Is Hemostatic Agent Effective and Safe in Minimally Invasive Partial Nephrectomy?
Renal cell carcinoma (RCC) ranks among the top ten most common cancers in adults. Partial nephrectomy (PN) is the standard treatment for small RCC. In recent decades, minimally invasive PN, including robotic-assisted partial nephrectomy (RAPN) and laparoscopic partial nephrectomy (LPN), has emerged as a viable alternative to open PN due to its less invasive approach. This shift has resulted in shorter hospital stays and favorable clinical outcomes for RCC patients. However, intraoperative or post-operative hemorrhage and urinary leakage (UL) remain the most common complications after PN, with incidence rates ranging from 1.2% to 9.5% and 1.2% to 4.5%, respectively. One of the primary challenges during minimally invasive PN is minimizing blood loss in the operating field, given the complexity of renal vascularity and vascular borders. Currently, suturing is the standard hemostatic method in PN for achieving renal parenchymal hemostasis. To enhance hemostasis and reduce surgical complications, various hemostatic agents (HAs) have been developed and implemented. Topical biodegradable HAs, such as fibrin sealants (e.g., TachoSil, Tisseel, and Evicel) and gelatin matrix thrombin sealants (e.g., FloSeal), are preferred due to their low toxicity and natural degradation.
A survey indicated that HAs were effectively used in 75.6% of LPN patients and 80.9% of RAPN patients. In clinical practice, HAs are often combined with suturing (referred to as additional HA) to achieve hemostasis. Another survey of 570 cases found that HAs were combined with suturing in 80.3% of cases. However, there is no clear evidence supporting the use of additional HA in PN. This study aimed to systematically review existing studies reporting the effects of additional HA plus suturing versus suturing alone on post-operative complications and hemostasis after minimally invasive PN.
A comprehensive literature search was conducted using PubMed, Ovid EMBASE, CENTRAL, and ClinicalTrials.gov databases to obtain related studies from inception to June 30, 2021. The inclusion criteria for this meta-analysis were: (1) patients diagnosed with RCC who underwent minimally invasive PN; (2) intervention: additional HA plus suturing versus suturing alone; and (3) study design: randomized controlled trials (RCTs) or cohort studies. The primary outcomes included blood transfusion rate (BTR), UL, and hemorrhagic complications (HCs). HCs were defined as the rates of post-operative bleeding (not requiring blood transfusion), pseudoaneurysm, arteriovenous fistula, hematoma, and hematuria. The secondary outcomes included length of stay (LOS), estimated blood loss (EBL), warm ischemia time (WIT), and operative time (OT).
Studies were excluded based on the following criteria: (1) renal tumors with lymph node and venous involvement; (2) studies including patients who underwent open PN; (3) HA alone versus suturing alone, or additional HA plus suturing versus HA alone; (4) only conference abstracts; (5) different interventions performed in the same group; and (6) duplicate publications. After removing duplicate studies, two independent reviewers screened all titles and abstracts and then reviewed the full text of related records. Disagreements were resolved through consensus after discussion. Data extraction included study characteristics, patient demographics, and perioperative outcomes. Risk-of-bias assessment was conducted using the Newcastle–Ottawa scale for cohort studies.
A total of ten studies involving 1976 patients were included. Seven studies were related to LPN, and three were related to RAPN. The methodological quality assessment showed that six studies were of high quality, while four were of moderate quality. The meta-analysis results indicated no significant differences in BTR, UL, HCs, LOS, EBL, WIT, and OT between the additional HA plus suturing and suturing alone groups during minimally invasive PN. However, subgroup analyses revealed variations based on different surgical procedures and HA types.
Subgroup analyses of different surgical procedures showed that additional HA significantly reduced the rates of UL (OR = 0.26, 95% CI = 0.09–0.78, P = 0.02) and HCs (OR = 0.25, 95% CI = 0.07–0.90, P = 0.03) in LPN. In contrast, no significant differences were observed in BTR, UL, and HCs between the additional HA plus suturing and suturing alone groups during RAPN. Additionally, the use of additional HA did not significantly improve LOS, EBL, WIT, and OT after LPN or RAPN.
Subgroup analyses of different HA types demonstrated a lower rate of HCs (OR = 0.40, 95% CI = 0.17–0.96, P = 0.04) in the fibrin sealants group and a shorter OT (MD = -25.49, 95% CI = -50.55 to -0.43, P = 0.05) in the gelatin matrix thrombin sealants group compared to the suturing alone group. However, neither HA type significantly reduced BTR, UL, LOS, EBL, and WIT compared to the suturing alone group.
The asymmetric funnel plot with Egger’s test indicated a low risk of publication bias for WIT (P = 0.06). No significant publication bias was found for BTR, UL, and HCs (P > 0.10). The meta-analysis showed no significant changes in BTR, UL, HCs, LOS, EBL, WIT, and OT between the additional HA plus suturing and suturing alone groups during minimally invasive PN. However, the results varied across different subgroups of surgical procedures and HA types. The effect of additional HA appeared to be more beneficial in LPN than in RAPN. Additional HA significantly reduced UL and HCs after LPN, while no significant differences were observed after RAPN. The use of additional HA had more pronounced advantages in reducing complications in LPN than in RAPN. This discrepancy may be attributed to the continuous development of surgical techniques, improved dexterity and visualization, and a more manageable learning curve for suturing in RAPN. Robotic assistance allows for more accurate suturing of renal parenchyma, and the sliding-clip technique is often used to avoid tying knots, which is sufficient to achieve hemostasis and prevent related complications. Therefore, the use of HAs may be unnecessary during RAPN procedures.
Subgroup analysis based on different HA types showed that HA types had little effect on post-operative outcomes during PN. Antonelli et al. reported no significant differences in perioperative outcomes between the TachoSil and FloSeal groups during PN procedures. The divergence in these results may be attributed to the impact of different surgical procedures of PN.
Significant heterogeneity was observed for EBL, WIT, and OT between the additional HA plus suturing and suturing alone groups. Pooling continuous outcomes is easily affected by various factors. For example, EBL can be measured using different methods with varying accuracy, such as the weighing method, area method, and volume method. The definitions of WIT and OT may differ across studies. These factors may contribute to the observed high heterogeneity, leading to wide confidence intervals of the pooled effect estimates and no statistically significant differences. Therefore, the relevant details of clinical outcomes should be reported in primary studies to achieve more effective secondary data analysis.
The average annual HA expenditures for RAPN and LPN were $1452.49 and $626.98, respectively. The use of additional HA significantly increases national expenses and financial burdens on patients undergoing PN, especially RAPN. Given the lack of improved post-operative outcomes and the additional costs of HAs, their implementation in RAPN seems highly questionable. Eliminating the use of unnecessary HAs may improve the cost-effectiveness of RAPN.
This study is currently the only systematic review and meta-analysis assessing the role of additional HA in improving hemostatic effects and preventing surgical complications during minimally invasive PN. However, several limitations should be acknowledged. First, all included studies were retrospective cohort studies, and although baseline characteristics (e.g., tumor size) were similar between the two groups, selection bias could not be avoided. Second, except for different surgical procedures of PN and HA types, high heterogeneity among studies may be attributed to varying operative experiences of surgeons, HA dosage, patient characteristics (e.g., tumor location and depth, comorbidity, use of anticoagulants), application of Surgicel bolster, and other details of surgical techniques (e.g., type of suture, tumor resection technique). These factors were neglected in some included studies, making it difficult to evaluate their impact on the results. The reporting quality of trials on this topic needs improvement in the future.
In conclusion, additional HA combined with suturing significantly reduced the occurrence of UL and HCs without increasing WIT and OT in LPN, while no significant differences were observed in RAPN. Therefore, HA may be considered as a supplement to suturing in LPN, and its routine use in RAPN is worth reconsideration due to the unimproved effectiveness and increased cost burdens. Nevertheless, these findings need to be verified through high-quality, prospective RCTs in the near future.
doi.org/10.1097/CM9.0000000000001992
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