University of Groningen
New measures to prevent inguinal infections in vascular surgery
Vierhout, Bastiaan Pieter
DOI:
10.33612/diss.97720548
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date: 2019
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Vierhout, B. P. (2019). New measures to prevent inguinal infections in vascular surgery. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.97720548
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
143
Chapter 8
Thesis summary and future perspectives
Postoperative wound complications remain a continuing challenge in surgery and especially in vascular surgery. This thesis focuses on novel medical devices with the major goal to prevent these complications and it explores the various causative agents of these infections.
Both known prerequisites for a surgical site infection (SSI) are a breach through the continuity of the skin and the introduction of (pathogenic) microorganisms into the wound. A skin incision is necessary in surgery, albeit, in general, incisions tend to decrease in length. The main cause of infection is the introduction of
microorganisms during the operation. To this context, the incisions for an endovascular aneurysm repair (EVAR) are essentially smaller compared to the incision necessary for an open repair of an abdominal aortic aneurysm, thereby theoretically minimizing the chance for SSI. Which microorganisms are introduced and in what way they are the root cause of infection, is still largely unknown. Obviously, host characteristics are of paramount importance, but the inflicting microorganism has to meet certain qualities, as well. This thesis first relates to the protection of the skin, then to a reliable closure of the incision, followed by
minimizing the incision-length, and finally to the role of remaining microorganisms after disinfection.
Bacteria on the skin and in surrounding structures near the incision site can cause contamination of the wound. Protection by disinfection and sterile draping is therefore essential (1). At the time of incision a wound should be relatively sterile, but during the operation, contamination increases (2). In case of surgical access through the groin, it is thought that microorganisms invade the wound even more easily, due to the proximity of the urinary tract and the rectal canal. These
microorganisms are thought to conceal in the skin structures and gradually invade the wound during operation. As microsealant glue (InteguSeal®) could be an effective preventive measure against bacterial invasion of the wound, this was evaluated in Chapter 2. Evaluation concerned a cohort of patients with an
indication for vascular reconstruction including the common femoral artery (CFA). Patients were randomized to a control group treated without the microsealant glue or an intervention group treated with the microsealant glue after disinfection. When 50 patients had been included, an interim analysis showed no difference between the two groups, with respect to the primary endpoint: an SSI. The review board that provided ethical approval for the study deemed the number of patients that would be required for adequate statistical power too large for the purpose of the study
(2 arms with 748 patients each). The study was therefore terminated early. The analysis performed on the included patients did not show an effect on the prevention of SSIs to develop. Based on these findings we concluded that the clinical relevance of InteguSeal® is relatively low when used in inguinal vascular procedures.
In our search for further improvement of prevention of SSIs we evaluated techniques used at the end of an operation. Most wounds are closed with
monofilament transcutaneous, intracutaneous sutures or with metallic staples. The staples as well as transcutaneous sutures leave an opening between the sutures enabling fluid to evacuate through these spaces. As inguinal wounds are known to produce much fluid, staples may have an advantage over running sutures
during wound healing. When the skin is sutured intracutaneously with the use of absorbable sutures, these running sutures prevent fluid from evacuation through the wound. The collection of fluid underneath the skin is thought to create a more favorable environment for the growth of microorganisms, despite absence of clear evidence (3). However, absorbable staples enable evacuation of fluid through the wound. This characteristic combined with the subcuticular aspect – no connection through the skin as seen in transcutaneous sutures – anticipated a favorable combination of both characteristics. An improvement was expected, thus
subcuticular absorbable staples were compared to a cohort of 38 patients treated with an absorbable running suture in Chapter 3. Despite a high technical success
rate, as stated by the company representative, and comparable duration of surgery, many wounds treated with absorbable staples showed dehiscence in the first days after surgery. These patients, who were indicated for a peripheral bypass operation, suffered from swelling and edema of the leg that caused dehiscence of the wounds and secondary infection of the wounds in four out of six patients. The subcuticular sutures were unable to hold the revascularization edema following bypass surgery.
The study was discontinued due to the SSI incidence of 67% (4). Again, no advantage was found in peripheral vascular surgery for a device introduced to prevent SSI.
Incidences of SSIs in open abdominal aortic aneurysm (AAA) repair seem to be comparable to SSI in endovascular aneurysm repair (EVAR)(5). Similar skin preparation and closure techniques are commonly used, as well as identical antibiotic prophylaxis. Although SSI incidence does not decline with shortening of incision-length from abdominal repair to EVAR, further shortening of incision length by percutaneous EVAR may reduce the infection percentage. Remote closure of the puncture in the CFA is possible with an artery closure device (ACD). Most
commonly used devices in such cases are Prostar XL® and Proglide® (Abbott Vascular, Redwood City, CA, USA). We showed in Chapter 4 the results of a
systematic review of the literature and meta-analysis, concerning ACDs in EVAR, thoracic endovascular aneurysm repair (TEVAR), and transcutaneous aortic valve repair (TAVR). A total of 17 studies (including 7889 CFA access wounds) showed a significant reduction of seromas, SSIs, and wound dehiscence when ACDs were used. Seromas dropped from 89 in 1360 incisions to 3 seromas in 1146 incisions (odds ratio [OR] 0.15, 95% confidence interval [CI] 0.06-0.35), SSIs reduced from 98/4758 to 15/2687 (OR 0.38, 95% CI 0.23-0.63), and wound dehiscence from 24/3363 to 0/1379 (OR 0.14, 95% CI 0.03-0.78) when comparing ACD with open surgical access. The infection rate did, however, not decline to zero. Regrettably, the studies included in the meta-analysis were of moderate quality, with a selection bias in most studies, and lack of blinding in all studies. Because of this moderate quality, the question remains whether a small reduction of incision length indeed benefits the patient with fewer complications.
With the widespread use of the ACD in mind, and the lack of robust evidence of its’ advantages over surgical cut down, a clinical randomized trial was designed to answer the question whether the use of an ACD does result in fewer
complications. The ‘Percutaneous in Endovascular Repair versus Open’ (PiERO) trial outline is described in Chapter 5 which included patients selected for an
elective EVAR. Randomization was performed on site of introduction of the main device of the endoprosthesis. This larger part of the endoprosthesis was introduced
146 147
percutaneous into the CFA in the intervention group, and through surgical cut down in the control group. Postoperatively, the patients rated wound pain on a visual analogue scale (VAS) and an independent researcher performed evaluation of the wound with the Southampton Wound Assessment score. With this self-evaluation and the objective inspection of the wound, it was possible to include and compare both groins in one single patient. By using the patient as his/her own control fewer subjects would have to be included, and the comparison of left and right inguinal wounds became independent to inter-patient variation.
Our interest primary focused on SSI and secondary on other wound complications, independent wound assessment, and patients’ VAS. Even after inclusion of 137 patients, the SSI incidence was zero in the percutaneous access group.
Unexpectedly, only two infections were reported in the open surgical access group, which was a good result for the patients, but this did not yield a significant dif-ference in wound infections in favor of the ACD. The ACD did, however, perform better in self-evaluation and clinical appearance. One day after surgery, pain was significantly less in the percutaneous group. Two weeks after surgery, wounds were scored significantly less inflamed in the percutaneous group. In conclusion, these two outcomes were the only benefits of the percutaneous device over the surgical cut down, as was shown in Chapter 6.
For complementary research, small biopsies of the skin were collected from all patients included in the PiERO trial. Before the first incision, biopsies were taken from the right groin, after administration of antibiotic prophylaxis and following skin disinfection with chlorhexidin. After completing the trial we analyzed the stored skin biopsies and related them to the outcome of the surgery and patient characteristics. Could skin characteristics and microorganisms hidden inside skin structures be associated with the occurrence of an SSI? Skin characteristics were examined with microscopy. Present microorganisms may be examined with conventional culture techniques and this could result in growth of bacterial species. However, it was expected that, after disinfection, the number of colony forming units (CFU) would be very small and probably undetectable with conventional culture. Fortunately, Next Generation Sequencing (NGS) of the 16S-23S rRNA regions can detect extremely small amounts of bacteria in the skin, even after disinfection. NGS 16S-23S rRNA has the ability to simultaneously identify multiple bacterial species in human tissue.
Results with this new technique to identify bacteria were presented in Chapter 7. In
ten patients of the PiERO trial, two of which had an SSI, skin biopsies were
examined with use of NGS of the bacterial 16S-23S RNA regions. The results were compared to standard techniques, such as regular culture for
Staphylococcus aureus (SA) and light microscopy. No relation was found between
preoperative skin characteristics or detected skin bacteria, and postoperative SSI. Patients with perineal SA were not at increased risk to acquire an SSI. With NGS mainly coagulase negative staphylococcal species (CoNS) were found after disinfection. These species rarely cause an SSI.
It remains difficult to interpret microbial findings in relation to SSI. A causative rela-tion between preoperative bacteria was suggested in earlier literature, but never adequately shown. Except in an experimental model in rats, in which a causative relation was shown between development of peritonitis and injection of a
combination of bacterial species intra-abdominally, but not with injection of a single species (6). A combination led to abdominal sepsis more easily than injection of one single bacterial species did, a phenomenon also known as microbial synergy and this could very well play an important role in SSI (7). Recent studies suggest a decline of SSIs after preoperative treatment with nasal Bactroban and washing with Hibiscrub, used for eradication of Staphylococcus aureus from the human body. Despite this preoperative eradication, SSIs with SA still occur (8).
The detailed process of the development of an SSI and the origin of causative pathogenic bacteria remains unclear (9, 10). When bacteria reach a sufficient amount, they can “communicate” with each other, a property termed quorum sens-ing, which may enhance their pathogenicity (11). The amount of bacteria necessary for quorum sensing varies per species, but previous studies suggested that at least 10,000 bacteria are necessary to develop an SSI (12). Still, SA is the only bacterial species of which preoperative carriage has been shown to be related to the
development of an SSI (8). Where does this pathogen causing the infection of the wound come from? Our studies were unable to demonstrate a relationship between the deep skin bacterial flora and postoperative infections.
Much knowledge has been gathered about the co-existence of bacteria and hu-mans. From the first day we are born, bacteria colonize us and in number of cells
we are outnumbered in an estimated ratio of 1.3 (13). The appearance of bacterial species in the gut flora seems related to the development of Crohn’s disease and Ulcerative Colitis (10). Associations with obesity, diabetes and neurodegenerative diseases are suggested (14-16). Otherwise, a protective effect of commensal bac-teria to fight viral pathogens has been accepted (17). In this co-existence between bacteria and humans, the human skin serves as a barrier, and various microorgan-isms colonize it. It appears that the development and treatment of SSI is much more complex than merely identifying a potential microorganism. Together with syner-gysms and quorum sensing, susceptibility and protection in individuals vary and different skin areas harvest different microbiota (18). With further knowledge of the microorganisms present at the inguinal locations, we might be able to increasingly orchestrate this ensemble of microbiota, biofilms, and patient characteristics preced-ing the operation and preventpreced-ing an SSI.
In which direction should we start to decrease the number of SSIs? And what may we learn about the origin of the pathogens causing infection? New medical devices tested in the course of this thesis did not alter the SSI outcome. In vascular surgery most infections are observed after surgery of the lower extremity. This may be due to poor vascularization and presence of ischemic wounds in these regions. There-fore, it seems plausible that the causative agent is already present in the ischemic wound or draining lymph nodes of the extremities before the operation. The next step would be to examine these wounds, lymph nodes and the vascular walls in pa-tients who have an indication for revascularization. This would enable us to identify pathogens that are surreptitious for standard disinfecting techniques and remain in the proximity of the skin incision. Several studies showed the presence of bacteria in the vascular wall and in inguinal lymph nodes (19, 20), even intracellular bacteria were identified (21). Further investigation with new molecular techniques is needed in order to locate the causative agent of SSIs.
As a result of this thesis, we have initiated a study for identification of microorgan-isms preceding the operation. Patients requiring a peripheral vascular bypass operation, due to rest pain or distal wounds, will be included for this study. During the operation, biopsies of lymph nodes, vascular wall and distal wounds will be obtained. From these samples, microorganisms shall be identified using NGS. The
SSI incidence in the Netherlands is estimated at 12.5% (22). With this incidence at the high end we hope to include a number of patients of whom one out of eight will develop an SSI. In these patients we may obtain more insight in the identification of currently unknown SSI-causing-microorganisms.
Besides the source of these microorganisms, factors of the host are of important influence. Macroscopic differences like smoking, diabetes mellitus, and the ASA score have been discussed, and we should also focus on preoperative bathing, exercise and dietary habits (23). Other local factors, situated at the surgical incision site, become increasingly valuable, such as, tissue oxygenation, local glucose levels and local anemia. These factors may be examined by measuring i.e. local pH, lactic acid, and Fe-levels. Contemporary local properties may also become important: The local concentration of preoperative antibiotics and their relation to fatty tissue (24), fat thickness (25), the influence of local electric stimulation on microbial communi-ties, known as biofilms (26), or even the application of bioactive glass (27). These new developments force us to renew our research activities on different fields. Usually, an SSI develops in different pathways: First, during the operation from the procedure itself or surrounding tissue (vascular wall or lymph nodes), second, after the operation through the wound or via indwelling drains, and finally, in a period later on, through bacteremia after nose, throat or other infections. Our future research will concentrate on the first pathway, infection through occult colonization of surrounding tissue. Then one could prevail infection, and in case of an early SSI, be able to treat the imminent graft infection empirically, due to the biopsies and knowledge about the cause of the infection. This could ultimately enable us to eradicate the patho-genic bacterial species in advance of the operation, thus preventing an infection from occurring.
Conclusion
We investigated prevention from SSIs in vascular surgery with three novel medical devices. These tests did not show a significant reduction in SSIs. We found that little is known about the first initiation of a wound infection. With further knowledge of the human microbiome and the postoperative local properties, we might be able to
150 151
References
1. Showalter BM, Crantford JC, Russell GB, Marks MW, DeFranzo AJ, Thompson JT, Pestana IA, David LR. The effect of reusable versus disposable draping material on infection rates in implant-based breast reconstruction. Ann Plast Surg. 2014;72:S165-9.
2. Wistrand C, Söderquist B, Falk-Brynhildsen K, Nilsson U. Exploring bacterial growth and recolonization after preoperative hand disinfection and surgery between operating room nurses and non-health care workers: a pilot study. BMC Infect Dis. 2018;18:466.
3. Thomson DR, Sadideen H, Furniss D. Wound drainage after axillary dissection for carcinoma of the breast. Cochrane Database of Syst Rev. 2013;CD006823.
4. Vierhout BP, De Korte JD, De Vos B, Bottema JT, Zeebregts CJ. First
application of an absorbable skin stapler in peripheral vascular surgical procedures. J Aesth Reconstr Surg. 2017;3:1-7.
5. Langenberg JCKJ, Groot HGW, Ho GH, Veen EJ, Buimer MG, van der Laan L. Surgical site and graft infections in endovascular and open abdominal aortic aneurysm surgery. Surg Infect (Larchmt). 2018;19:424-9.
6. Iriz E, Cirak MY, Zor MH, Engin D, Oktar L, Unal Y. Differential identification of atypical pneumonia pathogens in aorta and internal mammary artery related to ankle brachial index and walking distance. J Surg Res. 2013;183:537-43.
7. Rotstein OD, Timothy LP, Simmons RL. Michanisms of microbial synergy in polymicrobial surgical infections. Rev Infect Dis. 1985;7:151-70.
8. Rao N, Cannella BA, Crossett LS, Yates Jr AJ, McGough RL, Hamilton CW. Preoperative screening/decolonization for Staphylococcus aureus to prevent orthopedic surgical site infection. J Arthroplasty. 2011;26:1501-7.
9. Trung NT, Hien TTT, Huyen TTT, Quyen DT, Binh MT, Hoan PQ, Meyer CG, Velavan TP, Song LH. Simple multiplex PCR assays to detect common pathogens and associated genes encoding for acquired extended spectrum betalactamases (ESBL) or carbapenemases from surgical site specimens in Vietnam. Ann Clin Microbiol Antimicrob. 2015;14:23.
10. Lederer AK, Pisarski P, Kousoulas L, Fichtner-Feigl S, Hess C, Huber R. Postoperative changes of the microbiome: are surgical complications related to the gut flora? A systematic review. BMC Surg. 2017;17:2-10.
11. Rutherford ST, Bassler BL. Bacterial Quorum Sensing: Its role in virulence and possibilities for its control. Cold Spring Harb Perspect Med. 2012;2:a012427. 12. Lindberg RB, Mongrief JA, Switzer WE, Order SE, and Mills W. The successful control of burn wound sepsis. J Trauma. 1964;5:601-16.
13. Sender R, Fuchs S, Milo R. Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell. 2016;164:337-40.
14. Million M, Lagier JC, Yahav D, Paul M. Gut bacterial microbiota and obesity. Clin Microbiol Infect. 2013;19:305-13.
15. Kostic AD, Gevers D, Siljander H, Vatanen T, Hyötyläinen T, Hämäläinen AM, Peet A, Tillmann V, Pöhö P, Mattila I, Lähdesmäki H, Franzosa EA, Vaarala O, de Goffau M, Harmsen H, Ilonen J, Virtanen SM, Clish CB, Oresic M,Huttenhower C, Knip M, Xavier RJ, on behalf of the DIABIMMUNE Study Group. The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe. 2015;17:260-73.
16. Hopfner F, Künstner A, Müller SH, Künzel S, Zeuner KE, Margraf NG, Deuschl G, Baines JF, Kuhlenbäumer G. Gut microbiota in Parkinson disease in a northern German cohort. Brain Res. 2017;1667:41-5.
17. Mazel-Sanchez B, Yildiz S, Schmolke M. Ménage à trois: Virus, host, and microbiota in experimental infection models. Trends Microbiol. 2019;1649:1-13. 18. Byrd AL, Belkaid Y, Segre JA. The human skin microbiome. Nat Rev Microbiol. 2018;16:143-55.
19. Kurihara N, Inoue Y, Iwai T, Umeda M, Huang Y, Ishikawa I. Detection and localization of periodontopathic bacteria in abdominal aortic aneurysms. Eur J Vasc Endovasc Surg. 2004;28:553-8.
20. Iwai T, Inoue Y, Umeda M, Huang Y, Kurihara N, Koike M, Ishikawa I. Oral bacteria in the occluded arteries of patients with Buerger disease. J Vasc Surg. 2005;42:107-15.
21. Kubica M, GUzik K, Koziel J, Zarebski M, Richter W, Gajkowska B, Golda A, Maciag-Gudowska A, Brix K, Shaw L, Foster T, Potempa J. A potential new pathway for Staphylococcus aureus dissemination: the silent survival of S. aureus
phagocytosed by human monocyte-derived macrophages. PLoS ONE. 2008;3:e1409. 22. Rijksinstituut voor Volksgezondheid en Milieu RIVM. Referentiecijfers 2012-2015 2012-2015 [Table 1a]. Available from: https://www.rivm.nl/sites/default/files/2018-11/ referentiecijfers POWI_2015_v1.1-WD.pdf.
23. Berríos-Torres SI, Umscheid CA, Bratzler DW, Leas B, Stone EC, Kelz RR, Reinke CE, Morgan S, Solomkin JS, Mazuski JE, Dellinger P, Itani KMF, Berbari EF, Segreti J, Parvizi J, Blanchard J, Allen G, Kluytmans AJW, Donlan R, Schecter WP; for the Healthcare Infection Control Practices Advisory Committee. Centers for disease Control and Prevention guideline for the prevention of surgical site infection, 2017. JAMA Surg. 2017;152:784-91.
24. Cinotti R, Dumont R, Ronchi L, Roquilly A, Atthar V, Gré goire M, Planche L, Letessier E, Dailly E, Asehnoune K. Cefazolin tissue concentrations with a
prophylactic dose administered before sleeve gastrectomy in obese patients: a single centre study in 116 patients. Br J Anaesth. 2018;120:1202-8.
25. Lee JJ, Odeh KI, Holcombe SA, Patel RD, Wang SC, Goulet JA, Graziano GP. Fat thickness as a risk factor for infection in lumbar spine surgery. Orthopedics. 2016;39:e1124-e8.
26. Ashrafi M, Baguneid M, Alonso-Rasgado T, Rautemaa-Richardson R, Bayat A. Cutaneous wound biofilm and the potential for electrical stimulation in
management of the microbiome. Future Microbiol. 2017;12:337-57.
27. Hench LL, Jones JR. Bioactive glass: Frontiers and challenges. Front Bioeng Biotechnol. 2015;3:1-12.
