EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Despite surgical advances and effective prophylactic strategies in liver transplant, infection is still a major cause of morbidity and mortality. Up to 80% of liver recipients will develop at least 1 infection during the first year after liver transplant. The spectrum and manifestations of these infections are broad and variable. Their diagnosis and treatment are often delayed because immunosup-pressive therapy diminishes inflammatory responses. However, if an infection is not identified early enough and treated properly, it can have devastating consequences. In addition, prophylactic approaches remain controversial. Our aim was to review our early postoperative infection management after liver transplant.

Materials and Methods: We retrospectively evaluated infections that occurred during the first hospital stay of transplant patients. Infections were grouped as surgical site and nonsurgical site infections. Consequences and treatment protocols of infections were stratified according to the Clavien scale.

Results: Between December 1988 and January 2017, we performed 561 liver transplants at our center (patient age range, 6 months to 64 years), which included 401 living-donor (72%) and 160 deceased-donor (28%) liver transplants. Early postoperative infections were detected in 131 patients (23.3%), comprising 67 surgical site (51%), 56 nonsurgical site (43%), and 8 combined surgical and nonsurgical site infections (6%). Although no mortalities occurred in patients with single nonsurgical or surgical site infections, there were 4 mortalities in patients with combined surgical and nonsurgical site infections. In the 4 other patients with combined infections, 3 patients required endoscopic or radiologic intervention and 1 recovered from single-organ dysfunction.

Conclusions: Initiation of appropriate prophylactic and therapeutic protocols at the right time decreases morbidity and mortality due to infection in liver transplant recipients. Increased understanding and effective approaches to prevent infection are essential to improving both graft and recipient survival.

Key words : Cytomegalovirus, End-stage liver disease; Pneumocystis jiroveci, Surgical site infection

Liver transplantation is the standard therapeutic procedure for patients with end-stage liver disease. Liver transplant survival rates are reported as 85% in the first year. Despite surgical advances and effective prophylactic strategies, infection is still a major cause of morbidity and mortality after liver transplant. The incidence of infectious complications in liver transplant recipients remains higher than in any other solid-organ transplant procedure, with up to 80% of liver recipients developing at least 1 infection during the first year after transplant.¹ The incidence of infection-related mortality has decreased from more than 50% before 1980, to 25% to 35% in the 1980s, and to less than 10% in the 1990s.²

The spectrum and manifestations of these infections are broad and variable. Liver transplant patients are in impaired states of health before transplant, liver transplant is a technically complex operation, and liver transplant patients require lifelong immunosuppressive therapy, contributing to risk of infection. In addition, immunosuppressive therapy may be intensified due to possible rejection.

Infections not diagnosed early enough or treated appropriately can have devastating consequences. Diagnosis and treatment are often delayed because immunosuppressive therapy diminishes inflam-matory responses, and clinical signs of infection may be blunted or absent, symptoms of infection may mimic rejection, and it may be difficult to distinguish between true rejection and colonization. Although most infections are successfully treated, some will cause death.

Most infections are seen in the first 2 months after transplant. The prophylactic approaches for these early postoperative infections require proper patient monitoring, including knowledge of the time course of infections and possible risk factors. In this study, we aimed to review our early postoperative infection management after liver transplant.

Materials and Methods

All patients who underwent liver transplant at our center from December 1988 to January 2017 were investigated for occurrence of infections during their first hospital stay. The demographic findings and preoperative and intraoperative features were retrospectively recorded. All patients initially received a standard triple immunosuppressive regimen, consisting of prednisone, tacrolimus/cyclosporine, and mycophenolate mofetil.

Our standard surgical procedure starts with standard asepsis and preparation; a primary bilateral subcostal incision is then made and extended in the midline. The liver is then mobilized with dissection and cautery. The graft is placed in the abdominal cavity to determine the most appropriate site of hepatic venous anastomosis. Thereafter, portal vein anastomosis is constructed, which is followed by arterial anastomosis. Biliary anastomosis is performed last, via duct-to-duct or hepatica-jejunostomy anastomosis. Intraoperative hepatic blood flow and graft status are assessed routinely by Doppler ultrasonography. After suction drainage catheters are placed, the incision is closed and the patient is brought to the intensive care unit for postoperative follow-up. We follow a fast-track surgery pathway for patient care. Liver function is monitored by Doppler ultrasonography and liver function tests (twice per day during the first week); on day 7 after transplant, computed tomography scans are obtained.

For our patients, infections were defined as established previously.3 Organisms were identified using conventional methods and automated systems. Antimicrobial susceptibility was tested according to the criteria of the Clinical and Laboratory Standards Institute. Prophylaxis consisted of cefotaxime and ampicillin for 3 days before transplant. Recipients also received trimethoprim-sulfamethoxazole for Pneumocystis jiroveci prophylaxis and valganciclovir for Cytomegalovirus prophylaxis. Fluconazole prophylaxis was provided for 2 weeks.

For this study, we classified infections as surgical site infections (SSI) and nonsurgical site infections (NSSI). Infections with microbiologic evidence in the superficial and deep fascia and in the organ site were classified as SSI. Infections with microbiologic evidence in other systems (respiratory tract, blood, urinary tract) were classified as NSSI. Consequences and treatment protocols of infections were stratified according to the Clavien scale shown in Table 1.

Between 1988 and 2017, we performed 561 liver transplant procedures at our centers (age range of patients, 6 months to 64 years), which included 401 living-donor (72%) and 160 deceased-donor (28%) liver transplants. Early postoperative infections were detected in 131 liver transplant procedures (23.3%). The consequences and treatment protocols of infectious complications were stratified according to the Clavien classification scale (Table 2). Of 131 cases, we detected 67 with SSI (51%), 56 was NSSI (43%), and 8 with combined SSI and NSSI (6%).

There were no mortalities due to NSSI. Of 56 cases of NSSI, 34 patients (62%) were treated without any additional intervention, just with therapeutic regimens like antiemetic, antipyretic, analgesic, diuretic, and electrolyte agents and physiotherapy. Nine other patients with NSSI (16%) received pharmacologic treatment (including antibiotics, blood transfusion, and parenteral nutrition), 7 (12%) required endoscopic or radiologic intervention with or without general anesthesia, and 6 (10%) survived and recovered from single or multiorgan dysfunction.

We also observed no mortalities due to SSI. Of 67 cases of SSI, 37 patients (55%) were treated without any additional intervention, just with wound care and antibiotics. In the remaining SSI cases, 29 patients (44%) required endoscopic or radiologic intervention with or without general anesthesia and 1 (1%) survived and recovered from single or multiorgan dysfunction.

In the combined NSSI plus SSI group, we observed 4 mortalities (due to sepsis and multiorgan dysfunction).Three of the 8 patients with combined NSSI plus SSI required endoscopic or radiologic intervention with or without general anesthesia and 1 patient survived and recovered from single organ dysfunction. All patients with combined NSSI plus SSI were classified with Child class C disease(mean Model for End-Stage Liver Disease [MELD] score of 20) and impaired health status. Two patients had hepatic artery complications and repeated percutaneous interventions and surgical procedures (1 patient had 3 laparotomies, the other had 2 laparotomies for hepatic artery reconstruction), which were done in the first week posttransplant. Although patients are treated with fast-track surgery pathway protocol, all patients with combined NSSI plus SSI stayed more than 48 hours in the intensive care unit. Length of hospital stay in this patient group was also longer than in other patients (mean of 17 days).

Despite remarkable advances in liver transplant, infection can still be a frequent cause of morbidity and mortality posttransplant. Liver transplant recipients are more vulnerable to infection than other solid-organ transplant recipients due to the technical complexities of surgery, contamination in the abdominal cavity, and the preoperative impaired health status of recipients.⁴ Most infections occur in the early period posttransplant (in the first month) due to the technical difficulties of the surgery.⁵ Infections are associated with either pretransplant conditions or postoperative complications.⁶ Because symptoms of infection may mimic rejection and may be difficult to distinguish between true infection and mere colonization, a close follow-up of both recipient status and graft function is mandatory in the early postoperative period. At our center, to detect infections and implement therapy earlier, we monitor the transplanted liver with Doppler ultrasonography and liver function tests and obtain computed tomography scans on day 7 posttransplant.

The type, severity, and incidence of observed infections often depend on prophylactic practices. Because immunosuppressive regimens have been standardized, a timetable for determining when postoperative infections are most likely to occur has been developed. Knowledge of this timetable may allow clinicians to form differential diagnoses, initiate monitoring procedures for infection, and implement effective management strategies. Specific risk factors for infection in liver transplant recipients include underlying medical conditions, environmental exposures in the community or hospital, technical complications of the surgery, and the state of immunosuppression. Knowledge of these risk factors may allow identification of liver transplant recipients at greatest risk for infection and early management. Previous medical conditions, chronic underlying diseases, renal failure, mechanical ventilation, malnutrition, and high MELD score may predispose recipients to infection.^7,8 Indeed, all patients with NSSI and SSI were classified with Child class C disease (mean MELD score of 20) and impaired health status.

Exposure to nosocomial pathogens is also concerning. Risk factors for these pathogens include central venous or urinary tract catheters, extended use of systemic antibiotics or corticosteroids, colonization by a fungal pathogen, and total parenteral nutrition. To decrease infections caused by these factors, we follow a fast-track surgery pathway.⁹ Factors related to surgical procedures are also important. Disruption of the integrity of gastrointestinal tract and anas-tomotic leaks may cause infections by endogenous flora. Any technical complication that leads to devitalized tissue, vascular thrombosis, or fluid accumulation can enhance infection. Vascular devices and drainage catheters are also risk factors for infection since they disturb the physical barrier and provide entry portals for both endogenous and nosocomial organisms. The transplanted liver can also be a focus of infection as a result of ischemia and rejection. Infections are shown to be higher in liver transplant recipients who require prolonged operative time, retransplant, or repeat laparotomy.⁶ Retransplant, prolonged ventilator support, renal failure, extended renal replacement therapy, prolonged use of antimicrobial agents, colonization with resistant hospital flora, and immunosuppression play critical roles in postoperative development of infections.¹⁰ Our findings were similar, as 4 patients in our study group with combined NSSI plus SSI died from sepsis and multiorgan dysfunction. Two patients had hepatic artery complications, and repeated percutaneous interventions and surgical procedures were done in the first week posttransplant. In addition, all patients with NSSI plus SSI were in the intensive care unit for more than 48 hours and had longer hospital stays.

Multiple recipient and external factors increase infection risk for liver transplant patients. It is important to identify patients at greatest risk for serious infection. In our study, higher MELD scores and complicated and repeated surgical procedures increased incidence of infections. Initiation of appropriate prophylactic and therapeutic protocols at the right time can decrease morbidity and mortality due to infection in liver transplant recipients. A better understanding of infection risk and effective approach to prevent infection are also essential to improving graft and recipient survival.

Volume: 16 Issue: 1 March 2018 - Supplement - 1

FULL TEXT