Research ArticleClinical Studies

Impact of the Lysine-urethane Adhesive TissuGlu® on Postoperative Complications and Interventions After Drain-free Mastectomy

RALF OHLINGER, RICO RUTKOWSKI, THOMAS KOHLMANN, STEFAN PAEPKE, ZAHER ALWAFAI, CAROLIN FLIEGER, SYLKE MÖLLER, FRANZISKA LENZ, MAREK ZYGMUNT and JULIA UNGER
Anticancer Research May 2020, 40 (5) 2801-2812; DOI: https://doi.org/10.21873/anticanres.14253

Abstract

Background/Aim: The influence of a polyurethane-based tissue adhesive (TissuGlu®) on common complications following breast surgery was investigated. Patients and Methods: Within a Randomized-Controlled-Trial 70 women (n=35 TissuGlu®, n=35 drain) underwent a mastectomy with or without sentinel lymph node excision (SLNE), followed by a 90-day postoperative follow-up. Results: Postoperative interventions: Non-inferiority of the application of TissuGlu® was seen. Pain-Level/ Hospitalization: A statistically significant pain reduction from day four onwards (p<0.001) and a shorter hospitalization period (p<0.001) was observed. In contrast, the TissuGlu® group showed increased mean puncture incidence (p=0.013), and increased puncture volume (p=0.021). Conclusion: Application of the polyurethane-based tissue adhesive TissuGlu® after mastectomy, with or without SLNE, showed potential for improvement of the clinical outcome. In contrast, high intervention rates and increased puncture volume, caused by recurring seromas following application of the surgical adhesive TissuGlu®, have a negative impact on the patient-specific convalescence.

With a prevalence range of 3-85%, seromas are the most frequent postoperative complications following breast surgery (1-4). Up to 15 % of postoperatively developed seromas represent a problem of pronounced clinical relevance due to subsequent complications such as prolonged wound healing, wound infection, secondary wound healing disorders, necrosis, lymphedema, pain, aesthetic deficits and, as a result of this, the delay of any adjuvant therapeutic measures that may subsequently be necessary (1, 5-7). A universally applicable definition of a seroma, beyond the description of the collection of sterile fluid in a surgically preformed wound cavity (the dead space), does not exist in the current literature (2, 5, 8). However, inter alia, proinflammatory and inflammatory exudative and transudative processes in the adjacent tissue, via operative trauma-induced damage, appear to cause the pathophysiological development of seromas (9-12). Additionally, the intraoperative opening of lymphatics and the postoperative movement of the affected extremity, the increased discharge of lymph fluid into the wound area, and the simultaneous reduction of lymph drainage capacity post extensive lymphonodectomy, fosters the development of seromas (7, 9, 13, 14). Many studies have been able to determine other factors that benefit the development of seromas. Along with the type of operation [mastectomy, breast-conserving surgery (BCS) with or without the removal of locoregional lymph nodes (15)], the instruments used also appear to have an impact on seroma formation. It was shown that, to a lesser extent, damage produced mechanically (using a scalpel) and thermally (using electrocauterization) leads to the production and secretion of wound fluid (16, 17).

Furthermore, various comorbidities [including arterial hypertension (2), elevated BMI (18) and patient-specific characteristics, such as nicotine abuse (18) or age (≥ 40 years old) (19)], were identified as having an adverse effect on the risk factors related to the development of seromas. Along with tumor size (20), nodal involvement or neoadjuvant chemotherapy (17), the volume of drained wound fluid (2, 19, 21), the length of hospital stay and the number of drains (20) appear to play a role in the formation of seromas. Despite the placement of a high-vacuum drainage system, currently being the standard procedure for seroma reduction, studies over the last few years have shown that seroma formation can also be reduced via quilting sutures (3, 22). Numerous alternative methods for the reduction of dead space, such as the use of an ultrasonic dissector (20, 23), or postoperative immobilization of the shoulder (24, 25), have also been shown to have a positive effect on postoperative seroma reduction. Animal testing (26) and abdominoplasties (27, 28) were used to investigate the efficacy of a polyurethane-based, biocompatible and absorbable tissue adhesive (TissuGlu® Surgical Adhesive, Cohera Medical Inc., Pittsburgh, PA, USA) for the first time, showing varying results in terms of the postoperative complication and intervention rates. The first attempt to establish the tissue adhesive during breast surgery was documented by Eichler et al. (26-28) and Ohlinger et al. (29). The research group of Eichler et al. (28) studied the application of the tissue adhesive alongside the placement of a drain in a case report series and a retrospective study published in 2015 with a total population of 205 patients (173 underwent a mastectomy with subsequent drain placement, 32 were additionally to drainage treated using TissuGlu® tissue adhesive). Meanwhile, Ohlinger et al. (29) focused on a retrospective study with a total of 84 patients (42 women received a drain placement and 42 were treated exclusively using tissue adhesive without additional drain placement) studying the impact of the application of either a drain or the polyurethane-based tissue adhesive. The patient populations of both studies were similar with regard to mean patient age and BMI. There was a higher number of smokers in the tissue adhesive group led by Ohlinger et al. (0% vs. 9.5%). In both research groups, along with the study endpoints of the postoperative intervention and complication rates, the duration of drainage and the seroma fluid volume (Table I) were also studied. While Eichler et al. placed an additional focus on the postoperative pain level evaluated using the visual analogue scale (VAS), Ohlinger et al. focused on the duration of hospitalization (Table I). This study was planned and executed on the basis of the findings of these previous retrospective studies. The focus was on the relevance of postoperative complications and consecutive necessary interventions following the application of TissuGlu® tissue adhesive in comparison to the standard wound closure technique with drain placement. Pain [evaluated using the visual analogue scale (VAS)], the duration of hospitalization, the cumulative volume of wound fluid and the duration of drainage were also objects of investigation in this study.

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Table I.

Comparison of the retrospective trial of Eichler et al. (28) and the retrospective study of Ohlinger et al. (29).

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Table II.

Inclusion and exclusion criteria.

Patients and Methods

This prospective, randomized controlled, single-center, non-inferiority study was carried out between July 2014 and May 2017 in accordance with the Declaration of Helsinki, and approved by the local ethics commitee (ethics committee vote, internal registry number BB 049/14). A total of 89 patients participated in the study (87 women and two men). At the time of their inclusion in the study, the patients were either suffering from a breast carcinoma for the first time or a recurrence. All participating patients underwent a mastectomy. Due to the BRCA (breast cancer gene) status, a total of six patients underwent prophylactic bilateral mastectomy. In addition, a total of 27 patients also underwent sentinel lymph node excision (SLNE). Randomization was carried out one day prior to surgery by the Institute for Community Medicine in Greifswald following inclusion of the patients in the study and was performed per patient and not per breast. Bilateral mastectomy patients were therefore randomized within the same study arm. The process was conducted via a document which was faxed in advance to the Institute for Community Medicine and generally returned to the Breast Center the day before surgery. The patients were informed postoperatively which study arm they had been assigned to. Study inclusion and exclusion was carried out as per the criteria stated in the study protocol (Table II). A case report form (CRF) was used to anonymously record preoperative patient-related characteristics and risk factors, as well as to document previously completed therapeutic applications and histological findings. All patients had provided prior written consent to participate in the study.

Experimental surgical adhesive. TissuGlu® (Fa. Cohera Medical Inc., Pittsburgh, PA, USA) is a surgical, biocompatible and resorbable polyurethane-based tissue adhesive, which has been in use in Europe and the USA since 2011 and is approved for subcutaneous dead space reduction and flap adhesion following abdominoplasty. Using a custom applicator, the tissue adhesive is applied in its pre-polymerized form to the pectoral muscle directly before the subsequent tissue approximation. The hardening process of the adhesive is triggered by contact with the moist environment of the surrounding wound area. Light external compression to the wound area during approximation of the tissue surface directly following application of the surgical adhesive is crucial for achieving full adhesion of the tissue layers. According to the manufacturer adhesion takes place within one hour and is necessary to achieve the desired dead space reduction. To subsequently achieve optimal adhesive results, during the one-hour hardening process, along with the aforementioned light compression therapy, additional mobilization of the tissue surface above the wound area caused by shear forces (for example, during wound closure or movement of the patient) should be avoided.

Figure 1.
Figure 1.

Wound area after resection of mammary gland and surrounding fat tissue and meticulous haemostasis.

Figure 2.
Figure 2.

Traction sutures around the incision line for better positioning of the skin flaps over the wound and fast wound closure after application of the tissue adhesive.

Figure 3.
Figure 3.

Application of the tissue adhesive starting cranio-medially.

Figure 4.
Figure 4.

Continue application of the adhesive to the caudo-lateral.

Figure 5.
Figure 5.

Approximation of the tissue surfaces under constant external compression.

Surgery. The entire surgical procedure including tissue adhesive application was performed by a gynecological surgeon from the Breast Center at the Greifswald University, who had extensive experience in the field of oncological breast surgery and also in the intraoperative application of the tissue adhesive. The opening of the surgical site was carried out via scalpel incision, and all further dissections were performed using electrosurgical instrumentation (electric surgical knife, scissors) and devices (Medtronic, ForceTriad™EnergyPlatform). The following configurations were generally chosen: Incision 35-Watt, Effect Range 4; Coagulation 45-Watt, Effect Range 5. If a drain had been placed in the wound area, a slit silicon drain was always used (Privac® Redon bottle 200 ml, initial vacuum 900 mbar; Primed® Halberstadt Medizintechnik GmbH). In general, also following additional SLNE, only one drain was placed in the surgical site. The exception to this were the four patients in the drain group who had an additional axillary drain placed following SLNE, due to the large size of the wound cavity. After drainage insertion, the surgical site was closed with subcutaneous and intracutaneous suture or cutaneous clip suture. The adhesive was applied following mastectomy, removal of the muscle fascia and the surrounding fatty tissue, and careful hemostasis on the pectoralis major (Figure 1). Using previously placed loose traction sutures along the incision line, the tissue flap was positioned over the wound (Figure 2). A swivel head attached to the applicator enabled the simultaneous application of three drops (mean volume per drop: 0.025-0.040 ml) of the tissue adhesive in a linear arrangement onto the wound area. Where possible, the application began at the craniomedial area of the wound bed and continued in a caudolateral direction (Figures 3 and 4). The approximation of the wound surfaces was carried out by lifting the tissue flap, with the aid of the previously placed traction sutures, and by applying slight external pressure to the wound area (Figure 5). Manual compression was applied to the tissue layers to avoid additional shear forces, for example, unintentional lifting or displacement of the tissue layers, until the total adaptation of the wound margins was complete (Figure 6).

Figure 6.
Figure 6.

Manual compression of the wound area until final closure of the site to minimise shear forces or accidental lifting of the skin flaps.

After closure of the surgical site using subcutaneous and intracutaneous suture or cutaneous clip suture (Figure 7), a compression dressing was applied using an elastic bandage with the patient on the operating table to help reduce the possible influence of shear forces when moving the patient. The compression dressing was removed after 24 h.

Postoperative care and follow-up. During hospitalization and the subsequent 90-day follow-up period, which included outpatient check-ups on postoperative days 14, 30, 60, and 90, along with inspection and palpation of the surgical site, evaluation of the patient's general state and determination of postoperative pain intensity level using the visual analogue scale (VAS) was carried out. A specific focus was placed on possible hematoma development, seroma formation, wound dehiscence, necrosis, and infection, and where applicable, the placed drain. Along with daily drainage volume, the day of drain removal, and any drain-related complications (unintentional removal of the drain, new placement of a drain, infection at the drain exit point, drain blockage) were documentated. During the hospitalization phase, the drain was removed when the drain discharge flow was determined to be ≤30 ml/24 h. Placement of a new drain was not necessary in any of the cases, except in individual cases where the patient had unintentionally removed the drain or where the drain was not functioning correctly due to a loss of vacuum pressure. In cases where the TissuGlu® patients or the drain patients (following drain removal) developed clinically relevant seromas, i.e. with pre-existing symptomatology (reddening, pain, swelling, fluctuation) or ultrasound confirmation of fluid collection measuring at least 1 cm deep between the pectoralis major and the cutis, puncture was carried out. The volume of the aspirated fluid collected was also recorded in the CRF. If, during the follow-ups, puncture or other measures were necessary to promote wound healing, the patients were asked to return for further wound inspection 7 days after the puncture was carried out. Reintegration into the follow-up schedule was only possible for these patients when the wound healing process was determined to have stabilized. In the event that re-hospitalization was indicated for wound revision and/or drain placement, then, in accordance with the study protocol, this would be classified as a serious complication and documented in the CRF.

Figure 7.
Figure 7.

Final closure of the situs with a staple suture.

Outcome measures. The primary and secondary endpoints are displayed in Table III.

Sample size and statistics. The sample size was calculated using case series from previous applications of TissuGlu® tissue adhesive during mastectomies, with or without or SLNE, and aided by sample size software “PASS 13” (30). The statistical analysis was carried out using IBM SPSS, Version 22, by the Institute for Community Medicine in Greifswald. The analysis of normally distributed independent samples was carried out with the aid of t-tests. Non-normally distributed variables were analyzed using the Mann-Whitney U-test. The analysis of discrete variables was carried out exclusively using the Chi-squared test. For the analysis of non-inferiority of the tissue adhesive, both the Mann-Whitney U-test and the Hodges-Lehmann estimator were applied.

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Table III.

Study endpoints.

Results

An initial total of 89 patients were included in the study: 45 female patients in the TissuGlu® group, and 42 female and two male patients randomized in the drain group. Of these 89 patients, 11 women (five in the TissuGlu®, group and six in the drain group) and one male study participant (drain group) were unable to complete participation in the study due to the application of exclusion criteria stated in the study protocol. A further seven women (five in the TissuGlu® group and two in the drain group), decided against to the continuation of participation in the study following randomization. This resulted in a total study population of 69 women and one man (n=70), 35 in the TissuGlu® group and 35 in the drain group. All study participants underwent a mastectomy.

In cases where it was indicated, 27 female patients (12 from the TissuGlu® group and 15 from the drain group) additionally underwent sentinel lymphadenectomy. Due to a positive confirmation of BRCA mutations, six female study participants, with one affected breast, underwent bilateral mastectomy as a prophylactic measure. None of these women required an additional SLNE. Of all the women who underwent bilateral mastectomy, five were randomized into the TissuGlu® study arm and one into the drain study arm. The randomization was carried out per patient and not per breast. Therefore, patients who had undergone bilateral breast ablation had both breasts randomized in the same study arm. Please note that the following statistical analysis and representations do not reference the total study populations (n=70), but rather each treated breast (n=76).

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Table IV.

Number of aspirations related to the entire study population as well as to each study arm.

Primary and secondary endpoints. Regarding the primary endpoint, all necessary postoperative interventions, documentation and analysis of all preceding postoperative interventions (drain removal, new drain placement, seroma aspiration, wound revision, use of a vacuum assisted closure (VAC)) were carried out.

Additionally, due to the high rates of postoperative seromas in both study populations, all seroma-associated interventions (punctures and their incidence) were analyzed separately. Without a significant statistical difference, the drain group showed a lower rate of required interventions than the group that was treated using TissuGlu® (2.7±1.3 vs. 3.0±3.1; p=0.408).

On closer inspection of the seroma-associated interventions, in 30 (96.8%) of the 31 seromas recorded in the drain group, puncture was found to be indicated. In comparison, in the TissuGlu® group, of the 32 observed primary seromas, a total of 29 (90.6%) required puncture. Neither for the number of primary seromas (p = 0.688) nor for their puncture (p = 0.372) significant differences could be determined. However, there were significant differences between both groups with regard to the mean number of punctures per seroma and breast (p=0.013). While in the drain group an average of 1.6±1.2 punctures were required until the successful completion of seroma treatment, the tissue adhesive group required 2.8±2.6 punctures.

Table IV displays a detailed representation of the incidence of punctures for both the total study collective of n=76 breasts and for the drainage (n=36) and TissuGlu® group (n=40).

The mean puncture volume in the drain group was determined as 198.6±291 ml and 394.1±423 ml in the tissue adhesive group (p=0.021). The significantly higher mean drainage volume in the drain study arm (345.6±222 ml vs. 17.4±80 ml; p<0.001) resulted in a high cumulative volume for the entire study population, however, without statistical significance (544.1±381 vs. 411.5±454 ml; p<0.204).

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Table V.

Incidence of each complication.

In the drain group, the mean drain duration was determined as being 5.4±2.0 days. In the TissuGlu® group, no drain placement was carried out in addition to the adhesive application. The drainage volume listed above for the study population treated using tissue adhesive is derived from two cases during the follow-up phase that required wound revision and consecutive drain placement in the case of persisting wound healing disorder.

In the overall analysis of all postoperative complications (seroma, hematoma, wound dehiscence, wound necrosis), no significant difference (p=0.091) was identified when comparing both study groups (0.9±0.5 drain group vs. 1.1±0.7 TissuGlu® group). Table V displays the incidence of each individual complication in each group.

Furthermore, no differences were identified in the analysis of serious complications that made further inpatient hospital treatment necessary (0.028±0.2 drain group vs. 0.100±0.4 TissuGlu® group; p=0.721). With reference to the documented postoperative pain intensity level using VAS (scale of 0-10, 0=no pain, 10=unbearable pain), we observed a reduction of the reported pain level in the tissue adhesive group from the third postoperative day onwards (1.3±1.6 vs. 1.8±1.1 moderate pain level; p=0.053), and highly statistically significant results from day four onwards (0.5±1.1 vs. 1.4±1.1 ml; p≤0.001). Study participants from the TissuGlu® group were able to leave the hospital earlier (3.0±1.4 vs. 5.8±2.4 days, p≤0.001). An overview of the statistical analysis of the primary and secondary endpoints is shown in Table VI.

Discussion

This first prospective, randomized controlled, single-center study was able to show that the application of TissuGlu® tissue adhesive, despite a slightly higher but non-significant intervention rate, is not inferior to the application of a drain and thus represents an alternative to other methods of drainage-free mastectomy. This claim is supported by the lower primary seroma rate with reduced primary puncture indication in the TissuGlu® group. However, it should be critically reviewed that both the puncture frequency of seromas that occurred and their average aspiration volume until final freedom from symptoms was significantly higher comparing to the drainage group. The cause for this could be both intraoperative and postoperative. On the one hand, insufficient dryness of the wound before application of the adhesive can influence the curing process. On the other hand, in addition to sufficient external compression to the site of closure, the compression bandage, even before the patient is repositioned, is of decisive importance for reducing the loss of complete adhesive effect due to shear forces. Also, the reduction of postoperative pain level and the shortened hospitalization duration may cause the patient to over-estimate their physical resilience and lead to a comparatively intense and rapid mobilization. On the other hand, patients in the drain group, due to shame or fear of a foreign object placed in their body, and the pain-level, tend to spare the affected extremity.

It has been shown in several other studies that postoperative immobilization can lead to a reduction in the seroma rate (24, 25). However, immobilization is also a topic of intense debate in studies which have focused on a possible postoperative movement deficit (24, 31). Notwithstanding this, in the TissuGlu® group, a reduced but statistically insignificant cumulative volume (drainage volume + aspiration volume) was observed. However, this may best be explained by the lack of drain placement in patients of the TissuGlu® group.

Gilbert et al. for the first time reported in a preclinical animal study (dogs) that the application of the tissue adhesive can lead to a reduction of dead space after abdominoplasty (32). In this case, however, the comparison was made with an abdominoplasty performed on the same animal (internal split mouth design) without an additional procedure to reduce the dead space.

The research group of Ohlinger et al. (29) examined the efficacy of the wound adhesive following mastectomy in a retrospective study in 2018 with a total of 84 participants (42 drainage study arm, 42 TissuGlu® study arm). With reference to the postoperative intervention rate, despite a lower rate of an indicated intervention in the TissuGlu® group, the comparative assessment of the application of an adhesive and drains found no significant differences (1.4±1.9 vs. 1.8±1.1, p=0.298). In the tissue adhesive group, the reduced intervention rate when compared to drain application differs from the results obtained during this study, which ascertained a reduced intervention rate in the drain group (TissuGlu® arm: 3.0±3.1 Interventions; Drain study arm: 2.7±1.3 Interventions; p=0.408). There are a number of reasons for this. Alongside the lack of tightly scheduled postoperative follow-ups, which may first unmask the need for intervention, the lack of suitable documentation instruments and the resulting documentation deficits may cause the results to be skewed. The higher postoperative complication rate in the tissue adhesive group (3.0±3.8 vs. 1.2±2.4) identified in this study correlates to the findings of the Ohlinger et al. (3.0±3.1 vs. 2.7±1.3; p=0.408). However, this retrospective study showed significant differences with regard to the postoperative complication rate (p=0.012). The higher complication rate identified in the tissue adhesive group can be attributed to the higher incidence rate of postoperative seroma reported in this study population during the retrospective study. During the study, in the tissue adhesive study group, a total of 22 (55%) of the 42 women treated developed a seroma, however, in the drain group only 12 (28.6%) of the 42 women were affected. In contrast, with an incidence rate of 91.2% in the drain group and only 71.1% in the tissue adhesive group (p=0.688) identified during our prospective study, the higher rate of complications in the TissuGlu® group cannot be exclusively attributed to the incidence of postoperative seroma. Also, the incidence of postoperative hematoma (15.6% vs. 8.8%, p=0.317), necrosis (2.2% vs. 0.0%, p=1.000) and wound dehiscence (11.1% vs. 0.0%, p=0.056) played a role in the higher rate of complications in the tissue adhesive group. The significantly high seroma rate in both studies may be due to user error during the application of the adhesive as well as insufficient intraoperative and postoperative compression and immobilization. Furthermore, our findings differ from the findings recorded by Ohlinger et al. regarding the incidence of clinically relevant (requiring puncture) seromas. In the drainage group, 91.6% of the treated women were found to require puncture for a first clinically relevant seroma (p=0.014) and in the tissue adhesive group this was true of all participants (100%), however, in the prospective study no significant differences were identified (Drain vs. TissuGlu®: 83.3% vs. 72.5%; p=0372). With regard to the mean necessary puncture prevalence until full recovery from a recurring seroma, both studies showed significantly fewer necessary punctures in the drain group (retrospective: 0.52 vs. 1.31; p=0.025) (prospective: 1.6 vs. 2.8; p=0.013).

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Table VI.

Statistical analysis of primary and secondary endpoints.

On the basis of current studies, the incidence of seroma punctures observed during the prospective study, which was a partial aspect of all the necessary postoperative interventions, and the possible risk of further complications (for example, increased infection rate), is considered to be low (33, 34). Nevertheless, some authors have reported the disadvantages of repeated punctures to treat persisting seroma formations with regard to the physical and psychological healing process of the affected patients (33, 34). As proven in recent studies (35, 36), the fact that drains are a risk factor in the formation of seromas that require isolated analysis was underpinned in this study by the observed higher seroma rate in the drain group (91.2% vs. 71.1%); also, the calculated cumulative volume for this study population exceeds that of the TissuGlu® group (544.1±381 ml vs. 411.5±454 ml). The published results of the clinical study by Walgenbach et al. for the application of tissue adhesive following abdominoplasty showed that the combination of dead space reduction using tissue adhesive and drainage compared to the isolated application of drainage is a suitable option to enable the reduction of the drainage volume and drain placement duration (33). Additionally, the study conducted by Jain et al. showed that even the application of fibrin-based tissue adhesives offers a more effective option for the dead space reduction, with significantly reduced seroma rate and reduced seroma volume, than the isolated application of drains (12).

Due to the constant connection to the wound site, drains also carry the risk of postoperative wound infection (37, 38). Resulting wound healing disorders and the subsequent prolongation of hospitalization and treatment durations (12, 39) represent an important health economic factor which should not be neglected. During this study, drains were removed after a mean period of 5.4 days (drainage volume ≤30 ml/d). Xue et al. had previously reported that the drainage-associated infection risk correlates to a prolongation of the duration of the drain remaining in place (38). The rates of postoperative complications identified during this study are in contrast to the findings of an increased rate of wound infection following drain placement. This study identified increased numbers of complications following the application of tissue adhesive (1.1±0.7 vs. 0.9±0.5, p=0.945). Alongside a high rate of recurring seromas, the group that underwent treatment using TissuGlu® were documented with an increased rate of hematomas, wound dehiscence and necrosis. A possible explanation for the increased rate of hematomas may be residual humidity (i.e. due to a small lesion) in the wound site, which limits the efficacy of the tissue adhesive following applications and in turn leads to an unsatisfactory dead space reduction. Also, wound dehiscence and necrosis can be the result of seroma formation caused by insufficient dead space reduction which, depending on the extent of the condition, can cause permanent and constant pressure in the surgically treated integument. It was shown in a study by Ebner et al. that the conscious decision against drain placement following mastectomy does not automatically affect the postoperative rate of complications (40). In a study published in 2013, 33 patients from of total 148 women were not fitted with a drain following mastectomy. The working group was unable to identify any significant differences in the revision rate, based on the incidence of postoperative complications (p=0.54), despite a higher frequency of complications in the study population treated without drains (9.1% vs. 6.1%).

Additionally, the insertion of a drain is often associated with discomfort and pain for many patients (12, 41). This is underpinned by this study, which identified a significantly higher rate of postoperative pain in the drain group. A reduction in pain level was achieved using the tissue adhesive from the third postoperative day onwards. Statistical significance was confirmed from day four onwards. However, these results should be viewed bearing in mind that the mean inpatient stay for TissuGlu® group patients during this study was reduced to three days and that documentation of the postoperative pain level for the majority of the patients beyond the time of discharge was not carried out. In this study, drain group patients were hospitalized for three days longer due to the longer convalescence and the time until drain removal was completed. The Ohlinger et al. study (29) confirmed these facts. The authors were able able to identify a reduction in hospitalization duration from 3.5 days following tissue adhesive application compared with 5.5 days following drain application (3.5±1.3 vs. 5.5±2.1, p<0.001). In their retrospective study, Eichler et al. were also able to identify a significant reduction in drain placement duration following additional tissue adhesive application from 4.2±1.8 days to 3.5±1.5 days (p=0.008) (28). Further studies have also reported that a drain-free operative procedure reduces the required hospitalization duration (12, 39, 42). In contrast, some countries successfully practice discharging patients with the drain in situ. This is also an option for reducing the hospitalization duration while achieving a health economic benefit (43). However, it should be noted, that discharging a patient with the drain in situ is not only linked to feelings of insecurity and fear of the patient (44), but also requires tightly scheduled home care by specially trained staff (43) and is also related to a higher risk of postoperative wound infection (45).

Conclusion

Alongside numerous existing options for dead space reduction, such as surgical suture, fibrin glue, or the current standard procedure of drain placement, the application of TissuGlu® tissue adhesive provides a safe but contentious alternative for dead space reduction. A comparatively low complication rate was determined for drain placement; however, this plays no significant role in the overall rate of necessary postoperative interventions. The isolated analysis of seroma-associated clinical interventions showed a notably higher rate of seroma-associated puncture following the application of adhesive as well as a significantly higher puncture volume. Alongside the increased risk of infection, this can also protract the patient-specific convalescence duration. The use of tissue adhesive is superior with regard to postoperative pain level, patient comfort, and hospitalization duration and, due to the latter, valuable from a health economics perspective. For further evaluation of the reduction in postoperative complications and interventions, as well as the clinical benefit stemming from the use of the adhesive, a prospective multicenter study is necessary. Additionally, further studies should be carried out to determine the long-term complications.

Acknowledgements

The Authors would like to thank Cohera Medical Inc., Pittsburgh, PA, USA for the study-related sponsoring of TissuGlu® tissue adhesive.

Footnotes

  • Authors' Contributions

    Conceptualization, R.O., M.Z. and J.U.; methodology, T.K., S.P. and Z.A.; validation, T.K., R.R. and J.U.; formal analysis, T.K. and J.U.; investigation, R.O. and J.U.; data curation, C.F., F.L. and J.U.; writing—original draft preparation, J.U., R.O. and S.P.; writing—review and editing, S.M., Z.A., F.L., C.F., R.O., R.R., and M.Z.; visualization, J.U., Z.A. and T.K.; supervision, R.O.; project administration, R.O., M.Z. and S.P.; All Authors have read and agreed to the published version of the manuscript.

  • Conflicts of Interest

    Dr. med. Dipl. med. S. Paepke: Consulting contract with Cohera Medical Inc., Pittsburgh and advanced training assistance and travel cost coverage also by Cohera Medical Inc., Pittsburgh, PA, U.S.A.

  • Received March 12, 2020.
  • Revision received March 25, 2020.
  • Accepted March 27, 2020.

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Impact of the Lysine-urethane Adhesive TissuGlu® on Postoperative Complications and Interventions After Drain-free Mastectomy
RALF OHLINGER, RICO RUTKOWSKI, THOMAS KOHLMANN, STEFAN PAEPKE, ZAHER ALWAFAI, CAROLIN FLIEGER, SYLKE MÖLLER, FRANZISKA LENZ, MAREK ZYGMUNT, JULIA UNGER
Anticancer Research May 2020, 40 (5) 2801-2812; DOI: 10.21873/anticanres.14253
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