advantages and drawbacks of employing CSS in TKA outcomes [34].

The results of this systematic review suggest that CSS administration in TKA may lead to a significant reduction in postoperative bleeding [35]. The majority of the included studies reported a decreased postoperative blood loss in patients who received CSS compared to control groups. This finding is consistent with the known hemostatic properties of CSS, which is believed to promote platelet aggregation and enhance clot formation [36]. The reduction in postoperative bleeding can have several clinical implications, including a potential decrease in the need for blood transfusions and related complications [37].

However, the CSS impact on transfusion requirements was not consistent across the included studies. While some studies reported a significant reduction in transfusion rates with CSS, others did not find a significant difference compared to controls [33]. This discrepancy could be attributed to variations in CSS administration protocols, patient populations, or surgical techniques. It is important to note that transfusion requirements are influenced by multiple factors, including individual patient characteristics, preoperative hemoglobin levels, and surgical practices. Therefore, the role of CSS in transfusion reduction in TKA remains uncertain and requires further investigation [38].

In terms of wound-related complications, CSS showed a potential benefit in reducing the incidence of hematomas. Several studies reported a lower occurrence of hematomas in patients receiving CSS. However, the CSS effect on surgical site infections was inconclusive. While some studies suggested a lower infection rate in the CSS group, others did not find a significant difference compared to controls [39]. Wound-related complications are multifactorial and can be influenced by various factors, including surgical technique, postoperative care, and patient-specific factors [11].

Pain management and functional outcomes are crucial aspects of TKA. The majority of the included studies in this review reported improved pain scores and functional outcomes in patients who received CSS. Although a meta-analysis could not be conducted due to the variations in outcome measures and reporting methods, the overall trend suggests a potential benefit of CSS in reducing postoperative pain and improving functional recovery in TKA patients [40]. However, it is important to consider that pain and functional outcomes are influenced by various factors, including preoperative patient characteristics, surgical technique, and rehabilitation protocols. Therefore, the specific contribution of CSS to these outcomes warrants further investigation through well-designed randomized controlled trials with standardized outcome measures [19].

The quality assessment of the included studies revealed certain limitations, including potential selection bias, lack of blinding, and inadequate sample sizes in some studies [26]. These limitations highlight the need for more high-quality studies in this area to strengthen the evidence base. Future research should aim for rigorous study designs, adequate sample sizes [29], blinding procedures, and standardized CSS administration protocols to minimize bias and improve the validity of the findings [40].

Conclusion

This systematic review indicates a potential positive impact of CSS in total knee arthroplasty, potentially reducing postoperative bleeding and enhancing pain and functional outcomes. Nevertheless, the existing evidence is constrained, and additional meticulously designed randomized controlled trials with larger participant cohorts are essential to validate these observations. Standardizing CSS administration protocols and outcome measures would contribute to better comparability among future studies. When contemplating the use of CSS in TKA procedures, clinical decision-making should factor in individual patient characteristics, surgeon proficiency, and the overall quality of available evidence.

ORCID

Hamid Torkzadeh

https://orcid.org/0009-0004-0170-4680

Mohammad Irajian

https://orcid.org/0000-0001-6599-2600  

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Declarations

Conflict of interest: The authors have no relevant financial or non-financial interests to disclose.

Ethical approval: Not applicable.

Consent to participate: Not applicable.

Consent for publication: Not applicable