Background
Organ transplantation is considered as the most effective treatment for end-stage disease of the heart, lung, pancreas, liver, and kidney, with approximately 28000 solid organs transplanted every year in Europe and USA, and overall 114690 organs transplanted in 2012 worldwide [
1]. The high number of transplantations per year and the long-term graft survival had contributed to drastically increase the likelihood for an emergency surgeon to encounter a transplanted patient with a graft-unrelated surgical problem [
2‐
5].
The management of graft-unrelated acute abdominal disease in transplanted patients generally adheres to the fundamental principles of any surgical treatment. Preoperative evaluation should consider that transplanted patients are chronically immunosuppressed, and although most of them achieve an excellent functional capacity and are able to live normal productive lives, they remain at increased risk for any surgical complication, particularly infectious. Moreover, the clinical presentation of many disease may be different from the general population, sometimes leading to misdiagnosis or underestimation of the disease severity [
5]. Another important issue is the potential impact of any operative procedure on the functional capacity of the transplanted organ, which shows to have a reduced clinical reserve compared to the native organ. Even modest intra-operative insults, such as hypotension, may negatively affect the transplanted organ, and thus, when several options are available, the most cautious, conservative, minimally invasive, and standardized surgical approach should be preferred in these patients [
5].
When considering the incidence of several common general surgical problems and the ever-larger cohort of transplanted patients living and functioning under chronic immunosuppression [
6], it becomes apparent that all general surgeons, especially outside of transplant centers, should be familiar with the factors that influence the surgical outcomes in this particular subset of patients, along with the issues that are likely to affect the optimal surgery timing and the postoperative cares [
6].
The aim of the present systematic review is to provide an exhaustive analysis of the current available literature about the outcomes of emergency abdominal surgery (EAS) performed in transplanted patients for graft-unrelated abdominal diseases. The evidence-based assessment of EAS morbidity and mortality in transplanted patients may help the surgeon and clinician in the decision making process face to the challenging management of acute abdominal disease in this particular subset of patients.
Materials and methods
The methodological approach included the development of selection criteria, definition of search strategies, assessment of study quality, and abstraction of relevant data. The PRISMA statements checklist for reporting a systematic review was followed [
7].
Study inclusion criteria
The study selection criteria were defined before initiating data collection for proper identification of studies eligible for the analysis. All studies in which the primary objective was to describe EAS for graft-unrelated diseases in transplanted patients were retrieved and analyzed.
Types of study
Epidemiological studies, interventional trials, case–control studies, cross-sectional studies and case series including more than four patients [
8] were considered eligible for inclusion in this systematic review. Case reports, review articles, systematic reviews, meta-analyses, conference abstracts, letters and commentaries were not considered.
Types of participants
Patients who had received a solid organ transplantation (heart, lung, liver, pancreas, or kidney) presenting with graft-unrelated surgical abdominal diseases were considered.
Types of intervention
All types of surgical abdominal emergencies (e.g. appendectomy, cholecystectomy, colectomy, bowel resection, gastric resection, surgical repair of incisional hernia, explorative laparotomy) were considered.
Types of outcome measures
The primary outcomes were the post-operative 90-day morbidity and mortality following EAS. All secondary parameters (e.g. hospital stay and immunosuppressive therapy) reported in the selected studies were also evaluated.
Literature search strategy
A literature search was performed on the following online databases: MEDLINE (through PubMed), EMBASE, Scopus, Cochrane Oral Health Group Specialized Register, and ProQuest Dissertations and Thesis Database. To increase the probability of identifying all relevant articles, a specific research equation was formulated for each database, using the following keywords and/or MeSH terms: emergency, emergency surgery, urgent surgery, appendicitis, diverticulitis, perforation, cholecystectomy, colectomy, appendectomy, cholecystitis, humans, adult, transplant, transplantation, solid organ transplantation, transplant patient, transplanted patient.
In addition, the reference lists from the eligible studies and relevant review articles (not included in the systematic review) were crosschecked to identify additional records. The literature search was performed on January 2016 and was restricted to articles published since 1990. Only studies written in English and meeting the selection criteria were reviewed.
Study selection and quality assessment
The titles and abstracts of the retrieved studies were independently and blindly screened for relevance by two reviewers (FE and VL). To enhance sensitivity, records were removed only if both reviewers excluded the record at the title screening level. All disagreements were resolved by discussion with a third and fourth reviewers (NdeA and RM). Subsequently, both reviewers performed a full-text analysis of the selected articles. Two reviewers independently assessed the risk of bias and study quality by using appropriate tools. Precisely, The NICE guidelines [
9] was used for the quality assessment of case series, which was rated on a 8 points scale by answering eight questions concerning the following aspects:, study setting (i.e. uni or multicentric), study hypothesis/objective, case definition, outcome definition, data collection, patient recruitment, result description and analysis. Additionally, the Grading of Recommendations Assessment Development and Evaluation (GRADE) system [
10] was used to enable consistent judgment of the “body of evidence” included in the systematic review. GRADE specifies four categories: high, moderate, low, and very low. In the context of a systematic review, the quality of evidence reflects the confidence that the estimates of the effect are correct and overpasses the individual study risk of bias by evaluating the following aspects: study design, imprecision, inconsistency, indirectness of study results, and publication bias.
Data extracted from the studies included in the systematic review were processed for qualitative and possibly quantitative analyses. Outcome measures (mean and median values, standard deviation, and ranges) were extracted for each variable. Average morbidity and mortality rates were calculated.
Discussion
The present systematic review is the first to analyze the available literature concerning EAS in transplanted patients. Emergency surgery after transplantation for graft-unrelated acute diseases involved 2.5 % of patients, with the main causes being gallbladder diseases, gastrointestinal perforations, complicated diverticulitis, small bowel obstructions, and appendicitis. Overall, EAS was associated with high morbidity (up to 32.7 %) and mortality (up to 17.5 %) rates, which highlight the particularly challenging surgical management of transplanted patients.
Undoubtedly, one of the most important factors contributing to the high morbidity and mortality in transplanted patients operated for EAS is represented by the use of several immunosuppressive regimens, most frequently consisting in a triple-drug association: calcineurin inhibitors, antiproliferative agents, and corticosteriods [
49]. In general, immunosuppressive therapy predisposes transplanted patients to various gastrointestinal diseases [
50], lymphoproliferative disorders, infective complications (e.g. Cytomegalovirus, Clostridium difficile), and can mask the presenting signs and symptoms of many disease processes. Moreover, immunosuppression is known to interfere with the patient management for transplant-unrelated surgical procedures in terms of risk for drug interactions, adverse effects, wound healing, and postoperative complications [
49].
Gallbladder diseases were the most frequent reason for EAS after transplantation, which was mainly reported in heart-transplanted patients. Despite actual controversies, the high incidence of biliary tract diseases may be related to cyclosporine-induced perturbation of bile composition resulting in an increased prevalence of biliary stones formation [
51,
52]. Other putative explanations include vagotomy and associated biliary stasis, rapid weight loss following transplantation, atherosclerosis, and hemolysis [
53]. EAS for gallbladder diseases has been associated with high morbidity (up to 47 %) [
17,
20] and mortality rates (up to 29 %) [
17,
19], and thus a prophylactic cholecystectomy in asymptomatic patients awaiting transplantation has been proposed as a strategy to avoid symptomatic gallstone diseases later on [
54,
55]. This may be particularly indicated before heart and lung transplantation, after which a high incidence of clinical manifestations and increased mortality has been reported [
19,
56,
57]. However, this approach remains under debate and it is not routinely performed, also because an emergency cholecystectomy can be highly problematic in patients with end-stage diseases [
58]. Both laparoscopy and laparotomy were reported for the surgical management of emergency related to gallbladder diseases. Some evidence suggests that patients undergoing open cholecystectomy develop major post-operative complications (Dindo-Clavien Classification [
59] >3) more frequently than patients operated on by laparoscopy [
11]. Other studies showed that laparoscopic cholecystectomy can be performed safely in lung-, and kidney-transplanted patients [
11,
60], whereas pancreas-transplanted patients may require specific technical modifications in the laparoscopic cholecystectomy procedure, which need to be carefully evaluated preoperatively. In the present systematic review it was not possible to evaluate the rate of post-operative complications and mortality following EAS for gallbladder diseases by specific surgical approach. Nevertheless, the overall morbidity and mortality rates appears to be higher than those found in the literature for non-transplanted patients (estimated at <1 %) [
61‐
64].
Gastrointestinal perforations were the second most frequent cause of EAS after solid organ transplantation. The majority (57.5 %) of the described cases in the literature occurred in kidney-transplanted patients for polycystic kidney disease. Although no precise etiology was found, it seems that transplanted patients for polycystic kidney disease develop more gastrointestinal complications after transplantation than kidney-transplanted patients for other diseases [
33], probably due to several biologically active substances that influence the alimentary tract and contribute to the increased incidence of ileus in these patients [
65].
In particular, complicated diverticulitis requiring EAS in transplanted patients showed an incidence rate of 0.88 %, which is in accordance with other studies on transplanted patients (1–4 %) [
2,
66,
67] and definitely higher than in the general population (estimated incidence of 0.025–0.053 %) [
42,
68,
69]. The diagnosis and treatment of diverticulitis after solid organ transplantation are challenging, since immunosuppressive therapies may mask presenting signs and symptoms and impair the ability to contain the infective process [
70]. Often, the clinical manifestation and physical examination do not reflect the severity of intra-abdominal disease; signs of infection, such as fever and tachycardia, especially in heart-transplanted patients, could be absent or highly attenuated. Abdominal examination and laboratory testing may be irrelevant, and only the abdominal CT scan appears to be a reliable diagnostic tool to determine the location and severity of the disease. Moreover, morbidity and mortality following emergency colectomy for complicated diverticulitis in transplanted patients are higher (32.7 and 13.6 %, respectively) than those observed in immunocompetent individuals [
29,
39].
Another gastrointestinal complication observed in transplanted patients was small bowel obstruction. The most frequent etiologies were post-transplant lymphoproliferative disorders and mechanical obstruction due to adhesions. The first disease is usually diagnosed within the first 2 years after transplantation, and it is strongly associated with high levels of immunosuppressive drugs [
71]. The concomitant involvement of both small and large bowels may occur in one third of the patients [
72]. These findings stressed the importance of early recognition and systematic referral for endoscopy of any transplanted patient with gastrointestinal symptoms, particularly over the first 2 years after transplantation [
26].
Finally, EAS for appendicitis in transplanted patients was described in 0.29 % of cases, mainly in liver-transplanted patients (38.9 %). Appendicitis is one of the most common surgical disease in the general population, with an estimated lifetime risk of 8.6 % in males and 6.7 % in females [
73], however only few studies are found in transplanted patients. In all case series, appendectomy was approached by laparotomy. Only a case report in the literature describes laparoscopic appendectomy in two liver and renal transplanted patients with excellent results similar to those in non-transplanted patients [
74]. It must be noted that appendicitis in transplanted patients is frequently associated with delayed diagnosis or misdiagnosis, which can lead to complicated appendicitis including rupture and gangrene. As a general rule, appendicitis should be aggressively treated to minimize morbidity in the clinical setting of chronic immunosuppression. Based on the literature findings, surgical morbidity and mortality rates associated with this emergency procedure appear to be much lower than for other gastrointestinal complications [
18].
In almost all the included studies, immunosuppressive regimens were maintained unchanged during the post-operative period after EAS. Although the heterogeneity of the literature does not allow pooling data together and analyzing the direct impact of immunosuppressive therapies on post-operative complications, the role of immunosuppression remains crucial since it claims for a more aggressive treatment of acute abdominal diseases. On the other hand, this may contribute to have no cases of graft failure or late rejection following EAS.
Study limitations
The currently available literature on EAS in transplanted patients for graft-unrelated abdominal diseases is based on case series only, which represents a low quality of evidence. However, it may not be feasible to perform randomized controlled trials or even case–control studies in the setting of emergency surgery. Moreover, it was not possible in the present systematic review to perform any quantitative syntheses or risk analysis due to the observational nature of the included studies, the high heterogeneity, and the lack of control groups. Thus, caution should be paid in the interpretation of the results since several biases can be mentioned in the individual studies, such as selection bias, reporting bias, publication bias, and geographical bias. However, we tried to control for search biases by searching the literature on multiple databases, by manual crosscheck of the reference lists, and by performing the critical appraisal by two independent reviewers.
Acknowledgements
The authors would like to thank Dr Maria Clotilde Carra for her valuable help in revising the final version of the manuscript.