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Surgical procedures in liver transplant patients: A monocentric retrospective cohort study
International Journal of Surgery 41 (2017) 58e64
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Original Research
Surgical procedures in liver transplant patients: A monocentric retrospective cohort study Daniele Sommacale, M.D a, Ganesh Nagarajan, M.D b, Martin Lhuaire, M.D, M.Sc a, *, Federica Dondero, M.D b, Patrick Pessaux, M.D, PhD b, Tullio Piardi, M.D a, Alain Sauvanet, M.D, PhD b, Reza Kianmanesh, M.D, PhD a, Jacques Belghiti, M.D b ^pital Robert Debr Department of General and Digestive Surgery, Ho e, Centre Hospitalier Universitaire de Reims, Universit e de Reims Champagne-Ardenne, Reims, France ^pital Beaujon, Assistance Publique des Ho ^pitaux de Paris, Clichy, France Department of Hepato-biliary Surgery and Liver Transplantation, Ho
a
b
h i g h l i g h t s This study presents comprehensively the epidemiology of the surgical history in 1211 liver recipients who require further surgical procedures. Surgical procedures on liver transplanted patients are associated with a significantly high risk of complications, irrespective of the time elapsed since transplantation.
a r t i c l e i n f o
a b s t r a c t
Article history: Received 10 January 2017 Received in revised form 10 March 2017 Accepted 20 March 2017 Available online 24 March 2017
Background: Pre-existing chronic liver diseases and the complexity of the transplant surgery procedures lead to a greater risk of further surgery in transplanted patients compared to the general population. The aim of this monocentric retrospective cohort study was to assess the epidemiology of surgical complications in liver transplanted patients who require further surgical procedures and to characterize their post-operative risk of complications to enhance their medical care. Patients and methods: From January 1997 to December 2011, 1211 patients underwent orthotropic liver transplantation in our center. A retrospective analysis of prospectively collected data was performed considering patients who underwent surgical procedures more than three months after transplantation. We recorded liver transplantation technique, type of surgery, post-operative complications, time since the liver transplant and immunosuppressive regimens. Results: Among these, 161 patients (15%) underwent a further 183 surgical procedures for conditions both related and unrelated to the transplant. The most common surgical procedure was for an incisional hernia repair (n ¼ 101), followed by bilioenteric anastomosis (n ¼ 44), intestinal surgery (n ¼ 23), liver surgery (n ¼ 8) and other surgical procedures (n ¼ 7). Emergency surgery was required in 19 procedures (10%), while 162 procedures (90%) were performed electively. Post-operative mortality and morbidity were 1% and 30%, respectively. According to the Dindo-Clavien classification, the most common grade of morbidity was grade III (46%), followed by grade II (40%). Conclusion: Surgical procedures on liver transplanted patients are associated with a significantly high risk of complications, irrespective of the time elapsed since transplantation. © 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.
Keywords: Retrospective cohort study General surgery Liver transplantation Surgical complications
1. Introduction
Abreviation: LT, liver transplantation; OLT, orthotopic liver transplantation. ^ pital * Corresponding author. Department of General and Digestive Surgery, Ho , Centre Hospitalier Universitaire de Reims, 51092, Reims, France. Robert Debre E-mail address: [email protected] (M. Lhuaire).
In recent decades, there has been impressive progress in the management of liver transplantation (LT), resulting in a constantly growing liver transplant recipient population, as reported by the last annual reports of the French Biomedicine Agency (2014) [1] and the OPTN (2012) [2e4]. Pre-existing chronic liver diseases
http://dx.doi.org/10.1016/j.ijsu.2017.03.058 1743-9191/© 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.
D. Sommacale et al. / International Journal of Surgery 41 (2017) 58e64
and an initially aggressive surgical procedure using a large abdominal approach with vascular and biliary anastomosis, as well as the consequences of long-term immunosuppression can lead to subsequent surgical procedures for liver transplant recipients at a higher rate than in the general population [5e8]. Moreover, it is now well-known that the altered physiology and immunosuppression of these patients explain their increased exposure to postoperative complications. In this setting, it is safe to state that the progressively growing prevalence of the liver transplant target population has led to an increased rate of common surgical diseases. Taking into account the expected rise in live transplant survivors in coming years, an increase in further surgical procedures in this population is likely to lead significant problems for transplantation centers in terms of the allocation of beds, operating room availability and the use of hospital resources [5]. While most transplantation centers are already overburdened by transplantation activity alone, carrying out further general surgical procedures within these specialized units may also imply longer waiting periods, higher hospital costs and inconvenience to patients who may not live close to a transplantation centers. In this sense, non-transplantation surgical units will have to perform more general procedures on the liver transplant recipients, which would necessarily require close coordination with transplantation centers. Therefore, it is important that non-liver transplant surgeons are aware of the specific complications that they may have to manage when they encounter these specific patients. In this sense, epidemiological data about the incidence, type of surgery, post-operative complications and mortality are required for this specific patient population to managed them regarding medical and surgical care. The literature on the subject is very weak and insufficient, as only one benchmark study published in the past ten years ago has reported this specific aspect [6]. Therefore, an update on the epidemiology of post-LT surgical procedures seems relevant. The aim of this monocentric retrospective cohort study was to assess the epidemiology of surgical procedures and their complications in the liver transplant recipient population to enhance their medical care.
2. Patients and methods 2.1. Patients From January 1997 to December 2011, 1211 patients underwent orthotropic liver transplantation (OLT) in our center.
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2.3. Data collection and post-operative follow-up A retrospective analysis of prospectively collected data was performed. 2.4. Inclusion criteria All general surgical procedures performed on liver transplant recipients more than three months after the date of transplantation were included in the study. For each patient we recorded the general profile and demographic data, indication for LT, the type of transplant, type of surgical procedure, time period between transplantation and subsequent surgical procedures, intraoperative and post-operative course, and immunosuppression regimen. Patient follow-up was performed at our outpatient clinic on a weekly basis for the first three months and then twice per month for six months. Patients were then seen on a bimonthly schedule for two years and on a six-month schedule thereafter. Abdominal ultrasound or CT scan was performed every three months during the first year, every six months for the next two years and annually thereafter. 2.5. Exclusion criteria Procedures done at the same admission as the transplantation and re-transplantations or surgical procedures for the treatment of hepatic artery thrombosis and pseudoaneurysms were excluded from the study. 2.6. Definitions All surgical procedures were classified into elective or emergency and major or minor procedures. All procedures limited to the abdominal wall were categorized as minor procedures while all those involving opening the peritoneal cavity with a visceral surgical procedure (digestive resection and/or anastomosis) categorized as major procedures. Post-operative morbidity was graded according to the Dindo-Clavien classification [9]. Renal insufficiency was defined as plasma creatinine >150 mg/L [10]. Sepsis was defined by the presence or suspicion of an infection, in addition to evidence of increased levels of circulating inflammatory mediators, thus resulting in a systemic inflammatory response syndrome [11]. Rejection was defined on the basis of liver biopsy performed in suspected cases [12]. 2.7. Statistical methods
2.2. Transplantation technique A Mercedes abdominal incision and cavo-caval anastomosis was performed in each case. Portal reconstruction was carried out by means of an end-to-end anastomosis. Arterial anastomosis was done, whenever possible, between the donor celiac artery and the recipient hepatic artery. If the native hepatic artery was not suitable, anastomosis was done between the donor celiac artery and the recipient splenic artery or an arterial allograft conduit was interposed between the donor celiac artery and the recipient infrarenal aorta or splenic artery. In the presence of an accessory right hepatic artery, the graft was revascularized via the donor superior mesenteric artery (using the Carrel patch technique). Usually, a bilio-biliary anastomosis was done, but in cases of liver re-transplantation or primary sclerosing cholangitis, a bilioenteric anastomosis was performed. Grafts were invariably stored in University of Wisconsin solution. Immunosuppression was achieved using FK 506 (Astellas, Tokyo, Japan).
Chi-squared analysis and the Fisher exact test were used for statistical analysis. P values < 0.05 were considered statistically significant. 3. Results 3.1. Incidence and characteristics of surgical procedures Overall, of the 1211 patients who underwent liver transplantation, 161 patients underwent 183 further surgical procedures (15%) for conditions both related and unrelated to the transplant (Table 1). Among these, 154 were patients with liver transplants only, six had both liver and kidney transplants and one patient had both liver and lung transplants. Among the 183 procedures, postoperative morbidity was noticed after 54 procedures (30%) and mortality after two procedures (1%) secondary to sepsis and renal failure after emergency intestinal surgeries. Emergency surgery was required in 19 procedures (10%), while 162 (90%) were elective
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3.3. Delay between the surgical procedure and the LT
Table 1 Descriptive and analytic results of the current study. Parameters
Number
Percentage
p
LT cohort Surgical procedures Number of patients Overall morbidity Overall mortality Emergency surgery Morbidityc Mortalityd Elective surgery Morbidityc Mortalityd Major proceduresa Morbiditye Mortality f Minor proceduresb Morbiditye Mortality f
1211 183 161 54 2 19 6 2 162 48 0 78 38 2 103 16 0
e 15% e 30% 1% 10% 32% 11% 90% 30% 0% 43% 49% 2.6% 57% 16% 0%
e e e e e e NS 0.02 e NS 0.02 e 0.04 NS e 0.04 NS
LT: liver transplant. a Defined as procedures with peritoneal cavity opening with a visceral surgical procedure (digestive resection and/or anastomosis). b defined as procedures limited to the abdominal wall. c Morbidity comparisons between emergency and elective surgeries. d Mortality comparisons between emergency and elective surgeries. e Morbidity comparisons between major and minor surgeries. f Mortality comparisons between major and minor surgeries.
surgical procedures. Among the 19 emergency cases (10%), six were morbid (32%). Emergency cases accounted for both the mortalities (11%). Of the 164 electively operated cases, 48 had post-operative morbidity (30%). There was no mortality after elective surgery. While there was no statistical difference in the post-operative morbidity between the elective and emergency surgery groups, post-operative mortality was significantly higher after the emergency surgeries (p ¼ 0.02). Overall, 78 procedures (43%) were major and 103 procedures (57%) were minor. Among the 103 minor procedures, post-operative complications arose in 16% of cases, while among the 78 major procedures post-operative complications arose in 49% of cases. Post-operative morbidity was significantly higher after major surgery compared to minor surgery (p ¼ 0.04). Both the mortalities occurred after major surgeries (Table 1). 3.2. Type of surgical procedures The most common surgical procedure after liver transplant was a group of abdominal wall procedures consisting of incisional and inguinal hernias (101 cases; 55%). Biliodigestive anastomosis for biliary anastomotic-stricture was required in 44 cases (24%). All of these had not responded to endoscopic treatment. Intestinal surgery was required for 23 patients (13% of the surgical procedures), and liver surgery was performed in eight cases (4%). Other procedures included adrenalectomy for adrenal metastasis of hepatocellular carcinoma (n ¼ 2), lymph node clearance (n ¼ 1), peri-anal abscess drainage (n ¼ 1), adhesiolysis for acute intestinal obstruction (n ¼ 2) and mastectomy for breast cancer (n ¼ 1) (Table 2).
The delay between the LT and abdominal surgery varied; 33 procedures (18%) were performed within six months, 41 (22%) between six months and one year, 48 (26%) in the second year, 22 (12%) in the third year and 37 procedures (20%) were performed more than three years after LT. There was no statistically significant difference in the incidence of complications regarding the delay between the LT and the second abdominal surgery (Table 3). 3.4. Post-operative morbidity characteristics and mortality after surgical procedures following LT According to the Dindo-Clavien classification, the most common grade of morbidity was grade III (46% of complications), followed by grade II (40% of complications) (Table 4). The most frequent types of morbidity after general surgical procedures were renal insufficiency (n ¼ 11), systemic infection (n ¼ 11) and wound infection (n ¼ 11). Ascites developed in four patients, while five patients required evacuation of clots or hematoma drainage. Four patients suffered a post-operative intestinal obstruction which was settled with conservative management in two patients while two others required adhesiolysis. Two patients rejected the transplant after the procedure (Table 5). Transplant rejections were confirmed by percutaneous liver biopsies. The main explanation for these transplant rejections were in both cases related to the difficulty of maintaining the post-operative plasma level of FK 506 above the threshold limit secondary to renal function impairment. However, both patients responded well to an appropriate adaptation of immunosuppressive drugs and the degree of renal dysfunction with daily assessment of FK 506 plasma level. Sub-group analysis of post-operative complications and mortality according to the type of surgery are presented in Table 6. The two patients died on postoperative day 7 and 11 secondary to uncontrolled sepsis associated with irreversible renal failure. One patient died of these complications secondary to stercoral peritonitis due to a perforated sigmoid diverticula, and the second one died of these same complications secondary to small bowel necrosis. Finally, corticosteroid therapy was ongoing in 33 procedures (18%) when they underwent the surgery. Among them, post-operative morbidity was seen in 14 procedures (42%). Of the other 150 procedures where patients were off corticosteroid therapy (82%), post-operative morbidity was seen in 40 procedures (27%). The difference between groups was not statistically significant (Table 7). 4. Discussion In the last decade, there has been an exponential rise in LT recipient survivors worldwide [3e5]. The current study showed an overall incidence of LT recipients requiring any kind of further surgical procedure of 15%. This rate is lower compared to a report by Testa et al. (24.2%) which could be explained simply because we did not include extra-digestive surgeries like orthopedics or urologic surgeries, for example [6]. Another point could be attributed
Table 2 Surgical procedures performed on the liver transplant cohort. Type of surgery
Number (n ¼ 183)
Morbidity (n ¼ 54)
Percentage
Parietal Biliodigestive anastomosis Intestinal Liver Adrenal Others
101 44 23 8 2 5
22 17 8 4 2 1
21% 38% 34% 66% 100% 25%
D. Sommacale et al. / International Journal of Surgery 41 (2017) 58e64
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Table 3 Influence of the delay on morbidity incidence after a surgery on the liver transplant cohort. Delay
Number of surgeries
Number of morbidities
Percentages
6 months 6 months - 1 year 1 - 2 years 2 - 3 years >3 years
33 41 48 22 37
13 12 12 6 11
39%a 29%a 25%a 27%a 30%a
a
There were no statistically significant differences regarding the delay.
Table 4 Post-operative morbidity characteristics following surgical procedures on LT patients (n ¼ 54; 30%).
Table 6 Sub-group analysis of post-operative complications and mortality according to the type of surgery.
Dindo-Clavien classification
Number of patients
Percentages
Type of surgery
Number (n ¼ 183)
Percentages
I II III IV V
1 22 25 4 2
2% 40% 46% 7% 4%
Parietal Incisional hernia Others hernias Repair with mesh Recurrence Repair w/o mesh Recurrence Overall mortality Overall morbidity Grade I Grade II Grade III Wound abcess Renal dysfonction Biliodigestive anastomosis Overall mortality Overall morbidity Grade I Grade II Grade III Wound abcess Systemic infection Renal dysfonction Gastrointestinal Colonic resections Small bowel resections Appendicectomies Adhesiolysis for intestinal obstruction Ileostomy closure Sleeve gastrectomy Overall mortality Overall morbidity Grade I Grade II Grade III Grade IV Wound abcess Systemic infection Renal dysfonction Anastomotic leaks Liver resections Left lobectomy Right hepatectomy Posterior sectoriectomy Liver cyst excisions Overall mortality Overall morbidity Grade I Grade II Grade III Systemic infection Renal dysfonction Intraabdominal collection Adrenal Others
101 77 24 35 0 42 5 0 22 3 9 10 6 4 44 0 17 2 7 8 6 4 3 23 9 3 3 5 2 1 2 8 0 1 5 2 2 2 4 2 8 4 1 1 2 0 5 1 2 2 2 2 2 2 5
55% 76% 24% 35% 0% 42% 12% 0% 22% 14% 41% 45% 27% 18% 24% 0% 39% 12% 41% 47% 35% 24% 18% 13% 39% 13% 13% 22% 9% 4% 7% 35% 4% 7% 22% 9% 9% 9% 17% 9% 4% 50% 13% 13% 25% 0% 63% 13% 25% 25% 25% 25% 25% 1% 3%
Table 5 Post-operative morbidity characteristics following surgical procedures after LT (n ¼ 54 procedures with post-operative morbidity; 30%). Type of morbidity
Number of patients
Percentages
Renal insufficency Systemic infection Abdominal wall abscess Bleeding/hematoma Intestinal obstruction Ascites Cholangitis Intraabdominal collection Transplant rejection Pulmonary embolism
11 11 11 5 4 4 3 2 2 1
20% 20% 20% 9% 7% 7% 5% 3% 3% 2%
to major advances in non-surgical treatment of biliary and vascular complications coupled with safer immunosuppression regimes over the last two decades [13e17]. However, if we consider only digestive surgeries, the incidence was 14.2% in the report by Testa et al., which is very similar to ours [6]. As already reported by Testa et al., major procedures, arbitrarily defined in the current study as a surgery with opening of the abdominal cavity associated to a visceral surgical procedure (digestive resection and/or anastomosis), are more frequent than minor surgeries. It could be taken with safety because of the potential selection bias discussed before. Indeed, it is obvious that a patient who has undergone a minor procedure such as skin lesions removal or ophthalmologic surgery will not be referred to our center for their management and are thus lost to follow-up; these patients were unfortunately not included in this study. On first impression, it would be obvious that the incidence of minor surgical procedures would be more frequent with a negligible risk of post-operative complications, but no data on this topic are available in the literature. The original data provided by the current study shows that there is no post-LT critical period were the incidence of further abdominal surgeries is increased. The type of surgery, as well as the surgery being major or minor, emergent or elective are factors unrelated to the delay of further general abdominal surgeries following OLT. Indeed, an incidence of approximately 20% of further general abdominal surgeries was recorded between three to six months, six months to one year, within one year and two years following OLT. There were no significant differences in terms of post-operative morbidity or mortality regarding time elapsed since OLT. Two-thirds (67%) of the general surgeries took place in the first two years after
transplantation. The morbidity rate was similar, irrespective of the time elapsed after transplantation. To our knowledge, this aspect has not been mentioned previously. An important message is that
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Table 7 Descriptive and analytic results in patient under corticosteroid therapy at time of the surgical procedure (n ¼ 33; 18%). Parameters
Number
Percentages
p
Patient w/o corticoids Morbiditya Mortality Patient with corticoids Morbiditya Mortality <6 months with corticoids Morbidityb >6 months with corticoids Morbidityb <10 mg Prednisolone/day Morbidityc >10 mg Prednisolone/day Morbidityc
150 40 0 33 14 0 12 6 21 8 23 7 10 7
82% 27% 0% 18% 42% 0% 36% 50% 64% 38% 70% 30% 30% 70%
e NS e e NS e e e e e e e e e
a Morbidity comparisons between patient with and without corticoids at time of surgery. b Morbidity comparison between patients under corticoids <6 months and those >6 months. c Morbidity comparison between patients with prednisolone <10 mg/d and those with prednisolone >10 mg/d.
the number and type of post-operative complications expected after liver transplant do not diminish over time after transplantation. The current study confirms that emergency surgery is an undesirable event after OLT. Even though these represent only 10% of the surgical procedures, which could be considered as a nonfrequent situation following OLT, they constitute a feared complication with an overall mortality of 11%. Moreover, both mortalities occurred after major surgical procedures. We found that there were no significant differences in morbidity between emergency and elective cases. Earlier studies on transplanted patients (liver and other organs) have also shown significantly higher mortality in emergency cases [5,6,19]. As already reported by Testa et al., we confirm that extreme care must be afforded to these high risk patients, who should be addressed promptly to a liver transplant center whenever possible for adequate specialized surgical and post-operative intensive care management [6]. Even if medical and surgical care are provided in the liver transplant centers, one must keep in mind the poor prognosis of these patients. As already reported by Testa et al. and others, we confirm that the overall morbidity following general abdominal surgical procedures was as high as 30% with a mortality of 1% [5,6]. The most frequent surgical complication according to the Dindo-Clavien classification was grade III, i.e requiring surgical, endoscopic or radiological intervention (46% of cases), followed by grade II (40% of cases). This results highlights the need for a close collaboration between the interventional radiologist and the experienced endoscopist with a technical platform for the management of these complications. We did not find a statistically significant difference when we compared LT recipients on corticoids to others not on corticoid therapy regarding their post-operative morbidity rate. This finding is in accordance with some studies in the literature, which have also shown that patients on steroids do not suffer more post-operative complications [20,21]. Unfortunately, data about patients on mTOR inhibitors at the time of the surgery were not available in this current study, and should constitute a potential bias because it could influence the post-operative course and the incidence of post-operative complications. Nonetheless, it should be kept in mind that the descriptive data of the current study showed that post-operative morbidity was higher in patients on corticoid therapy (42% vs. 27% of cases in the current study), even though this difference was not statistically significant. Of all
morbidities, infection (either systemic or wound-related) was the most common type in our study, affecting about 20% of procedures, which is similar to the report of Testa et al. [6]. The second most frequent type of morbidity we noted was renal insufficiency (20%). Strikingly, renal insufficiency occurred after all types of surgery, including hernia repairs. Published guidelines strongly emphasize that immunosuppressive drugs predispose patients to renal insufficiency [18]. Hence, surgical and anesthetic teams must be aware of this complication and exercise caution while administering fluids and drugs to these patients. As already largely reported, we confirmed that a close control of the renal fonction by measuring the creatinine level associated with the daily assessment of the FK 506 plasma level is mandatory to prevent irreversible renal failure and transplant rejection [6]. It is currently well-defined that incisional hernias represent the most common late surgical complication following OLT [22e26]. The known factors responsible for the increased incidence of incisional hernias in these patients include pre-existing chronic ascites, which weaken the abdominal wall, thrombocytopenia, immunosuppressive and corticosteroid therapy [22,23]. In the present study, hernias repairs constituted the most common abdominal surgical procedure in LT recipients (55%). This incidence is much higher than that reported by Testa et al. (34%), which could be partly explained by the inclusion of several types of hernias in our study [6]. The post-operative morbidity level was 22%, ranging from grade II to grade III of the Dindo-Clavien classification. As already reported, the most frequent complication was wound infection, followed by renal insufficiency [6]. Hernias repairs do not present differences compared to the non-liver transplant population and should be managed in non-liver transplant centers, keeping in mind the prevention of renal insufficiency and strict aseptic conditions to minimize the incidence of wound infection, according to the current guidelines for ventral incisional hernia repair [27,28]. The current study also demonstrates that the second most common abdominal surgery was biliodigestive anastomosis, mainly due to late biliary complications (biliary strictures). The post-operative morbidity of this procedure was 39%, mainly grade III. As usually indicated for a late biliary complication following OLT, this procedure must be managed at an expert liver transplant center. However, the recent literature seems to suggest endoscopic and/or radiologic management as the first therapeutic approach to consider in cases of biliary complication, with good results in terms of success and recurrence rates with low complication rates [13,14,30e32]. Moreover, the very high post-operative morbidity, especially represented by infectious complications highlighted by our results, seems to confirm the tendency toward first endoscopic and/or radiologic procedures with surgical intervention in unsolvable cases. Regarding gastrointestinal surgery, general surgeons must be aware of these procedures, especially when done in the emergency setting because of the high morbidity rate (39%), including anastomotic leakage and infectious complications and a mortality rate of 9%. Particular attention should be given to these high risks patients who should be addressed promptly at a liver transplant center whenever possible, or at a center with an intensive care unit for post-operative management. Finally, one patient underwent a sleeve gastrectomy for the surgical management of morbid obesity. A recent report in the field reported that such a procedure on liver transplant recipients seems feasible with goods results in terms of efficacy and safety [33]. Moreover, beyond the worldwide obesity epidemic, one of the side effects of immunosuppressive therapy is the development of obesity, which makes this procedure timely. It is no doubt that the number of bariatric surgery indications will increase in the coming years for liver transplanted patients [33]. Among 183 procedures following OLT, eight patients underwent
D. Sommacale et al. / International Journal of Surgery 41 (2017) 58e64
liver resections with an overall morbidity of 62% and no mortality. It is safe to state that these very exceptional cases must to be managed at least at a specialized liver surgical center or at a liver transplant center with a particular attention to infectious and renal failure complications [29,34]. Our study presents several strong points. First, this is the second large cohort study to comprehensively report the epidemiology of post-OLT digestive surgeries. This is the first study to provide valuable data on post-operative complications and the mortality associated with such procedures. Finally, it strengthens the literature in this poorly investigated field. The main limitation of our study is without doubt the selection bias inherent in losing patients to follow-up. Even if, to the best of our knowledge, no patient was lost to follow-up and all patients were readmitted to our center for medical-surgical problems, it is inevitably not possible to be sure that some patients were managed at another centers due to the retrospective nature of our study. To conclude, abdominal surgical procedures after liver transplantation are associated with a significantly high risk of complications with an overall morbidity of 30%. Nonetheless, most of the surgeries undergone by LT recipients do not represent technical challenges compared to the non-transplant population. Since LT recipients are a steadily growing population, general surgical procedures will become increasingly common in this population and may require non-transplant surgical units to start performing these procedures with necessary input from the transplantation team. This would not only reduce the burden on transplant teams, but would also be faster, more convenient and cost-effective for hospitals. It is therefore necessary for non-transplant surgeons to be aware of the post-operative issues specific to LT recipients with specific attention to infectious and renal failure complications, which are the most frequent and, a fortiori, if they are on corticoid therapy. On contrary to popular belief, the dreaded transplant rejection is a very rare event after a surgical procedure in a LT recipient, occurring in only 1% of patients in the current study; this was fully cured after an adequate management. One important message regarding the prevention of rejection is to assess renal function and immunosuppressive drugs plasma levels daily. It is essential that non-transplant surgical units are aware of the specific complications that they should expect in LT patients before they perform any kind of surgery. Authors contributions All persons listed as authors have contributed substantially to the design, performance, analysis, and reporting of this work. GN, PP, FD: collected data, analyzed data. ML, TP, AS, RK: analyzed data, wrote paper. JB, DS: Designed study, analyzed data, wrote paper.
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Barge, M. Naya, Go transplant patients, Transplant. Proc. 39 (7) (2007), 2382e84. F.W. Su, D.B. Beckman, P.A. Yarnold, C. Grammer L.Low, Incidence of complications in asthmatic patients treated with preoperative corticosteroids, Allergy asthma Proc. 25 (5) (2004) 327e333. J.F. Colombel, E.V. Loftus Jr., W.J. Tremaine, J.H. Pemberton, B.G. Wolff, T. Young-Fadok, W.S. Harmsen, C.D. Schleck, W.J. Sandborn, Early postoperative complications are not increased in patients with Crohn's disease treated perioperatively with infliximab or immunosuppressive therapy, Am. J. Gastroenterol. 99 (5) (2004 May) 878e883. , B. Nardo, E. Piazzese, R. Montalti, P. Beltempo, R. Bertelli, L. Puviani, V. Pacile A. Cavallari, Incidence, predisposing factors, and results of surgical treatment of incisional hernia after orthotopic liver transplantation, Transpl. Proc. 36 (10) (2004 Dec) 3097e3098. J. Goulis, T.N. Chau, S. Jordan, A.B. Mehta, A. Watkinson, K. Rolles, A.K. Burroughs, Thrombopoietin concentrations are low in patients with cirrhosis and thrombocytopenia and are restored after orthotopic liver transplantation, Gut 44 (5) (1999 May) 754e758. T. Piardi, M. Audet, F. Panaro, F. Gheza, M. Cag, N. Portolani, J. Cinqualbre, P. Wolf, Incisional hernia repair after liver transplantation: role of the Mesh, Transpl. Proc. 42 (2010) 1244e1247. , F.W. Eigler, C.E. Broelsch, Causative H. Janssen, R. Lange, J. Erhard, M. Malago factors, surgical treatment and outcome of incisional hernia after liver transplantation, Br. J. Surg. 89 (8) (2002 Aug) 1049e1054. A.J. Vardanian, D.G. Farmer, R.M. Ghobrial, R.W. Busuttil, J.R. Hiatt, Incisional hernia after liver transplantation, J. Am. Coll. Surg. 203 (4) (2006 Oct) 421e425. Ventral Hernia Working Group, K. Breuing, C.E. Butler, S. Ferzoco, M. Franz,
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D. Sommacale et al. / International Journal of Surgery 41 (2017) 58e64 C.S. Hultman, et al., Incisional ventral hernias: review of the literature and recommendations regarding the grading and technique of repair, Surgery 148 (2010) 544e558. L. Gauduchon, C. Sabbagh, F. Mauvais, J.M. Regimbeau, Technical aspects of right subcostal incisional hernia repair, J. Visc. Surg. 151 (2014) 393e401. G. Marangoni, W. Faraj, H. Sethi, M. Rela, P. Muiesan, N. Heaton, Liver resection in liver transplant recipients, Hepatobiliary Pancreat. Dis. Int. 7 (6) (2008 Dec) 590e594. M. Wojcicki, P. Milkiewicz, M. Silva, Biliary tract complications after liver transplantation: a review, Dig. Surg. 25 (2008) 245e257. S.F. Pasha, M.E. Harrison, A. Das, C.C. Nguyen, H.E. Vargas, V. Balan, Douglas DD. ByrneTJ, D.C. Mulligan, Endoscopic treatment of anastomotic biliary
strictures after deceased donor liver transplantation: outcomes after maximal stent therapy, Gastrointest. Endosc. 66 (1) (2007 Jul) 44e51. [32] R. Memeo, T. Piardi, F. Sangiuolo, D. Sommacale, P. Pessaux, Management of biliary complications after liver transplantation, World J. Hepatol. 7 (2015) 2890e2895. [33] E.F. Elli, R. Gonzalez-Heredia, L. Sanchez-Johnsen, N. Patel, R. Garcia-Roca, J. Oberholzer, Sleeve gastrectomy surgery in obese patients post-organ transplantation, Surg. Obes. Relat. Dis. 12 (2016) 528e534. [34] D. Sommacale, F. Dondero, A. Sauvanet, C. Francoz, F. Durand, O. Farges, R. Kianmanesh, J. Belghiti, Liver resection in transplanted patients: a singlecenter Western experience, Transpl. Proc. 45 (2013) 2726e2728.
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Original Research
Surgical procedures in liver transplant patients: A monocentric retrospective cohort study Daniele Sommacale, M.D a, Ganesh Nagarajan, M.D b, Martin Lhuaire, M.D, M.Sc a, *, Federica Dondero, M.D b, Patrick Pessaux, M.D, PhD b, Tullio Piardi, M.D a, Alain Sauvanet, M.D, PhD b, Reza Kianmanesh, M.D, PhD a, Jacques Belghiti, M.D b ^pital Robert Debr Department of General and Digestive Surgery, Ho e, Centre Hospitalier Universitaire de Reims, Universit e de Reims Champagne-Ardenne, Reims, France ^pital Beaujon, Assistance Publique des Ho ^pitaux de Paris, Clichy, France Department of Hepato-biliary Surgery and Liver Transplantation, Ho
a
b
h i g h l i g h t s This study presents comprehensively the epidemiology of the surgical history in 1211 liver recipients who require further surgical procedures. Surgical procedures on liver transplanted patients are associated with a significantly high risk of complications, irrespective of the time elapsed since transplantation.
a r t i c l e i n f o
a b s t r a c t
Article history: Received 10 January 2017 Received in revised form 10 March 2017 Accepted 20 March 2017 Available online 24 March 2017
Background: Pre-existing chronic liver diseases and the complexity of the transplant surgery procedures lead to a greater risk of further surgery in transplanted patients compared to the general population. The aim of this monocentric retrospective cohort study was to assess the epidemiology of surgical complications in liver transplanted patients who require further surgical procedures and to characterize their post-operative risk of complications to enhance their medical care. Patients and methods: From January 1997 to December 2011, 1211 patients underwent orthotropic liver transplantation in our center. A retrospective analysis of prospectively collected data was performed considering patients who underwent surgical procedures more than three months after transplantation. We recorded liver transplantation technique, type of surgery, post-operative complications, time since the liver transplant and immunosuppressive regimens. Results: Among these, 161 patients (15%) underwent a further 183 surgical procedures for conditions both related and unrelated to the transplant. The most common surgical procedure was for an incisional hernia repair (n ¼ 101), followed by bilioenteric anastomosis (n ¼ 44), intestinal surgery (n ¼ 23), liver surgery (n ¼ 8) and other surgical procedures (n ¼ 7). Emergency surgery was required in 19 procedures (10%), while 162 procedures (90%) were performed electively. Post-operative mortality and morbidity were 1% and 30%, respectively. According to the Dindo-Clavien classification, the most common grade of morbidity was grade III (46%), followed by grade II (40%). Conclusion: Surgical procedures on liver transplanted patients are associated with a significantly high risk of complications, irrespective of the time elapsed since transplantation. © 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.
Keywords: Retrospective cohort study General surgery Liver transplantation Surgical complications
1. Introduction
Abreviation: LT, liver transplantation; OLT, orthotopic liver transplantation. ^ pital * Corresponding author. Department of General and Digestive Surgery, Ho , Centre Hospitalier Universitaire de Reims, 51092, Reims, France. Robert Debre E-mail address: [email protected] (M. Lhuaire).
In recent decades, there has been impressive progress in the management of liver transplantation (LT), resulting in a constantly growing liver transplant recipient population, as reported by the last annual reports of the French Biomedicine Agency (2014) [1] and the OPTN (2012) [2e4]. Pre-existing chronic liver diseases
http://dx.doi.org/10.1016/j.ijsu.2017.03.058 1743-9191/© 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.
D. Sommacale et al. / International Journal of Surgery 41 (2017) 58e64
and an initially aggressive surgical procedure using a large abdominal approach with vascular and biliary anastomosis, as well as the consequences of long-term immunosuppression can lead to subsequent surgical procedures for liver transplant recipients at a higher rate than in the general population [5e8]. Moreover, it is now well-known that the altered physiology and immunosuppression of these patients explain their increased exposure to postoperative complications. In this setting, it is safe to state that the progressively growing prevalence of the liver transplant target population has led to an increased rate of common surgical diseases. Taking into account the expected rise in live transplant survivors in coming years, an increase in further surgical procedures in this population is likely to lead significant problems for transplantation centers in terms of the allocation of beds, operating room availability and the use of hospital resources [5]. While most transplantation centers are already overburdened by transplantation activity alone, carrying out further general surgical procedures within these specialized units may also imply longer waiting periods, higher hospital costs and inconvenience to patients who may not live close to a transplantation centers. In this sense, non-transplantation surgical units will have to perform more general procedures on the liver transplant recipients, which would necessarily require close coordination with transplantation centers. Therefore, it is important that non-liver transplant surgeons are aware of the specific complications that they may have to manage when they encounter these specific patients. In this sense, epidemiological data about the incidence, type of surgery, post-operative complications and mortality are required for this specific patient population to managed them regarding medical and surgical care. The literature on the subject is very weak and insufficient, as only one benchmark study published in the past ten years ago has reported this specific aspect [6]. Therefore, an update on the epidemiology of post-LT surgical procedures seems relevant. The aim of this monocentric retrospective cohort study was to assess the epidemiology of surgical procedures and their complications in the liver transplant recipient population to enhance their medical care.
2. Patients and methods 2.1. Patients From January 1997 to December 2011, 1211 patients underwent orthotropic liver transplantation (OLT) in our center.
59
2.3. Data collection and post-operative follow-up A retrospective analysis of prospectively collected data was performed. 2.4. Inclusion criteria All general surgical procedures performed on liver transplant recipients more than three months after the date of transplantation were included in the study. For each patient we recorded the general profile and demographic data, indication for LT, the type of transplant, type of surgical procedure, time period between transplantation and subsequent surgical procedures, intraoperative and post-operative course, and immunosuppression regimen. Patient follow-up was performed at our outpatient clinic on a weekly basis for the first three months and then twice per month for six months. Patients were then seen on a bimonthly schedule for two years and on a six-month schedule thereafter. Abdominal ultrasound or CT scan was performed every three months during the first year, every six months for the next two years and annually thereafter. 2.5. Exclusion criteria Procedures done at the same admission as the transplantation and re-transplantations or surgical procedures for the treatment of hepatic artery thrombosis and pseudoaneurysms were excluded from the study. 2.6. Definitions All surgical procedures were classified into elective or emergency and major or minor procedures. All procedures limited to the abdominal wall were categorized as minor procedures while all those involving opening the peritoneal cavity with a visceral surgical procedure (digestive resection and/or anastomosis) categorized as major procedures. Post-operative morbidity was graded according to the Dindo-Clavien classification [9]. Renal insufficiency was defined as plasma creatinine >150 mg/L [10]. Sepsis was defined by the presence or suspicion of an infection, in addition to evidence of increased levels of circulating inflammatory mediators, thus resulting in a systemic inflammatory response syndrome [11]. Rejection was defined on the basis of liver biopsy performed in suspected cases [12]. 2.7. Statistical methods
2.2. Transplantation technique A Mercedes abdominal incision and cavo-caval anastomosis was performed in each case. Portal reconstruction was carried out by means of an end-to-end anastomosis. Arterial anastomosis was done, whenever possible, between the donor celiac artery and the recipient hepatic artery. If the native hepatic artery was not suitable, anastomosis was done between the donor celiac artery and the recipient splenic artery or an arterial allograft conduit was interposed between the donor celiac artery and the recipient infrarenal aorta or splenic artery. In the presence of an accessory right hepatic artery, the graft was revascularized via the donor superior mesenteric artery (using the Carrel patch technique). Usually, a bilio-biliary anastomosis was done, but in cases of liver re-transplantation or primary sclerosing cholangitis, a bilioenteric anastomosis was performed. Grafts were invariably stored in University of Wisconsin solution. Immunosuppression was achieved using FK 506 (Astellas, Tokyo, Japan).
Chi-squared analysis and the Fisher exact test were used for statistical analysis. P values < 0.05 were considered statistically significant. 3. Results 3.1. Incidence and characteristics of surgical procedures Overall, of the 1211 patients who underwent liver transplantation, 161 patients underwent 183 further surgical procedures (15%) for conditions both related and unrelated to the transplant (Table 1). Among these, 154 were patients with liver transplants only, six had both liver and kidney transplants and one patient had both liver and lung transplants. Among the 183 procedures, postoperative morbidity was noticed after 54 procedures (30%) and mortality after two procedures (1%) secondary to sepsis and renal failure after emergency intestinal surgeries. Emergency surgery was required in 19 procedures (10%), while 162 (90%) were elective
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3.3. Delay between the surgical procedure and the LT
Table 1 Descriptive and analytic results of the current study. Parameters
Number
Percentage
p
LT cohort Surgical procedures Number of patients Overall morbidity Overall mortality Emergency surgery Morbidityc Mortalityd Elective surgery Morbidityc Mortalityd Major proceduresa Morbiditye Mortality f Minor proceduresb Morbiditye Mortality f
1211 183 161 54 2 19 6 2 162 48 0 78 38 2 103 16 0
e 15% e 30% 1% 10% 32% 11% 90% 30% 0% 43% 49% 2.6% 57% 16% 0%
e e e e e e NS 0.02 e NS 0.02 e 0.04 NS e 0.04 NS
LT: liver transplant. a Defined as procedures with peritoneal cavity opening with a visceral surgical procedure (digestive resection and/or anastomosis). b defined as procedures limited to the abdominal wall. c Morbidity comparisons between emergency and elective surgeries. d Mortality comparisons between emergency and elective surgeries. e Morbidity comparisons between major and minor surgeries. f Mortality comparisons between major and minor surgeries.
surgical procedures. Among the 19 emergency cases (10%), six were morbid (32%). Emergency cases accounted for both the mortalities (11%). Of the 164 electively operated cases, 48 had post-operative morbidity (30%). There was no mortality after elective surgery. While there was no statistical difference in the post-operative morbidity between the elective and emergency surgery groups, post-operative mortality was significantly higher after the emergency surgeries (p ¼ 0.02). Overall, 78 procedures (43%) were major and 103 procedures (57%) were minor. Among the 103 minor procedures, post-operative complications arose in 16% of cases, while among the 78 major procedures post-operative complications arose in 49% of cases. Post-operative morbidity was significantly higher after major surgery compared to minor surgery (p ¼ 0.04). Both the mortalities occurred after major surgeries (Table 1). 3.2. Type of surgical procedures The most common surgical procedure after liver transplant was a group of abdominal wall procedures consisting of incisional and inguinal hernias (101 cases; 55%). Biliodigestive anastomosis for biliary anastomotic-stricture was required in 44 cases (24%). All of these had not responded to endoscopic treatment. Intestinal surgery was required for 23 patients (13% of the surgical procedures), and liver surgery was performed in eight cases (4%). Other procedures included adrenalectomy for adrenal metastasis of hepatocellular carcinoma (n ¼ 2), lymph node clearance (n ¼ 1), peri-anal abscess drainage (n ¼ 1), adhesiolysis for acute intestinal obstruction (n ¼ 2) and mastectomy for breast cancer (n ¼ 1) (Table 2).
The delay between the LT and abdominal surgery varied; 33 procedures (18%) were performed within six months, 41 (22%) between six months and one year, 48 (26%) in the second year, 22 (12%) in the third year and 37 procedures (20%) were performed more than three years after LT. There was no statistically significant difference in the incidence of complications regarding the delay between the LT and the second abdominal surgery (Table 3). 3.4. Post-operative morbidity characteristics and mortality after surgical procedures following LT According to the Dindo-Clavien classification, the most common grade of morbidity was grade III (46% of complications), followed by grade II (40% of complications) (Table 4). The most frequent types of morbidity after general surgical procedures were renal insufficiency (n ¼ 11), systemic infection (n ¼ 11) and wound infection (n ¼ 11). Ascites developed in four patients, while five patients required evacuation of clots or hematoma drainage. Four patients suffered a post-operative intestinal obstruction which was settled with conservative management in two patients while two others required adhesiolysis. Two patients rejected the transplant after the procedure (Table 5). Transplant rejections were confirmed by percutaneous liver biopsies. The main explanation for these transplant rejections were in both cases related to the difficulty of maintaining the post-operative plasma level of FK 506 above the threshold limit secondary to renal function impairment. However, both patients responded well to an appropriate adaptation of immunosuppressive drugs and the degree of renal dysfunction with daily assessment of FK 506 plasma level. Sub-group analysis of post-operative complications and mortality according to the type of surgery are presented in Table 6. The two patients died on postoperative day 7 and 11 secondary to uncontrolled sepsis associated with irreversible renal failure. One patient died of these complications secondary to stercoral peritonitis due to a perforated sigmoid diverticula, and the second one died of these same complications secondary to small bowel necrosis. Finally, corticosteroid therapy was ongoing in 33 procedures (18%) when they underwent the surgery. Among them, post-operative morbidity was seen in 14 procedures (42%). Of the other 150 procedures where patients were off corticosteroid therapy (82%), post-operative morbidity was seen in 40 procedures (27%). The difference between groups was not statistically significant (Table 7). 4. Discussion In the last decade, there has been an exponential rise in LT recipient survivors worldwide [3e5]. The current study showed an overall incidence of LT recipients requiring any kind of further surgical procedure of 15%. This rate is lower compared to a report by Testa et al. (24.2%) which could be explained simply because we did not include extra-digestive surgeries like orthopedics or urologic surgeries, for example [6]. Another point could be attributed
Table 2 Surgical procedures performed on the liver transplant cohort. Type of surgery
Number (n ¼ 183)
Morbidity (n ¼ 54)
Percentage
Parietal Biliodigestive anastomosis Intestinal Liver Adrenal Others
101 44 23 8 2 5
22 17 8 4 2 1
21% 38% 34% 66% 100% 25%
D. Sommacale et al. / International Journal of Surgery 41 (2017) 58e64
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Table 3 Influence of the delay on morbidity incidence after a surgery on the liver transplant cohort. Delay
Number of surgeries
Number of morbidities
Percentages
6 months 6 months - 1 year 1 - 2 years 2 - 3 years >3 years
33 41 48 22 37
13 12 12 6 11
39%a 29%a 25%a 27%a 30%a
a
There were no statistically significant differences regarding the delay.
Table 4 Post-operative morbidity characteristics following surgical procedures on LT patients (n ¼ 54; 30%).
Table 6 Sub-group analysis of post-operative complications and mortality according to the type of surgery.
Dindo-Clavien classification
Number of patients
Percentages
Type of surgery
Number (n ¼ 183)
Percentages
I II III IV V
1 22 25 4 2
2% 40% 46% 7% 4%
Parietal Incisional hernia Others hernias Repair with mesh Recurrence Repair w/o mesh Recurrence Overall mortality Overall morbidity Grade I Grade II Grade III Wound abcess Renal dysfonction Biliodigestive anastomosis Overall mortality Overall morbidity Grade I Grade II Grade III Wound abcess Systemic infection Renal dysfonction Gastrointestinal Colonic resections Small bowel resections Appendicectomies Adhesiolysis for intestinal obstruction Ileostomy closure Sleeve gastrectomy Overall mortality Overall morbidity Grade I Grade II Grade III Grade IV Wound abcess Systemic infection Renal dysfonction Anastomotic leaks Liver resections Left lobectomy Right hepatectomy Posterior sectoriectomy Liver cyst excisions Overall mortality Overall morbidity Grade I Grade II Grade III Systemic infection Renal dysfonction Intraabdominal collection Adrenal Others
101 77 24 35 0 42 5 0 22 3 9 10 6 4 44 0 17 2 7 8 6 4 3 23 9 3 3 5 2 1 2 8 0 1 5 2 2 2 4 2 8 4 1 1 2 0 5 1 2 2 2 2 2 2 5
55% 76% 24% 35% 0% 42% 12% 0% 22% 14% 41% 45% 27% 18% 24% 0% 39% 12% 41% 47% 35% 24% 18% 13% 39% 13% 13% 22% 9% 4% 7% 35% 4% 7% 22% 9% 9% 9% 17% 9% 4% 50% 13% 13% 25% 0% 63% 13% 25% 25% 25% 25% 25% 1% 3%
Table 5 Post-operative morbidity characteristics following surgical procedures after LT (n ¼ 54 procedures with post-operative morbidity; 30%). Type of morbidity
Number of patients
Percentages
Renal insufficency Systemic infection Abdominal wall abscess Bleeding/hematoma Intestinal obstruction Ascites Cholangitis Intraabdominal collection Transplant rejection Pulmonary embolism
11 11 11 5 4 4 3 2 2 1
20% 20% 20% 9% 7% 7% 5% 3% 3% 2%
to major advances in non-surgical treatment of biliary and vascular complications coupled with safer immunosuppression regimes over the last two decades [13e17]. However, if we consider only digestive surgeries, the incidence was 14.2% in the report by Testa et al., which is very similar to ours [6]. As already reported by Testa et al., major procedures, arbitrarily defined in the current study as a surgery with opening of the abdominal cavity associated to a visceral surgical procedure (digestive resection and/or anastomosis), are more frequent than minor surgeries. It could be taken with safety because of the potential selection bias discussed before. Indeed, it is obvious that a patient who has undergone a minor procedure such as skin lesions removal or ophthalmologic surgery will not be referred to our center for their management and are thus lost to follow-up; these patients were unfortunately not included in this study. On first impression, it would be obvious that the incidence of minor surgical procedures would be more frequent with a negligible risk of post-operative complications, but no data on this topic are available in the literature. The original data provided by the current study shows that there is no post-LT critical period were the incidence of further abdominal surgeries is increased. The type of surgery, as well as the surgery being major or minor, emergent or elective are factors unrelated to the delay of further general abdominal surgeries following OLT. Indeed, an incidence of approximately 20% of further general abdominal surgeries was recorded between three to six months, six months to one year, within one year and two years following OLT. There were no significant differences in terms of post-operative morbidity or mortality regarding time elapsed since OLT. Two-thirds (67%) of the general surgeries took place in the first two years after
transplantation. The morbidity rate was similar, irrespective of the time elapsed after transplantation. To our knowledge, this aspect has not been mentioned previously. An important message is that
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Table 7 Descriptive and analytic results in patient under corticosteroid therapy at time of the surgical procedure (n ¼ 33; 18%). Parameters
Number
Percentages
p
Patient w/o corticoids Morbiditya Mortality Patient with corticoids Morbiditya Mortality <6 months with corticoids Morbidityb >6 months with corticoids Morbidityb <10 mg Prednisolone/day Morbidityc >10 mg Prednisolone/day Morbidityc
150 40 0 33 14 0 12 6 21 8 23 7 10 7
82% 27% 0% 18% 42% 0% 36% 50% 64% 38% 70% 30% 30% 70%
e NS e e NS e e e e e e e e e
a Morbidity comparisons between patient with and without corticoids at time of surgery. b Morbidity comparison between patients under corticoids <6 months and those >6 months. c Morbidity comparison between patients with prednisolone <10 mg/d and those with prednisolone >10 mg/d.
the number and type of post-operative complications expected after liver transplant do not diminish over time after transplantation. The current study confirms that emergency surgery is an undesirable event after OLT. Even though these represent only 10% of the surgical procedures, which could be considered as a nonfrequent situation following OLT, they constitute a feared complication with an overall mortality of 11%. Moreover, both mortalities occurred after major surgical procedures. We found that there were no significant differences in morbidity between emergency and elective cases. Earlier studies on transplanted patients (liver and other organs) have also shown significantly higher mortality in emergency cases [5,6,19]. As already reported by Testa et al., we confirm that extreme care must be afforded to these high risk patients, who should be addressed promptly to a liver transplant center whenever possible for adequate specialized surgical and post-operative intensive care management [6]. Even if medical and surgical care are provided in the liver transplant centers, one must keep in mind the poor prognosis of these patients. As already reported by Testa et al. and others, we confirm that the overall morbidity following general abdominal surgical procedures was as high as 30% with a mortality of 1% [5,6]. The most frequent surgical complication according to the Dindo-Clavien classification was grade III, i.e requiring surgical, endoscopic or radiological intervention (46% of cases), followed by grade II (40% of cases). This results highlights the need for a close collaboration between the interventional radiologist and the experienced endoscopist with a technical platform for the management of these complications. We did not find a statistically significant difference when we compared LT recipients on corticoids to others not on corticoid therapy regarding their post-operative morbidity rate. This finding is in accordance with some studies in the literature, which have also shown that patients on steroids do not suffer more post-operative complications [20,21]. Unfortunately, data about patients on mTOR inhibitors at the time of the surgery were not available in this current study, and should constitute a potential bias because it could influence the post-operative course and the incidence of post-operative complications. Nonetheless, it should be kept in mind that the descriptive data of the current study showed that post-operative morbidity was higher in patients on corticoid therapy (42% vs. 27% of cases in the current study), even though this difference was not statistically significant. Of all
morbidities, infection (either systemic or wound-related) was the most common type in our study, affecting about 20% of procedures, which is similar to the report of Testa et al. [6]. The second most frequent type of morbidity we noted was renal insufficiency (20%). Strikingly, renal insufficiency occurred after all types of surgery, including hernia repairs. Published guidelines strongly emphasize that immunosuppressive drugs predispose patients to renal insufficiency [18]. Hence, surgical and anesthetic teams must be aware of this complication and exercise caution while administering fluids and drugs to these patients. As already largely reported, we confirmed that a close control of the renal fonction by measuring the creatinine level associated with the daily assessment of the FK 506 plasma level is mandatory to prevent irreversible renal failure and transplant rejection [6]. It is currently well-defined that incisional hernias represent the most common late surgical complication following OLT [22e26]. The known factors responsible for the increased incidence of incisional hernias in these patients include pre-existing chronic ascites, which weaken the abdominal wall, thrombocytopenia, immunosuppressive and corticosteroid therapy [22,23]. In the present study, hernias repairs constituted the most common abdominal surgical procedure in LT recipients (55%). This incidence is much higher than that reported by Testa et al. (34%), which could be partly explained by the inclusion of several types of hernias in our study [6]. The post-operative morbidity level was 22%, ranging from grade II to grade III of the Dindo-Clavien classification. As already reported, the most frequent complication was wound infection, followed by renal insufficiency [6]. Hernias repairs do not present differences compared to the non-liver transplant population and should be managed in non-liver transplant centers, keeping in mind the prevention of renal insufficiency and strict aseptic conditions to minimize the incidence of wound infection, according to the current guidelines for ventral incisional hernia repair [27,28]. The current study also demonstrates that the second most common abdominal surgery was biliodigestive anastomosis, mainly due to late biliary complications (biliary strictures). The post-operative morbidity of this procedure was 39%, mainly grade III. As usually indicated for a late biliary complication following OLT, this procedure must be managed at an expert liver transplant center. However, the recent literature seems to suggest endoscopic and/or radiologic management as the first therapeutic approach to consider in cases of biliary complication, with good results in terms of success and recurrence rates with low complication rates [13,14,30e32]. Moreover, the very high post-operative morbidity, especially represented by infectious complications highlighted by our results, seems to confirm the tendency toward first endoscopic and/or radiologic procedures with surgical intervention in unsolvable cases. Regarding gastrointestinal surgery, general surgeons must be aware of these procedures, especially when done in the emergency setting because of the high morbidity rate (39%), including anastomotic leakage and infectious complications and a mortality rate of 9%. Particular attention should be given to these high risks patients who should be addressed promptly at a liver transplant center whenever possible, or at a center with an intensive care unit for post-operative management. Finally, one patient underwent a sleeve gastrectomy for the surgical management of morbid obesity. A recent report in the field reported that such a procedure on liver transplant recipients seems feasible with goods results in terms of efficacy and safety [33]. Moreover, beyond the worldwide obesity epidemic, one of the side effects of immunosuppressive therapy is the development of obesity, which makes this procedure timely. It is no doubt that the number of bariatric surgery indications will increase in the coming years for liver transplanted patients [33]. Among 183 procedures following OLT, eight patients underwent
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liver resections with an overall morbidity of 62% and no mortality. It is safe to state that these very exceptional cases must to be managed at least at a specialized liver surgical center or at a liver transplant center with a particular attention to infectious and renal failure complications [29,34]. Our study presents several strong points. First, this is the second large cohort study to comprehensively report the epidemiology of post-OLT digestive surgeries. This is the first study to provide valuable data on post-operative complications and the mortality associated with such procedures. Finally, it strengthens the literature in this poorly investigated field. The main limitation of our study is without doubt the selection bias inherent in losing patients to follow-up. Even if, to the best of our knowledge, no patient was lost to follow-up and all patients were readmitted to our center for medical-surgical problems, it is inevitably not possible to be sure that some patients were managed at another centers due to the retrospective nature of our study. To conclude, abdominal surgical procedures after liver transplantation are associated with a significantly high risk of complications with an overall morbidity of 30%. Nonetheless, most of the surgeries undergone by LT recipients do not represent technical challenges compared to the non-transplant population. Since LT recipients are a steadily growing population, general surgical procedures will become increasingly common in this population and may require non-transplant surgical units to start performing these procedures with necessary input from the transplantation team. This would not only reduce the burden on transplant teams, but would also be faster, more convenient and cost-effective for hospitals. It is therefore necessary for non-transplant surgeons to be aware of the post-operative issues specific to LT recipients with specific attention to infectious and renal failure complications, which are the most frequent and, a fortiori, if they are on corticoid therapy. On contrary to popular belief, the dreaded transplant rejection is a very rare event after a surgical procedure in a LT recipient, occurring in only 1% of patients in the current study; this was fully cured after an adequate management. One important message regarding the prevention of rejection is to assess renal function and immunosuppressive drugs plasma levels daily. It is essential that non-transplant surgical units are aware of the specific complications that they should expect in LT patients before they perform any kind of surgery. Authors contributions All persons listed as authors have contributed substantially to the design, performance, analysis, and reporting of this work. GN, PP, FD: collected data, analyzed data. ML, TP, AS, RK: analyzed data, wrote paper. JB, DS: Designed study, analyzed data, wrote paper.
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