**4. Liver allograft function**

Assessment of graft function is necessary and is performed by combining clinical parameters, laboratory values, and imaging examinations. The first positive signs of adequate function of the new liver can be evident by the correction of metabolic acidosis, coagulation disturbances, hemodynamic stabilization, and temperature normalization in addition to diuresis restoration. Continuous monitoring in the postoperative period is required for the immediate recognition of early, subtle findings of graft dysfunction which necessitate aggressive treatment. Traditionally, the evaluation of liver function involves static and dynamic tests [48].

Static tests include hematology, coagulation, and biochemistry blood tests, in order to evaluate the main liver functions. The hepatic enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which rather indicate hepatocyte necrosis, display a rise postoperatively reaching their peak during the first 2 days before they finally start decreasing. Their elevation is attributed to preservation injuries and/or prolonged cold ischemia time (CIT). A persisting elevated value raises concerns about liver function and requires further investigation. The canalicular enzymes γ-glutamyl transferase and alkaline phosphatase increase after day four and usually five-fold before their decline begins. The synthetic function of the liver is evaluated by the prothrombin time or international normalized ratio (INR), which estimate the production of coagulation factors by the liver. Bilirubin levels define the liver excretory function while its metabolic function is assessed by glucose and lactate levels. A resistant to the treatment hypoglycemia is an indicator of graft dysfunction. The levels of lactates should also be carefully considered, if increased, due to the fact that such result may derive from peripheral tissue hypoxia.

The dynamic tests express the ability of the liver to metabolize or excrete certain substances. The lidocaine conversion to monoethylglycinexylidide metabolite (MEGX test) assesses the metabolic capacity and the liver blood flow [48, 49].

The indocyanine green (ICG) clearance test is routinely used in several centers. The functional activity of the graft is assessed by ICG dye administration, which is almost exclusively eliminated from the liver into the bile without undergoing enterohepatic circulation. Its removal from the blood depends on the hepatic blood flow, parenchymal cell function, and biliary excretion. It is expressed as half-life time, blood clearance, or plasma disappearance rate (ICG-PDR) smaller than 15% associated with a higher rate of primary dysfunction [50]. The bedside ultrasound imaging methods with hepatic blood vessel Doppler examination are usually performed on the day of surgery or on the first postoperative one in order to evaluate the patency of the hepatic artery, the portal vein, and the hepatic vein. It is particularly useful in the presence of intraoperative technical difficulties or when there is graft dysfunction, with a view to identify vascular abnormalities that could be treated [51].

Recovery of the graft is a combination mainly of the severity of the recipient's condition, donor quality, intraoperative events, perioperative hemodynamic stability, and preservation injuries, while adequate blood flow to the organs and prevention of venous stasis in the new liver have to be ensured (**Table 2**) [49]. On the other hand, the risk of poor outcome is increased in case of ESLD-associated syndromes and co-morbidities coexistence, especially in sicker patients, as estimated by the MELD score [4, 7].

Donor quality has a major impact on the graft function since the use of marginal donors is now commonplace [4]. The prolonged time of cold ischemia for more than 12 h increases ischemia reperfusion injuries. Macrosteatosis greater than 30% reduces tolerances in such injuries, while the risk of rejection and PNF is increased. Grafts from donors older than 60 years of age are considered to be of higher risk for PNF or exhibit delayed recovery mainly owing to cholestasis, whereas grafts from donors older than 75 show reduced liver regeneration capacity [52–54].

**197**

graft functionality [63].

*Management of Patients with Liver Transplantation in ICU*

**Donor related Recipient related Intraoperative** 

Pretransplant HD/renal

ESLD-associated syndromes

dysfunction Cardiovascular disease BMI < 18.5 kg/m2

Nevertheless, the results in the literature are contradictory; and in 2016, the donors older than 65 years old reached a percentage of 20.7%. In a recent study, Gilbo et al. concluded that older grafts can be safely used in older recipients without endangering their survival, if the remaining risk factors have been minimized [55]. The best practice for graft allocation is the use of scores that include donor and recipient data, such as the survival outcomes following liver transplantation (SOFT) and/or the BAR-score, which offer excellent prognostic ability for survival after transplantation and could lead to the final decision on using or rejecting the graft [56].

**events**

Massive transfusion Reperfusion syndrome High vasopressors dose

**Allograft related**

Graft inflow (Right HF, Hepatic vein stenosis/thrombosis) Graft outflow (Hepatic artery and portal vein patency) Small-for-size syndrome

I/R Injury

**5. Ventilatory support and weaning from mechanical ventilation**

The intraoperative use of short-acting anesthetics and neuromuscular blocking agents allows a prompt recovery of consciousness and facilitates the rapid release from mechanical support and early extubation (EE), which can occur in the operating theater or within the first three postoperative hours and is associated with shorter ICU and hospital stay. In a recent meta-analysis comparing early versus conventional extubation, the authors report a reduction in re-intubation rate, morbidity, respiratory complications, incidence of graft dysfunction, and ICU/hospital stay [57–59]. In a study published by Taner et al., it was exhibited that early extubation failed only in 1.90% of patients when performed on selected cases. According to these researchers, patients with HCC and low MELD score are appropriate candidates for EE [60]. Prolonged mechanical ventilation (MV) remains a critical risk factor for infections development, especially ventilator-associated pneumonia, tracheal trauma, prolongation of neuromuscular recovery, graft venous congestion due to positive intrathoracic pressures, and reduced venous return to the inferior vena cava and hepatic veins [61, 62]. It has also been correlated by Yuan et al. with the recipient's age, female gender, preoperative need for renal replacement therapy (RRT), ascites, higher MELD score, prolonged cold ischemia, and the number of transfusions [62]. Emphasis is placed on the fact that optimal selection criteria and timing of EE have not been clearly defined yet. Patients with encephalopathy, marked hypoxemia, obesity (BMI > 30), severe hemodynamic instability, pulmonary edema, cardiac or renal dysfunction, and multiple transfusions are not indicated for EE. The personalized and selective approach is likely to be the best strategy with a focus on avoiding delayed extubation, preserving hemodynamic stabilization, and ensuring

The criteria of weaning from MV applied to liver transplanted patients in ICU conform to those of the rest patient groups [64]. Distinct sequelae may often arise

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

Donor age Macrovesicular steatosis >30% High dose of vasopressors Hypernatremia Prolonged ICU stay Prolonged CIT Donation after cardiac death

**Table 2.**

*Factors related to graft function.*

*Management of Patients with Liver Transplantation in ICU DOI: http://dx.doi.org/10.5772/intechopen.89435*


**Table 2.**

*Liver Disease and Surgery*

**4. Liver allograft function**

Assessment of graft function is necessary and is performed by combining clinical parameters, laboratory values, and imaging examinations. The first positive signs of adequate function of the new liver can be evident by the correction of metabolic acidosis, coagulation disturbances, hemodynamic stabilization, and temperature normalization in addition to diuresis restoration. Continuous monitoring in the postoperative period is required for the immediate recognition of early, subtle findings of graft dysfunction which necessitate aggressive treatment. Traditionally,

Static tests include hematology, coagulation, and biochemistry blood tests, in order to evaluate the main liver functions. The hepatic enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which rather indicate hepatocyte necrosis, display a rise postoperatively reaching their peak during the first 2 days before they finally start decreasing. Their elevation is attributed to preservation injuries and/or prolonged cold ischemia time (CIT). A persisting elevated value raises concerns about liver function and requires further investigation. The canalicular enzymes γ-glutamyl transferase and alkaline phosphatase increase after day four and usually five-fold before their decline begins. The synthetic function of the liver is evaluated by the prothrombin time or international normalized ratio (INR), which estimate the production of coagulation factors by the liver. Bilirubin levels define the liver excretory function while its metabolic function is assessed by glucose and lactate levels. A resistant to the treatment hypoglycemia is an indicator of graft dysfunction. The levels of lactates should also be carefully considered, if increased, due to the fact that such result may derive from peripheral tissue hypoxia. The dynamic tests express the ability of the liver to metabolize or excrete certain

substances. The lidocaine conversion to monoethylglycinexylidide metabolite (MEGX test) assesses the metabolic capacity and the liver blood flow [48, 49]. The indocyanine green (ICG) clearance test is routinely used in several centers. The functional activity of the graft is assessed by ICG dye administration, which is almost exclusively eliminated from the liver into the bile without undergoing enterohepatic circulation. Its removal from the blood depends on the hepatic blood flow, parenchymal cell function, and biliary excretion. It is expressed as half-life time, blood clearance, or plasma disappearance rate (ICG-PDR) smaller than 15% associated with a higher rate of primary dysfunction [50]. The bedside ultrasound imaging methods with hepatic blood vessel Doppler examination are usually performed on the day of surgery or on the first postoperative one in order to evaluate the patency of the hepatic artery, the portal vein, and the hepatic vein. It is particularly useful in the presence of intraoperative technical difficulties or when there is graft dysfunction,

with a view to identify vascular abnormalities that could be treated [51].

Recovery of the graft is a combination mainly of the severity of the recipient's condition, donor quality, intraoperative events, perioperative hemodynamic stability, and preservation injuries, while adequate blood flow to the organs and prevention of venous stasis in the new liver have to be ensured (**Table 2**) [49]. On the other hand, the risk of poor outcome is increased in case of ESLD-associated syndromes and co-morbidities coexistence, especially in sicker patients, as estimated by the MELD score [4, 7].

Donor quality has a major impact on the graft function since the use of marginal

donors is now commonplace [4]. The prolonged time of cold ischemia for more than 12 h increases ischemia reperfusion injuries. Macrosteatosis greater than 30% reduces tolerances in such injuries, while the risk of rejection and PNF is increased. Grafts from donors older than 60 years of age are considered to be of higher risk for PNF or exhibit delayed recovery mainly owing to cholestasis, whereas grafts from donors older than 75 show reduced liver regeneration capacity [52–54].

the evaluation of liver function involves static and dynamic tests [48].

**196**

*Factors related to graft function.*

Nevertheless, the results in the literature are contradictory; and in 2016, the donors older than 65 years old reached a percentage of 20.7%. In a recent study, Gilbo et al. concluded that older grafts can be safely used in older recipients without endangering their survival, if the remaining risk factors have been minimized [55]. The best practice for graft allocation is the use of scores that include donor and recipient data, such as the survival outcomes following liver transplantation (SOFT) and/or the BAR-score, which offer excellent prognostic ability for survival after transplantation and could lead to the final decision on using or rejecting the graft [56].

#### **5. Ventilatory support and weaning from mechanical ventilation**

The intraoperative use of short-acting anesthetics and neuromuscular blocking agents allows a prompt recovery of consciousness and facilitates the rapid release from mechanical support and early extubation (EE), which can occur in the operating theater or within the first three postoperative hours and is associated with shorter ICU and hospital stay. In a recent meta-analysis comparing early versus conventional extubation, the authors report a reduction in re-intubation rate, morbidity, respiratory complications, incidence of graft dysfunction, and ICU/hospital stay [57–59]. In a study published by Taner et al., it was exhibited that early extubation failed only in 1.90% of patients when performed on selected cases. According to these researchers, patients with HCC and low MELD score are appropriate candidates for EE [60].

Prolonged mechanical ventilation (MV) remains a critical risk factor for infections development, especially ventilator-associated pneumonia, tracheal trauma, prolongation of neuromuscular recovery, graft venous congestion due to positive intrathoracic pressures, and reduced venous return to the inferior vena cava and hepatic veins [61, 62]. It has also been correlated by Yuan et al. with the recipient's age, female gender, preoperative need for renal replacement therapy (RRT), ascites, higher MELD score, prolonged cold ischemia, and the number of transfusions [62].

Emphasis is placed on the fact that optimal selection criteria and timing of EE have not been clearly defined yet. Patients with encephalopathy, marked hypoxemia, obesity (BMI > 30), severe hemodynamic instability, pulmonary edema, cardiac or renal dysfunction, and multiple transfusions are not indicated for EE. The personalized and selective approach is likely to be the best strategy with a focus on avoiding delayed extubation, preserving hemodynamic stabilization, and ensuring graft functionality [63].

The criteria of weaning from MV applied to liver transplanted patients in ICU conform to those of the rest patient groups [64]. Distinct sequelae may often arise 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 spontaneous breathing trial facilitates weaning from MV [63].

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

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

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

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].
