Duration of operation and diagnosis of hepatitis B (HBV) is an independent risk factor for surgical site infections after liver transplantation
Department of General Surgery, Bursa Uludağ University Faculty of Medicine, Bursa, Türkiye
Objective: Surgical site infections (SSI) are the most common complications after liver transplantation (LT). Although there are some risk factors known in the literature after LT, the available data is insufficient for routine use. In the present study, it was aimed to define the parameters that may be used to clearly determine the risk of SSI after LT in our clinic.
Material and Methods: In the present study, we evaluated 329 patients who underwent liver transplantation with regard to risk factors for surgical site infections. The relation between demographic data and SSI was evaluated using SPSS, Graphpad, and Medcalc statistical programs.
Results: In a total of 329 patients, SSIs were determined in 37 (11.24%). Among the 37 patients, 24 were classified as organ space (64.9%) and 13 as deep SSI (35.1%). None of these patients developed superficial incisional infection. SSI showed statistically significant relation with operation time (p= 0.008), diabetes (p= 0.004), and cirrhosis due to hepatitis B (p< 0.001).
Conclusion: As a result, deep and organ space infections are much more observed in patients undergoing liver transplantation with hepatitis B, diabetes mellitus and prolonged surgery. This is thought to have developed because of chronic irritation and increased inflammation. Since data on hepatitis B and duration of surgery are limited in the literature, this study is considered to be a contribution to the literature.
Keywords: Surgical site infection, liver transplantation, operation time
Liver transplantation (LT) is one of the most effective therapeutic options for patients with liver diseases. However, complications constitute most of the previously reported causes of death in these patients. Postoperative infections are the most common complications after LT (1-8). Hospital infections, which occur as a result of invasive procedures and applications in the hospital, lead to prolonged hospital stay and cause significant morbidity and mortality. Surgical site infections (SSIs) constitute a significant part of hospital infections (2). SSIs are divided into three distinct types as superficial incisional, deep incisional and organ space. Although advances have been made in infection control practices, including improved operating room ventilation, sterilization methods, surgical technique, and availability of antimicrobial prophylaxis, SSIs remain a substantial cause of morbidity, prolonged hospitalization, and mortality (3).
Previous studies have documented increased risk for SSI based on patient and operative characteristics (3-5). Studies have shown that MELD score, diabetes, hyperglycemia, age, operation time, high volumes of blood transfusion are risk factors for SSI (5-7). The aim of this study was to determine and understand the risk factors of SSI in patients undergoing LT in our general surgery department.
Material and Methods
Patients who underwent transplantation for chronic liver disease at Bursa Uludağ University from January 2007 and August 2020 were included in the current study. Ethics approval of the study was obtained from the local institutional ethics committee (No: 2011-KAEK-26/413, Date: 20.07.2020).
The same immunosuppression regimen was applied to all patients included in the study, which consisted of tacrolimus, steroid and mycophenolate mofetil (MMF). Standard dose steroid and MMF were used, and tacrolimus doses were checked daily to keep them within a certain range. Perioperative antibacterial prophylaxis consisted of ampicillin and sulbactam for the first 48 hours after transplantation. Anti-fungal and anti-viral prophylaxis included a combination of nystatin swish-and-swallow, micafungin, fluconazole, ganciclovir and valganciclovir for 3-6 months, depending on the risk profile. Post-transplantation antimicrobial therapy was changed on an individual basis considering clinical factors and speciation of microbiology results.
Surgical site infections were classified according the centers for disease control and prevention classification system as follows:
(a) superficial incisional involving only the skin or subcutaneous tissue of the incision;
(b) deep incisional involving the fascia and/or muscular layers in the primary incision (deep incision primary) in a patient who had an operation involving one or more incisions and an SSI identified in the secondary incision (deep incision secondary) in an operation with more than one incision; and
(c) organ-space involving any part of the body opened or manipulated during the procedure excluding the skin incision, fascia, or muscle layers. In the presence of more than one SSI type, the more complex SSI type was selected. Patients’ demographic information, operative details, post-operative outcomes and infection outcomes were collected from the archive of the department of general surgery. SSIs were defined by using standardized Centers for Disease Control and Prevention’s National Healthcare Safety Network.
The relation between demographic data and SSI was analyzed using SPSS, Graphpad, Medcalc statistical programs. Chi-square test was used between types of organism and source of infection. Overall survival details were presented for each of the three different SSI groups. The Kaplan Meier method was used to determine the effect of SSI on survival. Multivariate analyses were performed using a Cox proportional hazards regression model to investigate associations of patients features, operative information and postoperative complications within 30 days of liver transplantation with development of SSI after liver transplantation. Logistic regression analysis was performed to analyze the risk factors. Student’s t-test was used for comparison of quantitative outcome parameters.
The present study included 329 unrelated patients who had undergone LT. Of these patients, 215 were males and 114 were females, with a median age of 51.4 years (range 5-76 years). Median body mass index was 27 (Range 18-33), and median model for end-stage liver disease (MELD) score was 18 (range 15-30). The most common principal liver disease diagnosis was chronic hepatitis B (n= 126, 38.3%). Median operative time was 238 min (range 100-747 min). SSIs were determined in 37 (11.3%) patients. Among the 37 patients, 24 was classified as organ space (64.9%) and 13 (35.1%) as deep (Table 1). None of these patients developed superficial incisional infection. As reported in Table 2, the highest SSI incidence rates were observed in HBV-infected patients (56.8%; 95% CI 4.5-9.2). The growth of various bacterial pathogen was determined in 29 patients, and fungal pathogen was determined in eight. The most common micro-organisms isolated was Escherichia coli in 20 of 37 (54.0%) patients.
|Sodium MELD score||18 (15-30)|
|Age (years, median)||51.4 (5-76)|
|Organ Space||24 (7.3)|
|Diagnosis||None (n= 292)||Organ Space (n= 24)||Deep (n= 13)||Total (n= 329)|
|HBV||105 (83.3%)||16 (12.7%)||5 (4.0%)||126|
|HCV||17 (81.0%)||1 (4.8%)||3 (14.2%)||21|
|NASH||24 (100%)||0 (0.0%)||0 (0.0%)||24|
|PBC||16 (100%)||0 (0.0%)||0 (0.0%)||16|
|Cryptogenic||42 (97.6%)||0 (0.0%)||1(2.4%)||43|
|Wilson||24 (100%)||0 (0.0%)||0 (0.0%)||24|
|Others||40 (85.4%)||7 (9.3%)||4 (5.3%)||75|
First, the relation between SSI and prognosis was investigated by Kaplan Meier analysis, and the effect of SSI development on short overall survival was determined (Log-rank, p= 0.003, HR= 4.614, Figure 1).
In our study, SSI was 22 in males and 15 in females, and no statistically significant relation was found (p> 0.05). In single variable analysis, there was an association between HBV-infection and SSI (p= 0.001). SSI, which was associated with poor prognosis, showed a statistically significant relation with operation time (p= 0.008), diabetes (p= 0.004), HBV-infection p< 0.001).
In our study, the operative time lasted longer than two hours, which resulted in an increase in the risk of SSI (Table 3). In the study, 21 of the 94 patients with diabetes mellitus developed SSI. In the modeling based on logistic regression analysis with all parameters showing significance, operative time and HBV diagnosis were determined as independent risk factors for SSI (Table 4).
|Operative Time (hour)||95% CI||p||Total (n= 329)|
|<2||0.93 to 1.56||0.956||24|
|2-4||1.23 to 2.01||0.025||47|
|4-5||0.88 to 1.77||<0.001||100|
|>6||1.25 to 2.20||<0.001||16|
|Operation Time (>2 vs <2)||2.5||2.01-5.43||0.022|
|Diabetes (Yes vs. No)||-||0.066|
|HBV-mediated (Yes vs. No)||2.01||1.02-7.23||0.002|
SSI is an important cause of morbidity in the early post-transplant period due to the complexity of the surgery, immunosuppression and patient comorbidities (8). Although progress has been made in infection control practices, SSI remains one of the most common health-related infections (8).
The incidence of SSI following liver transplantation ranges between 8.8% and 37.6%, depending on the definition of SSI and the differences in follow-up times (5,8-11). Softness et al., in their single center experience with 252 patients, have found SSI rate to be 9.5% (9). RA Oliveira et al. have determined an SSI rate of 26.9% in their study (10). In the study of Freire MP et al. in 2021, SSI rate was 30.1% (11). In our retrospective study, the incidence of SSI was 11.24% (37/329) and was consistent with the literature.
We observed solid evidence of a strong association between diagnosis, operative time and SSI, and these relationships were independent of other variables. As stated in many studies in the literature, operative time is closely related with surgical site infection. In the results of our study, operative time was found to be an independent risk factor in terms of surgical site infection, which was consistent with the literature (8-11).
In our study, the relation of SSI with diabetes mellitus was not statistically significant. According to a meta-analysis published by Martin et al in 2016, surgical site infections were found to be closely related to diabetes mellitus. According to this analysis, pre and post hyperglycemia and a history of diabetes mellitus were found to be risk factors for the development of surgical site infection, and our study is consistent with this result (12).
In our patient group who developed surgical site infection, the duration of intensive care and hospital stay increased in the postoperative period, but this result was not statistically significant.
Sangrasi et al. have shown the duration of postoperative stay as a risk factor for SSI, and hospitalization of the group with SSI was 16.2 days while the hospitalization period of the group without SSI was 6.3 days. In this study, it was shown that hospitalization time increased more than two times in patients who developed infection (13).
According to a study conducted by Işık et al. in 2015, operation time exceeding four hours was found to be a risk factor for the development of SSI (14). Our study was consistent with the results of this study. In our study, the operative time lasted longer than two hours and resulted in an increase in the risk of SSI. Malone et al. have compared patients with a duration of operation <2 hours, 2-4 hours, and >4 hours and found that as duration increased, so did the rates of SSI (2.1%-3.3%-6.4%, respectively) (15).
There is no reported relation between surgical site infection and hepatitis B in the literature. Although mechanisms that trigger the development of cirrhosis in the liver are thought to be induced by chronic inflammation, the current literature on the mechanisms of surgical site infection is insufficient, and more studies are needed. According to the findings of our study, the development of surgical site infection was found to be significantly higher in patients who had undergone liver transplantation due to hepatitis B cirrhosis compared to the other groups. According to this result, the determination of hepatitis B as an independent risk factor for the development of surgical site infection is a significant contribution to the literature.
Risk factors for the development of SSI have been determined in previous studies. In our study, risk factors of the patient were associated with increased operative time and hepatitis B. As a result of our work with this data, it can be changed to prevent the development of SSI, and intervention of predictable factors can be evaluated. However, studies that evaluate risk factors and have more patients are needed.
Our study has several limitations. As our study was a cohort study, we did not check the interventions that could have affected the results. Clinical parameters in the study are few.
In conclusion, we found that HBV-infection and operative time were associated with an increased risk of SSI. In order to reduce the rate of SSI in patients with LT, studies should be increased.
Cite this article as: Aksoy F, Dündar HZ, Kaya E. Duration of operation and diagnosis of hepatitis B (HBV) is an independent risk factor for surgical site infections after liver transplantation. Turk J Surg 2022; 38 (3): 289-293.
The approval for this study was obtained from Uludağ University Faculty of Medicine Clinical Research Ethics Committee (Decision no: 2020-12/17, Date: 08.07.2020).
Concept - E.K.; Design - F.A.; Supervision - H.Z.D.; Fundings - F.A.; Materials - F.A.; Data Collection and/or Processing - E.K.; Analysis and/or Interpretation - H.Z.D.; Literature Search - F.A.; Writing Manuscript - H.Z.D., F.A.; Critival Review - E.K.
The authors have no conflicts of interest to declare.
The authors declared that this study has received no financial support.
- Oliveira RA, Mancero JMP, Faria DF, Poveda VB. A retrospective cohort study of risk factors for surgical site infection following liver transplantation. Prog Transplant 2019; 29: 144-9. https://doi. org/10.1177/1526924819835831
- GlobalSurg Collaborative. Surgical site infection after gastrointestinal surgery in high-income, middle- income, and low-income countries: a prospective, international, multicentre cohort study. Lancet Infect Dis 2018; 18: 516-25. https://doi.org/10.1016/S1473-3099(18)30101-4
- Hellinger WC, Crook JE, Heckman MG, Diehl NN, Shalev JA, Zubair AC, et al. Surgical site infection after liver transplantation: risk factors and association with graft loss or death. Transplantation 2009; 87: 1387- 93. https://doi.org/10.1097/TP.0b013e3181a25133
- Oliveira RA, Turrini RNT, Poveda VB. Risk factors for development of surgical site infections among liver transplantation recipients: an integrative literature review. Am J Infect Control 2018; 46: 88-93. https:// doi.org/10.1016/j.ajic.2017.05.021
- Vasavada B, Chen CL. Vascular complications in biliary atresia patients undergoing living do-nor liver transplantation: Analysis of 110 patients over 10 years. J Indian Assoc Pediatr Surg 2015; 20: 121-6. https://doi.org/10.4103/0971-9261.154651
- Avkan-Oguz V, Ozkardesler S, Unek T, Ozbilgin M, Akan M, Firuzan E, et al.Risk factors for early bacterial infections in liver transplantation. Transplant Proc 2013; 45: 993-7. https://doi.org/10.1016/j.transproceed.2013.02.067
- Antunes M, Teixeira A, Fortuna P, Moya B, Martins A, Bagulho L, et al. Infections after liver transplantation: A retrospective, single-center study. Transplant Proc 2015; 47: 1019-24. https://doi.org/10.1016/j. transproceed.2015.03.009
- Abbo LM , Grossi PA. Surgical site infections: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant 2019; 33: e13589. https://doi.org/10.1111/ ctr.13589
- Softness KA, ElSabbagh A, Kroemer A, Hawksworth J, Matsumoto Cal S, Fishbein T, et al. Surgical site infection after liver transplantation: Single-center. Experience Int J Transplant Res Med 2018; 4: 037.
- Oliveira RA, Mancero JMP, Faria DF, Poveda VB. A retrospective cohort study of risk fac-tors for surgical site infection following liver transplantation progress in transplantation. Prog Transplant 2019; 29: 144-9. https://doi.org/10.1177/1526924819835831
- Freire MP, Song ATW, Oshiro ICV, Andraus W, D’Albuquerque LAC, Abdala E. Surgical site infection after liver transplantation in the era of multidrug- resistant bacteria: What new risks should be considered? Diagn Micr Infec Dis 2021; 99: 115220. https://doi.org/10.1016/j.diagmicrobio.2020.115220
- Martin ET, Kaye KS, Knott C, Nguyen H, Santarossa M, Evans R, et al. Diabetes and risk of surgical site infection: A systematic review and meta-analysis. Infect Control Hosp Epidemi-ol 2016; 37: 88-99. https:// doi.org/10.1017/ice.2015.249
- Sangrasi AK, Leghari AA, Memon A, Talpur AK, Qureshi GA, Memon JM, et al. Surgical site infection rate and associated risk factors in elective general surgery at a public sector medi-cal university in Pakistan. Int Wound J 2008; 5: 74-8. https://doi.org/10.1111/j.1742- 481X.2007.00365.x
- Isik O, Kaya E, Dündar HZ, Sarkut P. Surgical site infection: Reassessment of the risk factors. Chirurgia 2015; 110: 457-61.
- Malone DL, Genuit T, Tracy JK, Gannon C, Napolitano LM. Surgical site infections: Re-analysis of risk factors. J Surg Res. 2002; 103: 89-95. https://doi.org/10.1006/jsre.2001.6343