Improvement of Perioperative Outcomes in Major Gynecological and Gynecologic–Oncological Surgery with Hemostatic Gelatin–Thrombin Matrix

Discussion

Surgical site bleeding can occur from identifiable vessels or as difficult-to-manage, massive capillary oozing, or as combination thereof (4, 11). Such bleeding and accompanying changes (e.g. secondary blood dilution) can initiate intraoperative coagulopathy, which in turn enhances bleeding. In a substantial number of cases (e.g. 8% of our whole cohort), surgery must be performed in patients with current anticoagulant use. The inability to achieve sufficient hemostasis can lead to suboptimal surgical results (e.g. suboptimal cytoreduction), unintended organ loss (e.g. hysterectomy), reoperation or even perioperative death. Generally, increased PBL is associated with prolonged duration of surgery, higher perioperative morbidity, delayed patient recovery, more frequent blood transfusions, and, in oncological patients, poorer long-term outcomes (1, 7, 8-10, 27). Perioperative blood transfusions can be associated with numerous immunological and infectious side-effects (28). Last but not least, the consequences and complications of PBL generate costs to the healthcare system. Therefore, there is an increasing trend towards restricted use of blood products and rising interest in more effective and safe intraoperative methods of hemostasis (1). A variety of hemostatic agents have been developed in the past two decades and an increasing use of hemostatic agents was noted (1, 12). Pro-hemostatic agents are roughly divided into three partially overlapping groups: topical hemostats promoting clot building at a bleeding source, sealants preventing vessel or tissue leakage, and adhesives which bond tissues. Topical hemostats consist mostly of a mechanical agent promoting clot formation (e.g. oxidized cellulose gauze, collagen sponge, gelatin), often in combination with the coagulation factors thrombin or fibrinogen (1, 12). Only two such products are offered in a flowable form, Floseal® (Baxter Healthcare, Deerfield, IL, USA) and Surgiflo® (Ethicon, Somerville, NJ, USA). Floseal® is a kit of bovine cross-linked gelatin with 2,500 IU or 5,000 IU of human thrombin, resulting in 5 ml or 10 ml or ready-to-use HM, respectively (12, 13). Surgiflo® consists of 6 ml porcine gelatin which can be mixed either with 2-5 ml saline solution or with 2,000 IU lyophilized human thrombin, resulting in 8-11 ml ready-to-use hemostat (12, 29). The flowable consistency and portionability allow application to irregular and diffuse bleeding surfaces (12, 30).

In the field of gynecological surgery, excluding our own preliminary data of 2012 (21), we identified only one comparison of 25 cases and 25 controls focusing on Floseal® use and PBL (20). In abdominal conservative myomectomy, HM use was associated with decreased PBL and lower transfusion rates (20). According to other endpoints, Floseal® has been shown to reduce bleeding and to increase the chance of organ preservation in tubal and non-tubal ectopic pregnancies (17, 18). Cases of effective HM use in massive obstetric hemorrhage have been reported (19). By measuring serum anti-Müllerian hormone levels after adnexal surgery, Sönmezer et al. (22) and Song et al. (23) found less decline in ovarian reserve as compared to use of bipolar thermal hemostasis.

In the present study, we analyzed the largest cohort of gynecological patients with intraoperative Floseal® use so far, treated in one institution according to a similar surgical algorithm and with uniform perioperative (e.g. anesthesiological) management. Our results demonstrated a significant improvement of numerous short-term perioperative outcomes after HM use. Fewer transfusions, complications and re-operations, as well as faster recovery were benefits relevant both to patients as well as to the healthcare system. Although a formal cost-utility analysis was not the aim of the present study, several outcomes (e.g. reduced surgical times, fewer ICU stays, shorter hospitalization, lower utilization of blood products) were clearly translated into reduced hospital costs. These findings and conclusions concur with results obtained in other surgical disciplines (15). One of the most striking observations in our cohort (see Table IV) was that within the subgroup with coagulopathy, despite significant fewer blood transfusions, patients treated with HM recovered faster and were discharged earlier. Of note, coagulopathy or history of bleeding disorder were exclusion criteria in the studies of abdominal myomectomy (20) and of thyroid surgery (16). There are only few studies concerning the specific advantages of HM use in patients with coagulopathy. HM provides local restoration of hemostasis at the bleeding site, independently of and without influencing systemic coagulation. Hammes et al. used HM to stop gastrointestinal bleeding in anticoagulated pigs (31). Landi et al. observed that the use of both available HMs (Floseal® and Surgiflo®) enhanced the effectiveness of bleeding control in patients using antiaggregant or anticoagulant drugs who underwent spinal surgery (32). Del Verme et al. used HM in patients with intraparenchymal hemorrhage on anticoagulant or antiplatelet therapy. They reported “excellent”, “safe” and “reproducible” results both in terms of decreased bleeding and patient outcome (33). In the field of gynecological surgery as far as we are aware our observations are unique.

We used CRP, an acute-phase protein increasing in response to both infectious and non-infectious exposures e.g. tissue damage, as a rough follow-up parameter for the degree of postoperative systemic inflammation. Significantly lower CRP levels in the study group indicated a generally lower degree of inflammation in patients receiving HM. The shortcoming of this approach is, however, that we did not separately analyze patients with and without postoperative infections.

Reported complications following HM use in different areas of surgery are rare and generally do not outweigh the benefits (12, 14-16). The manufacturer's instructions contains warnings that “Floseal® matrix contains thrombin made from human plasma”, and therefore “may contain infectious agents, such as viruses” (13). Additionally, “gelatin-based hemostatic agents may serve as a nidus for infection and abscess formation” (13). Increased adhesion formation after HM application was observed in a rat model (34). In human gynecology, cases of small bowel obstruction (35), local eosinophil-rich inflammatory response (30) or intra-abdominal granulomata (36) have been reported. However, in the reported cases, an inappropriate use of HM may be discussed. For instance, Shashoua et al. described caseating giant cell granulomata following Floseal® application “to the cervical stump for adhesion prevention” during laparoscopic supracervical hysterectomy (36), although HM is not an anti-adhesive barrier. In other reports, the authors directly stated that it was not known if the manufacturer's recommendation to remove excess Floseal® had been followed (30, 36). Our data indicate a favorable safety profile of HM. Nevertheless, as potential adverse effects can occur, the application of HM should always outweigh the potential harm of bleeding or transfusion and the surgeon should follow the instructions for use.

A further matter of concern is the possible impact of local thrombin application on cancer development. The manufacturer states that long-term animal studies to evaluate the carcinogenic potential of Floseal® matrix have not been performed (13). In ovarian cancers – whose first-line treatment requires extensive surgery with high bleeding potential – thrombin has been shown to stimulate the growth of cancer cells in vitro (37). In our opinion, as long as the application of HM is restricted to the bleeding surface and all of the thrombin from HM is incorporated into the clot, the pro-cancerogenic action of HM will remain rather speculative.

The limitations of our study result from its retrospective design. The first source of bias was the individual decision of the surgeon to apply HM according to the clinical scenario and not per randomization or per strict protocol. However, assuming that some HM applications could take place during more difficult surgeries with more bleeding, the significantly better outcomes in the HM group are even more interesting. Additionally, subtle changes in surgical performance over time (e.g. more differentiated use of conventional hemostatic maneuvers due to a learning curve) are not exactly measurable, and their contribution to PBL in individual surgeries cannot be quantified. In any event, since the final results obtained in a total of 215 patients did not substantially differ from the preliminary data of 87 patients (21), a selection bias or changing surgical habits during the study period were not likely to have influenced the use of HM.

A further source of bias in retrospective studies can be the control group. Fortunately, both cohorts had similar characteristics according to diagnoses and procedures. The proportion of oncological to non-oncological and of emergent to scheduled surgeries did not significantly differ within the whole cohort. In both groups, similar requirements for discharge were followed in the study period, which is reflected by similar Hb and CRP levels at discharge irrespective of perioperative course.

Our intention was the evaluation of the HM use under ‘real-world’ conditions, with additional focus on patients with intraoperative coagulopathy. Therefore, in this study, we did not limit our analyses to more homogenous subgroups (e.g. radical oncologic surgeries), or to specific procedure types (e.g. only hysterectomies). However, such focused observations could be useful in forthcoming studies.

Although we recognize the retrospective design as a shortcoming of our study, we do not think that a prospective randomized study comparing HM against no hemostats would be ethically justifiable, given the obvious benefits afforded by HM use (14). We believe that further studies should focus on comparing different hemostats under different clinical scenarios or in regard to specific procedure types, under medical, economical and safety aspects [similar to (32)]. The results of the present study and of earlier case series, however, support the conclusion that HM is a helpful tool for gynecologic surgeons, provided it is used correctly.

In conclusion, as far as we are aware, this is the largest case–control observation of HM (Floseal®) application in gynecological surgery to date. In our study, the intraoperative use of HM was associated with shortened surgical and hospitalization times, less postoperative anemia and fewer blood transfusions, as well as a reduced number of re-operations and ICU stays. Since Floseal® enhances local clot building at the bleeding site without affecting the systemic hemostasis, it seems to be particularly suitable for patients whom perioperatively should continue therapeutic anticoagulant use.