**6. Immunosuppression**

Advances in immunosuppression have greatly impacted the survival of patients following LT. The initial endpoint was to prevent rejection; but in recent years, the interest has also been shifted to avoiding long-term complications from immunosuppressant agents and relapsing of the disease. In spite of the latest developments in this field, most centers commence immunosuppression with calcineurin inhibitors (CNIs) and corticosteroids with or without an anti-proliferative agent depending on protocols [72, 73].

**199**

*Management of Patients with Liver Transplantation in ICU*

**Calcineurin inhibitors**: Tacrolimus and cyclosporine inhibit calcineurin by impairing interleukin-2 (IL-2) transduction. Used as first-line immunosuppressant, tacrolimus is considered 100 times more potent than cyclosporine, and is superior in graft and patient survival with fewer acute and steroid-resistant rejection episodes. The main side effect is nephrotoxicity, while hypertension, hyperkalemia, uremic hemolytic syndrome, and neurotoxicity have lesser incidence [72]. Corticosteroids are important both in the initial immunosuppressive therapy and in

Mycophenolate mofetil has been widely used as an adjuvant and alternative immunosuppressive agent. It is a potential inhibitor of B- and T-cell proliferation. It is mainly utilized when a dose reduction or discontinuation of CNI is demanded due

Mammalian target of rapamycin (mTor) inhibitors, sirolimus, and everolimus, prevent B- and T-cell proliferation prompting the cell to arrest at G1 to S phase of the cell cycle. Although accounted for wound healing delay incidents, they can be administered as primary and rescue immunosuppression therapy with the advantages of being renal sparing as well as reducing the need for high doses of steroids. The newer IL-2 receptor-blocking antibody preparations daclizumab (Zenapax) and basiliximab (Simulect) are often used to initiate immunosuppression and avoid

Prevention of infections is a major problem as they are the leading cause of death following LT [74]. The most common ones in the immediate postoperative period are of bacterial or fungal origin and include bloodstream, catheter related, surgical site, pulmonary, urinary tract, *Clostridium difficile* infections, and intra-abdominal collections. The identification of risk factors and the stratification of patients according to them determine the prophylactic perioperative antimicrobial treatment [75, 76]. Antimicrobial chemoprophylaxis depends on the patient's immune status, intraoperative events, recent or recurrent hospitalization, and donor infections at the time of liver graft procurement while it has been tailored in accordance with the colonization of the patients, recently characterized by a prevalence of multidrug-resistant Gram-negative bacilli [76, 77]. Other recipient-related risk factors are malnutrition, re-operation, acute liver failure, biliary complications, and the existence of postoperative catheters, lines, and drains. Antibiotics right before surgery cover Gram-negative bacteria (*Pseudomonas* sp., *Enterobacter* sp., and *Klebsiella* sp.), Gram-positive organisms (*Staphylococcus aureus*), fungi, and viruses according to the center protocols and their epidemiology*.* Antifungal prophylaxis is administered to higher risk patients determined by factors such as renal dysfunction with a need for RRT, re-transplantation, multiple transfusions, prolonged ICU stay, colonization by *Candida*, and graft rejection incidents with administration of high doses of corticosteroids. In many centers, azoles or liposomal amphotericin are used [76–78]. Siddique et al. reported that the rate of post-transplant infections was 24.5% with no difference between deceased and living donors; however, mortality

to certain adverse effects such as nephrotoxicity and neurotoxicity [72].

CNIs, and can also play a part in steroid-resistant rejection [72].

was higher in bacterial infections in deceased donor recipients [79].

reviewed according to cultures results [75].

Herpes family viral infections, due to immunosuppression mainly by administration of T-cell-specific agents, are adequately treated with acyclovir. Ganciclovir or valganciclovir is sufficient for CMV seronegative recipients with CMV-seropositive grafts, or after rejection treatment. In case of suspected infection during hospitalization, broad spectrum antimicrobial therapy is administered and

*DOI: http://dx.doi.org/10.5772/intechopen.89435*

the treatment of acute rejection.

**7. Infection prophylaxis**

*Liver Disease and Surgery*

from ESLD-related disorders such as encephalopathy, massive transfusions, graft dysfunction, preoperative nutrition disorders, volume overload, and postoperative respiratory complications including pulmonary edema, pleural effusions, or pneumonia. During MV, lungs and liver allograft interaction should be taken into account with the aim of improving oxygenation without impairing the outflow of the liver graft. Implementation of daily withdrawal of sedation combined with

Acute respiratory distress syndrome (ARDS), one of the prominent respiratory complications following LT, is usually attributed to reperfusion syndrome, substantial blood loss and transfusions, prolonged operation time, and early postoperative infections and sepsis. Lung-protective ventilator strategies with low tidal volumes (6 ml/kg IBW), higher respiratory rate, and positive end-expiratory pressure (PEEP) are recommended to limit lung injury from shear forces and atelectasis [64]. There is debate about optimum PEEP in LT since some consider that higher PEEP values impair venous return and visceral blood flow leading to hepatic edema. Evaluation of transpulmonary pressure has been proposed to optimize PEEP titration [65]. Saner et al. concluded that PEEP up to 15 cm H2O affects neither blood flow to the liver, nor flow and velocity in the hepatic artery, right hepatic vein, and portal vein [66]. In refractory ARDS and persistent hypoxia, prone positioning, high frequency ventilation, and extracorporeal membrane oxygenation support

There are certain syndromes related to ESLD characterized by severe hypoxemia which require special management in the ICU such as hepatopulmonary syndrome

Hepatopulmonary syndrome is caused by intrapulmonary capillary dilatation that leads to hypoxemia and shortness of breath. LT is considered the treatment of choice; however, in most cases, severe hypoxemia might persist for a 6–12 months period. In the ICU, fluids should be managed carefully and lung-protective strategies should be employed during MV. In persistent hypoxemia, high frequency ventilation and/or venovenous extracorporeal membrane oxygenation is recommended. Some authors suggest early extubation and the immediate application of

Portopulmonary hypertension resulting from pulmonary vasoconstriction due to portal hypertension requires prevention of hypoxemia, maintaining oxygen saturation >90% and correcting factors involved such as acidemia, arrhythmia, and anemia. Administration of diuretics and/or renal replacement therapy is advised if volume overload cannot be avoided. MV can both compromise venous return from the allograft and increase pulmonary vascular resistance through alveolar overdistension; therefore, lung-protective ventilation is considered to be the most appropriate strategy. The use of pulmonary vasodilators, that can be both administered IV such as epoprostenol and orally, via nasogastric tube, such as phosphodiesterase V inhibitor or nonselective endothelin receptor antagonist, is recommended during ICU stay [71].

Advances in immunosuppression have greatly impacted the survival of patients following LT. The initial endpoint was to prevent rejection; but in recent years, the interest has also been shifted to avoiding long-term complications from immunosuppressant agents and relapsing of the disease. In spite of the latest developments in this field, most centers commence immunosuppression with calcineurin inhibitors (CNIs) and corticosteroids with or without an anti-proliferative agent depend-

noninvasive ventilation with high-inspired fraction of oxygen [70, 71].

spontaneous breathing trial facilitates weaning from MV [63].

have been utilized as rescue therapy [67–69].

and portopulmonary hypertension.

**6. Immunosuppression**

ing on protocols [72, 73].

**198**

**Calcineurin inhibitors**: Tacrolimus and cyclosporine inhibit calcineurin by impairing interleukin-2 (IL-2) transduction. Used as first-line immunosuppressant, tacrolimus is considered 100 times more potent than cyclosporine, and is superior in graft and patient survival with fewer acute and steroid-resistant rejection episodes. The main side effect is nephrotoxicity, while hypertension, hyperkalemia, uremic hemolytic syndrome, and neurotoxicity have lesser incidence [72]. Corticosteroids are important both in the initial immunosuppressive therapy and in the treatment of acute rejection.

Mycophenolate mofetil has been widely used as an adjuvant and alternative immunosuppressive agent. It is a potential inhibitor of B- and T-cell proliferation. It is mainly utilized when a dose reduction or discontinuation of CNI is demanded due to certain adverse effects such as nephrotoxicity and neurotoxicity [72].

Mammalian target of rapamycin (mTor) inhibitors, sirolimus, and everolimus, prevent B- and T-cell proliferation prompting the cell to arrest at G1 to S phase of the cell cycle. Although accounted for wound healing delay incidents, they can be administered as primary and rescue immunosuppression therapy with the advantages of being renal sparing as well as reducing the need for high doses of steroids. The newer IL-2 receptor-blocking antibody preparations daclizumab (Zenapax) and basiliximab (Simulect) are often used to initiate immunosuppression and avoid CNIs, and can also play a part in steroid-resistant rejection [72].
