Glanemann et al. 
546 patients analyzed, immediate extubation in 18.7 %. No increased incidence of reintubation when compared with patients successfully extubated later.
Mandell et al. 
147 sequential patients, 111 successfully extubated immediately. 83 patients transferred directly to surgical ward. 1 day ICU reduction in 75.5 % of patients with no problems reported with patient safety.
Biancofiore et al. 
207 out of 354 patients extubated immediately, two re-intubated. In the final year of the study 82.5 % of patients were successfully extubated immediately.
Mandell et al. 
Multicenter prospective trial
391 patients who met criteria for early extubation. Complication rate of 7.7 %, however was skewed as two institutions had higher complication rates. Removing these two centers the complication rate fell to 3.6 %. This difference may be related to a center’s experience with early extubation.
Mechanical Ventilation Management
Liver transplant patients who are not candidates for early extubation in the operating room are common, particularly among patients with pre-existing pulmonary pathology. A subset of patients will require prolonged mechanical ventilation and may develop additional pulmonary complications in the postoperative period. It is critical for the intensivist to recognize these patients and work to prevent ventilator associated lung injury.
Post-liver transplant patients in the ICU may develop acute respiratory distress syndrome . The differential for ARDS is broad and includes infection [including ventilator-associated pneumonia (VAP)], systemic reperfusion injury, transfusion reaction, or graft failure. Patients who meet criteria for ARDS should be placed on low tidal volume ventilation . While patients with severe liver disease were excluded from the ARDSNet study, there currently is no evidence to suggest that low tidal volume ventilation is harmful. In fact, recent studies have shown expanded benefit of low tidal volume ventilation even in patients who do not have ARDS .
The data in regards to other forms of mechanical ventilation are minimal for all critical care patients, and nonexistent for the post-OLT patient with ARDS. Airway pressure release ventilation , high-frequency oscillatory ventilation [30, 31], prone ventilation , inhaled nitric oxide , neuromuscular blocking agents , and recruitment maneuvers  have all been studied, but for most randomized studies, patients with cirrhosis and liver failure were excluded. All the studies have shown the ability to improve oxygenation; some have shown a mortality benefit, but none have been as definitive as ARDSnet . Lung-protective mechanical ventilation should be the underlying ventilator support strategy of post-liver transplant patients with ARDS requiring mechanical ventilation.
Several theoretical concerns related to liver transplant patients and ARDSNet ventilation exist. In the ARDSNet protocol, permissive hypercapnia is used. There is some concern that this elevated PCO2 may affect graft function, but there is currently no significant data addressing this potential complication. A second concern has been the administration of positive end-expiratory pressure (PEEP) and the corresponding increase in intrathoracic pressure, which in turn may impede venous return from the new liver. No studies have addressed high PEEP, but there is published evidence that PEEP up to 10 cm H2O does not adversely affect graft function .
A subset of posttransplant patients will be difficult to wean from ventilator support and can prove challenging. Liver transplant patients should be treated like other patients who are mechanically ventilated and when feasible, given daily sedation holidays and spontaneous breathing trials in an effort to evaluate readiness for extubation. For patients with prolonged ventilation requirements, tracheostomy should be considered as with other intubated patients in the ICU setting.
Hepatopulmonary syndrome is a complication of cirrhosis that adds unique concerns to the postoperative course. The presence of hepatopulmonary syndrome can lead to increased postoperative mortality, particularly for severe cases of hepatopulmonary syndrome (PaO2 < 50 mmHg on room air) . Diagnosis and intra-operative management of hepatopulmonary syndrome is covered in other chapters.
The complication most commonly seen in patients with hepatopulmonary syndrome is prolonged hypoxia in the postoperative setting. Management of hypoxia is important, as prolonged mechanical ventilation in these immunosuppressed patients is associated with an increased risk of adverse events. There have been case reports of using nitric oxide to improve oxygenation, but no randomized trials exist to demonstrate the efficacy of this therapy . In some patients with severe hepatopulmonary syndrome, the recovery of oxygenation may be prolonged. Recent data from two Canadian centers reported a mean rate of increase in PaO2 of 3.1 ± 2.3 mmHg/month, and mean time to resolution of the intrapulmonary shunt of 4.5–18 months (median 11 months posttransplant) . For these patients, prolonged mechanical ventilation may not be the most appropriate therapy and it may be appropriate to consider extubation with administration of supplemental oxygen or noninvasive ventilation. This strategy can be effective in reducing ventilator related complications and will allow for a postoperative patient to leave the ICU and avoid a prolonged stay. Further studies will be necessary to determine the feasibility of this approach.
Sedation of the mechanically ventilated patient is challenging; this is especially true in the post-liver transplant patient. Mental status changes can be an early clue to graft dysfunction and efforts should be made to avoid excessive sedation. Benzodiazepines are not recommended as they have been shown to increase delirium in the ICU setting . Propofol and dexmedetomidine have become popular sedatives due to their favorable pharmacokinetics. A recent meta-analysis suggested that use of dexmedetomidine or propofol infusions rather than a benzodiazepine infusion in critically ill adults reduced ICU length of stay and duration of mechanical ventilation . There have been only a few recent case reports of safe use of dexmedetomidine infusions in post-liver transplant patients [42, 43]. The short acting agents have a favorable profile and allow for serial neurologic exams while still providing adequate sedation and anxiolysis.
Liver transplant is a major surgical procedure and may be accompanied by significant postoperative surgical pain. Pain control intra- and postoperatively is usually achieved with fentanyl, via infusion or intermittent bolus. Other opioids such as morphine and hydromorphone are avoided if possible due to their prolonged half-lives in liver failure. Fentanyl derivatives such as sufentanil, alfentanil, and remifentanil have superior pharmacokinetic properties but are not routinely used in the postoperative setting due to higher cost, insufficient staff experience, and lack of data showing improved efficacy. Some patients may require use of a patient controlled analgesia (PCA) pump along with longer acting agents, or transition to around-the-clock oral medications if pain persists.
Thoracic epidurals are beneficial for pain control following abdominal surgery , however they are not routine for liver transplant patients. The varied coagulation status of posttransplant patients raises concerns regarding the use of thoracic epidurals for postoperative analgesia. Hypotension from the epidural also raises concern that graft function may be compromised, particularly in posttransplant patients who have complex hemodynamic indices. For certain patients, other than transplant recipients (i.e.: hepatectomy patients) thoracic epidurals may be an acceptable option for postoperative analgesia.
Non-opioid adjuncts for pain control have received significant attention. While there have been few studies examining these agents in liver transplant patients, some generalizations can be made. Nonsteroidal anti-inflammatory drugs (NSAIDs) , while efficacious for pain, should probably be avoided in the setting of increased bleeding risk and potential renal insufficiency. Acetaminophen is usually given at lower doses (2 g/day) for liver failure patients and should be avoided in the immediate postoperative period. However, for patients with functioning grafts, it is reasonable to consider acetaminophen administration due to its synergy with opioids.
Unfortunately there does not exist a one-size-fits all approach to pain management in the liver transplant patients. Each patient’s individual risk for postoperative pain must be weighed against potential side effects. At this point, opioids such as fentanyl remain the mainstay of therapy until further studies are completed that can validate the safety of other interventions.
Patients with liver failure often suffer from hepatic encephalopathy . The underlying etiology of hepatic encephalopathy is not entirely understood but current theories suggest that increased ammonia in the systemic circulation crosses the blood brain barrier where it is converted into glutamine by astrocytes. The glutamine causes swelling of the astrocytes, which impairs neurotransmission regulation. Interestingly, the level of ammonia does not correlate with neurologic symptom severity, so trending ammonia levels may not be helpful. In the postoperative period, a patient with a newly functioning liver should have steady clearance of toxins and a continual improvement in mental status. If there is no improvement or mental status declines, then a workup for graft nonfunction and infection should be undertaken and electrolyte imbalances corrected. Given the extreme changes in coagulation status, there should also be a low threshold to obtain imaging if there is concern for intracranial hemorrhage.
Osmotic Demyelination Syndrome
Hyponatremia in the setting of liver failure will be discussed below. However, it is important to note a potential neurologic complication that is associated with rapid correction of hyponatremia: central pontine myelinolysis or osmotic demyelination syndrome. The exact etiology of osmotic demyelination syndrome is unknown. The symptoms are usually seen 1–6 days after the insult of rapid sodium correction . The most common clinical manifestation is fluctuations in consciousness. Eventually, pseudobulbar palsy and quariparesis may develop. If a patient is known to be hyponatremic preoperatively, then clinicians must closely monitor electrolytes and choose intravenous fluids appropriately to avoid rapid over correction postoperatively.
Electrolyte and Endocrine Issues
Adequate management of electrolytes can be challenging in posttransplant patients. The patients often have numerous abnormalities that should be closely monitored and corrected. Treatment of the more common electrolyte abnormalities found in posttransplant patients will be discussed below.
Alterations in sodium levels are very common in pre- and posttransplant patients. In fact, there is clinical evidence to suggest that adding serum sodium to model for ESLD (MELD) scoring improves mortality prediction . The first step in management is to determine the acuity of the situation. Patients with acute hyponatremia (development in under 48 h) are at risk for developing neurologic impairment and, consequently, require prompt correction of serum sodium levels. Administration of a hypertonic (3 %) saline infusion may be necessary for this situation. In patients with more chronic hyponatremia (development in over 48 h), rapid correction of hyponatremia is an independent risk factor for the development of posttransplant neurological complications . Serum sodium correction should be performed in a controlled manner in this instance. The goal is usually 1–2 mmol/L per hour for the first 48 h. If the level rises too quickly, then hypotonic intravenous fluids should be started to restore the goal correction rate.
Hypernatremia is a less-frequent complication associated with liver transplant patients. The etiology is frequently related to excessive loss of free water in patients using an osmotic laxative (such as lactulose) to reduce hepatic encephalopathy. These patients are unable to adequately regulate their own free water balance due to impaired thirst mechanisms. This derangement may continue into the postoperative setting. As the mental status improves, the patient should begin to appropriately regulate water intake. For a hypernatremic patient who is unable to tolerate oral free water boluses, hypotonic maintenance fluids are recommended with close monitoring of electrolytes.
Hyperkalemia may be the most lethal electrolyte abnormality due to the rapid progression of arrhythmias and death. The causes of hyperkalemia in the posttransplant patient are often multifactorial. Many liver transplant patients either have pre-existing renal dysfunction  or will develop transient renal dysfunction in the perioperative period which can impair mechanisms of potassium homeostasis.
For patients that had significant blood loss and transfusion requirements during the operation, there may be a significant potassium burden in the form of lysed cells from aged units that are transfused. Many liver transplant centers have a high usage rate of blood products and will often be assigned aged units by the blood bank because they are unlikely to be wasted. While this is an excellent use of resources, these units contain less-functional cells and correspondingly represent a higher potassium load to the patient. Washing the cells before transfusion can partially attenuate the hyperkalemia, but frequent potassium monitoring remains necessary.
Hyperkalemia can be exacerbated acutely by reperfusion of the preserved graft and release of a significant potassium load from ischemic tissues. This is often managed with temporizing measures such as administration of calcium, sodium bicarbonate, and insulin with glucose, but the total body potassium may continue to be elevated in the postoperative setting. Dialysis may be needed if renal insufficiency and hyperkalemia persist in the ICU.
Hypocalcemia is frequently identified in liver transplant patients. However, it is important to remember that these patients often have low albumin levels and the total calcium is not necessarily reflective of free calcium levels . Ionized calcium levels are more accurate in this situation. Low calcium levels can result from chelation with the anticoagulant citrate, found in blood products and renal replacement therapy infusions. Hypocalcemia should be suspected in a patient with hypotension despite adequate resuscitation. Calcium gluconate or calcium chloride can be used for replacement.
Glucose levels following liver transplantation have significant implications for both prognosis and complications. Hypoglycemia in the postoperative period may be a marker for sepsis or poor graft function . Hyperglycemia, which is much more common in the postoperative setting, may be a reflection of underlying diabetes, stress response, or steroid administration. Severe hyperglycemia (glucose > 200 mg/dL) is associated with an increased risk of liver allograft rejection , surgical site infection , and increased mortality . Hyperglycemia is known to aggravate ischemia reperfusion injury in several organ systems.
Although hyperglycemia has complications, tight glucose control (between 80 and 120 mg/dL) is not recommended due to poor outcomes in the ICU setting [53, 54]. The best approach is to achieve modest glucose control (150–180 mg/dL), which is consistent with current ICU guidelines. In the immediate postoperative setting, an insulin infusion with frequent blood glucose checks is often required, as fluctuations in the stress response make steady state dosing difficult.
Renal insufficiency following liver transplant is a common occurrence. Some studies report up to a 50 % incidence, though numbers vary widely due to the lack of a uniform definition. Acute ischemic tubular necrosis (ATN) is the most common cause of early renal failure following liver transplant . A number of contributing factors increase the risk of renal dysfunction postoperatively. They include: hepatorenal syndrome, hepatitis C, diabetes mellitus, intraoperative and postoperative hemodynamic instability, massive transfusion, vasopressor infusions, infections, frequent radiologic studies, and nephrotoxic immunosuppressants and antibiotics [56, 57]. Management usually includes judicious fluid management, medication dose reductions based on creatinine clearance, and avoidance of further renal insults.
Eight to seventeen percent of patients with posttransplant acute kidney injury go on to require renal replacement therapy despite supportive care . Risk factors for renal replacement therapy (RRT) following transplant include preoperative serum creatinine (Cr) greater than 1.9 mg/dL, blood urea nitrogen (BUN) greater than 27 mg/dL, ICU duration of greater than 3 days, and MELD score greater than 21 . Some patients will progress to end stage renal disease (ESRD) and require kidney transplantation in the future. One percent of all kidney transplant patients in the United States are prior liver transplant patients with ESRD. The risk for kidney injury is further increased in recipients of living donor liver transplantation. These patients may develop small for size syndrome (see section below), which worsens fluid and hemodynamic derangements .
Hepatorenal syndrome (HRS) involves severe vasoconstriction of the renal vasculature and renal hypoperfusion in the presence of decreased systemic vascular resistance and normal renal parenchyma [59, 60]. Patients with HRS pre-liver transplant have been found to require longer ICU stays postoperatively and more dialysis, and are more likely to progress to ESRD following transplant than patients without HRS. Calcineurin inhibitor (CNI) initiation should be withheld for the first several days following transplantation to allow for reversal of HRS physiology and recovery of renal function .
Monitoring renal function in liver transplant patients is challenging, as elevations in serum creatinine are late indicators of renal insufficiency and proteinuria may not develop in the presence of calcineurin inhibitors . A formula for calculating glomerular filtration rate should be utilized for the detection of renal dysfunction, but the results may be less reliable in patients with liver disease. A recent study suggested that cystatin C levels in the immediate posttransplant period are superior to creatinine based equations for estimation of GFR and may be useful as a confirmatory test for kidney injury . Although it may be more accurate, cystatin C is not universally available, and it is more expensive. Until better markers are discovered and validated, serum creatinine will remain the main criterion used for the diagnosis of AKI.
Once renal failure begins to develop, nephrotoxic immunosuppressants, namely CNIs, should be withdrawn, and immunosuppression should be maintained with renal-sparing protocols. CNI-induced nephropathy results from afferent arteriolar vasoconstriction and subsequent decrease in renal perfusion . Using a reduced dose of cyclosporine, or replacing cyclosporine with mycophenolate mofetil (MMF) and sirolimus reduces the incidence of CNI-induced renal injury . While CNI-induced nephropathy was reduced with MMF and sirolimus, the incidence of biopsy-proven acute rejection in the liver increased. Fortunately, this was not associated with increased rates of graft loss. A recently conducted Cochrane review of the literature surrounding CNI toxicity did not reach a conclusion regarding the role of CNI minimization in preventing nephrotoxicity in liver transplant patients . Many centers now delay the administration of these drugs following surgery. The dosages used today are also substantially lower than those prescribed in the past in order to reduce the subsequent risk of chronic kidney disease .
Infections are the leading cause of morbidity and mortality after liver transplantation. The early posttransplant course (first month) is often complicated by surgical site infections and infections related to hospitalization including urinary tract infections, pneumonias, blood stream infections, and pseudomembranous colitis . Patients post-liver transplant are at particular risk for developing bacterial infections of the liver and surgical site including abscesses, cholangitis, and peritonitis. Standard perioperative antibiotic prophylaxis with third generation cephalosporins should be used to reduce the risk of infections . Although prior studies had suggested that selective bowel decontamination with prolonged antibiotic use prior to transplantation may help reduce the occurrence of infections, a Cochrane Database analysis concluded that there was no clear benefit of this intervention, and that decontamination may in fact increase the risk of infection and length of hospital stay . Prebiotics and probiotics may provide some benefit, and should be further studied.
Opportunistic infections generally occur in the second through sixth months, when immunosuppression is most profound. Trimethoprim/sulfamethoxazole (TMP-SMX) prophylaxis for Pneumocystis jirovecii should be instituted for the first 6 months following transplant, and continued in patients requiring monoclonal OKT3 antibodies for rejection and in patients with graft dysfunction. An additional benefit of TMP-SMX administration is prophylaxis for Toxoplasma gondii, Listeria monocytogenes, and Nocardia asteroids .
CMV infection is notable for its association with increased opportunistic infections in liver transplant patients, including fungemia and bacteremia, and its association with transplant rejection . Infection with CMV within the first year of transplant is associated with increased mortality. Effective prophylaxis can be provided with ganciclovir or valganciclovir for 3 months following transplant . Herpes simplex virus (HSV) reactivation may occur posttransplantation, but antivirals used for CMV prophylaxis should also be effective in these patients. If the patient is not receiving CMV prophylaxis, acyclovir can be used for the prevention of HSV. Varicella vaccination should be administered prior to transplantation. Beyond 6 months, patients are no longer at risk for most opportunistic infections if the level of immunosuppression has been reduced.
Candida is the most common fungal pathogen following liver transplantation and accounts for nearly 80 % of postoperative fungal infections, followed by Aspergillus. Most fungal infections occur within the first 2 months following transplantation. Risk factors for opportunistic fungal infections are retransplantation, renal failure, and reoperation involving the thoracic or abdominal cavity . The use of antifungal prophylaxis is highly variable between liver transplant centers, and can include nystatin suspension, fluconazole, amphotericin B, or no empiric prophylaxis .
Blood transfusions for bleeding are indicated to maintain adequate oxygen delivery. No firm transfusion threshold exists, but evidence in other patient populations suggests that a more restrictive strategy is appropriate. In the most recent clinical practice guidelines published, the taskforce, comprised of surgeons, anesthesiologists, and intensivists, felt there was good evidence to recommend a restrictive strategy of red blood cell (RBC) transfusion (hemoglobin < 7 g/dL) in critically ill patients with hemodynamically stable anemia . Acute blood loss with hemodynamic instability should probably be addressed by more aggressive resuscitation with blood products. Further trials testing rigorous transfusion protocols are necessary, but the trend has been toward more restrictive transfusion practices.
Colloid Versus Crystalloid
No evidence for the superiority of albumin over crystalloid has been found in the critical care literature, but it is important to note that liver transplant patients were excluded from the trial . Either crystalloid or colloid can be used effectively when administered in bolus doses for hypotension. In a patient with significant ascites, colloids may be the fluid of choice for resuscitation. It does appear that among colloids, albumin may be safer than hydroxyethyl starchs because of the lower incidence of anaphylactic reactions, coagulation disorders, renal or liver failure, pruritus, and better hemodynamic stability . Hydroxyethyl starch has also been found to increase the need for renal replacement therapy when compared with normal saline  and lactate ringers .
Thoughtful selection of crystalloid is essential as significant electrolyte derangements may be present in the postoperative setting. Boniatti and colleagues showed recently that hyperchloremia, possibly due to the administration of normal saline, is the primary cause of metabolic acidosis in liver transplant recipients . Among critically ill patients with sepsis, large chloride loads from saline resuscitation have been associated with increased renal failure , and hospital mortality . While this has not been exhaustively studied in the posttransplant setting, this concept may translate to the care of liver transplant patients as well. Future studies are needed to assess the utility of various balanced salt solutions in the care of patients post-OLT.
Coagulopathy does not resolve immediately after transplantation and often persists into the postoperative ICU period. The etiology is multifactorial and can involve hyperfibrinolysis, disseminated intravascular coagulopathy, platelet activation, platelet sequestration within the graft, and the presence of heparin-like effect (HLE). Some patients are actually hypercoagulable posttransplant, which further complicates the evaluation of their coagulation status . The cause of this hypercoagulability is not entirely clear but maybe due to impaired synthesis of antithrombin by the liver.
As the new graft improves in function, synthesis of coagulation factors should improve and laboratory values should return to baseline. While laboratory value correction may not correlate well with bleeding risk, it does correlate with improved graft function. Failure to see improvement in coagulopathy should prompt a work up for graft nonfunction and infection, two serious causes of impaired coagulation in the postoperative setting. Routine transfusion for laboratory abnormalities is not indicated unless there is evidence for ongoing bleeding and hemostatic problems . Aggressive transfusion can worsen cardiac function and consequently graft perfusion, so it should be reserved as therapy for clinically significant bleeding.
In addition to hypofibrinogenemia from transfusions and blood loss, the new graft releases t-PA and tissue factor, which results in an accelerated fibrinolytic state that frequently causes significant consumption of fibrinogen in the post-reperfusion setting [83, 84]. Refractory bleeding should prompt an investigation for low fibrinogen and fibrinolysis. Administration of antifibrinolytic drugs has shown benefit in reduction of transfusion requirements, and with the small number of patients studied so far, there does not appear to be an increased risk in thrombotic events (Table 29.2). Due to the lack of definitive data, it is not routine practice to administer antifibrinolytics, but practice patterns may change with further results.
Trials on use of antifibrinolytic agents in liver transplantation
Boylan et al. 
Randomized controlled trial
TXA: 25 patients, Controls: 20 patients. Statistically significant reduction in intraoperative blood loss (20.5 units vs. 43.5 units). No difference in hepatic artery or portal venous thrombosis.
Kaspar et al. 
Randomized controlled trial
32 patients randomized to TXA or control. No difference in transfusion, but decreased fibrinolysis seen on TEG
Dalmau et al. 
Randomized controlled trial
Tranexemic Acid/ε-Aminocaproic Acid
132 patients randomized to TXA, ε-aminocaproic acid, or placebo. Statistically significant reduction in intraoperative transfusion for TXA, not for ε-aminocaproic acid. No differences in thrombotic events or post-operative transfusion.
Dalmau et al. 
Randomized controlled trial
127 patients randomized to TXA or Aprotinin. No difference in transfusion requirements or thrombotic complications.
Ickx et al. 
Randomized controlled trial
51 patients randomized to TXA or Aprotinin. No difference between intraoperative blood loss or transfusion requirements.
Molenaar et al. 
Meta-analysis including the above trials showing no increased risk of thrombotic complications with antifibrinolytic agents.
Gurusamy et al. 
TXA/Aprotinin (additionally looked at other interventions to reduce blood loss)
Only aprotinin may reduce blood transfusion requirements. No difference seen between TXA and controls; no difference seen between aprotinin and TXA (only 3 trials included comparing the two).
Heparin-Like Effect (HLE)
The prevalence of HLE in patients undergoing liver transplant is not uncommon, and can range from 25 to 95 % of cases . Patients who have acute liver failure, primary nonfunction of the liver graft or require retransplant have a higher prevalence of HLE. The problem appears to be worse in patients with acute liver failure; however, the problem can persist in the posttransplant period regardless of the etiology of the liver failure .
The HLE can come from an exogenous source as well as an endogenous source. Residual heparin bound to the endothelium of the donor liver, which is perfused with heparin before clamping, is the exogenous source of heparin. The endogenous source comes from substances known as heparinoids. The increased release of heparinoids is thought to occur from activation of macrophages or hepatocytes following ischemic injury to the liver. There is currently no evidence for reversing the HLE and supportive care is the best treatment option. An infusion of protamine sulfate has been attempted, but did not result in reduced bleeding or transfusion requirements . If impaired coagulation persists several days into the postoperative period, then a sepsis workup is indicated as infection can worsen the production of these heparin-like molecules.
Low platelet counts are a commonly seen abnormality in the posttransplant patient. The etiology for the thrombocytopenia is varied but is related to decreased circulation and decreased production. With severe cirrhosis, there is often significant sequestration of platelets in the spleen due to portal hypertension, and the new graft will also sequester platelets. There is decreased platelet production because of low thrombopoietin levels in liver failure patients . In the postoperative period, massive blood transfusions can result in a dilutional thrombocytopenia. Finally, even if the platelet count is adequate, platelets in a patient with liver disease may have decreased function because of adenosine diphosphate-induced and collagen-induced aggregation . Platelet function may be further impaired by uremia in the setting of coexistent renal dysfunction. Thromboelastography (TEG) may be beneficial in measuring platelet function , but definitive studies relating use of TEG in liver transplant patients are needed.
Coagulation Factor Deficiencies
All coagulation factors except for factor VIII and von Willebrand factor are synthesized by the liver and are therefore decreased in the setting of severe hepatic impairment. Fresh frozen plasma (FFP) can replace these factors, but administration of plasma carries the risk of transfusion reactions and large volumes are often needed to reverse the laboratory coagulopathy .
For patients with refractory bleeding, many clinicians have used recombinant activated factor VII (rFVIIa) . No randomized clinical trials have been conducted in postoperative liver transplant patients; however, case series have shown some benefit. There are risks associated with the off-label use of rFVIIa. Mayer and colleagues demonstrated increased risk of thrombosis with rFVIIa administration in patients presenting with intracerebral hemorrhages . The exact role of rFVIIa in liver transplantation is unclear due to lack of data. Given the uncertainty, recommendations are that rFVIIa should be used only as “rescue therapy” in patients with severe life-threatening bleeding where other therapies have failed.
Posttransplant immunosuppression is necessary to prevent rejection of the donor organ. However, immunosuppression must be balanced with the maintenance of other immunologic functions, especially the prevention or recurrence of infection and malignancy. Fortunately, the rejection of transplanted livers occurs less frequently than in other organs , so lower dosages can be used. Side effects and complications can still occur in the postoperative period, so the intensivist should be familiar with the indications and side effects of immunosuppressants (Table 29.3).
Immunosuppressants : their mechanisms of action and side effects
Mechanism of action
Reduce antigen presentation and lymphocyte activation
– HCV recurrence
– HCC recurrence
– Metabolic effects
– Hepatic fibrosis
Reduce IL-2-mediated T cell activation
– Metabolic effects
– HCC recurrence
– Mycophenolate mofetil
Inhibit DNA synthesis
– GI distress
– Bone marrow suppression
Reduce IL-2-mediated T cell activation
– Bone marrow suppression
– Delayed wound healing
The immunosuppressive effects of corticosteroids include a decrease in IL-1-induced lymphocyte activation, a decrease in CD4+ T-cells, and a decrease in antigen presentation by dendritic cells . Steroids are used for induction and maintenance during the first year following transplant, and also for treating episodes of acute rejection. Concern exists for the use of high-dose corticosteroids accelerating rates of HCV recurrence, HCC recurrence, and hepatic fibrosis. However, the avoidance of steroids in immunosuppression has not been shown to be beneficial in HCV positive transplant recipients . Commonly seen acute side effects from high-dose steroids include: hypertension, glucose intolerance, agitation/insomnia, infection risk, and poor wound healing. Most of the signs and symptoms can be managed, so corticosteroid cessation is rare.
The calcineurin inhibtors (CNIs) , cyclosporine and tacrolimus, are used frequently in order to prevent rejection. Calcineurin inhibition results in a decrease in the pro-inflammatory cytokine IL-2 and subsequent decrease in T-cell activation. Both CNIs undergo metabolism by the cytochrome P450 system, and require careful monitoring of levels, especially when used in conjunction with other medications that induce or inhibit cytochrome P450 . Common side effects of CNIs include nephrotoxicity and neurotoxicity, including seizures, delirium, cognitive impairment, neuropathy, and coma. If a posttransplant patient develops concerning neurologic symptoms, tacrolimus levels should be checked. Unfortunately, neurologic symptoms can develop even at therapeutic levels of tacrolimus. Treatment is largely supportive as there is no way to acutely lower tacrolimus levels other than dose adjustment. A strategy of using low dose CNI for maintenance of immunosuppression has been suggested in order to minimize renal dysfunction [96, 97]. Additional side effects from CNIs include hypertension, hyperlipidemia, metabolic acidosis, and diabetes. CNIs have also been found to increase levels of the transcription factor TGF-beta, which may increase the risk of hepatocellular carcinoma recurrence or posttransplant lymphoproliferative disorder [93, 94].
Mycophenolate mofetil (MMF) undergoes metabolism into mycophenolic acid (MPA). MPA inhibits the synthesis of guanosine nucleotides, necessary for DNA transcription, and subsequently decreases lymphocyte proliferation . Side effects of MMF include gastrointestinal distress and bone marrow suppression. An advantage of MMF is its lack of renal toxicity, and MMF levels do not need to be regularly monitored. Unfortunately, monotherapy with MMF is associated with higher rates of rejection, so the combination of MMF with a low dose CNI has been proposed as a strategy for reducing renal dysfunction and graft rejection .
The mammalian target of rapamycin (mTOR) inhibitors , sirolimus and everolimus, are similar to the CNIs in many ways. They too inhibit IL-2-mediated activation of T-cells, and are metabolized by the cytochrome P450 system . There is some concern for increased risk of hepatic artery thrombosis  with sirolimus when used as de novo therapy , and the FDA has issued a black-box warning in regards to this risk. Side effects of the mTOR inhibitors include bone marrow suppression, interstitial pneumonitis, edema, and delayed wound healing. In patients with CNI-induced nephrotoxicity, early conversion to sirolimus helps to prevent kidney damage. However, the recently published PROTECT trial did not demonstrate any benefit with the early substitution of everolimus for CNI in patients with a normal baseline renal function .
The role of mTOR inhibitors versus CNIs in patients with HCV remains controversial [101, 102]. Antiangiogenic properties of mTOR inhibitors may prevent recurrence of HCC, when used in conjunction with systemic chemotherapy posttransplant . The data are strong enough that the American Association for the Study of Liver Diseases recommended patients undergoing transplant for hepatocellular carcinoma (HCC) receive sirolimus for immunosuppression .
After liver transplantation, there are many types of graft rejection that may occur. Rejection of the allograft can be hyperacute, acute, chronic, or graft-versus-host (GVHD). Since chronic rejection is not usually an issue for the ICU patient, it will not be covered in this chapter.
Hyperacute rejection, mediated by antibodies, occurs within minutes to hours after the transplant procedure. Sixty percent of the cases of hyperacute rejection are due to ABO-incompatible allografts. In the presence of ABO-incompatible transplants, plasmapheresis, splenectomy, and the CD20 monoclonal antibody, rituximab, have been reported to prevent hyperacute rejection , but immediate retransplantation is often the only lasting option. Because antibody-mediated rejection with ABO-compatible allografts is so rare, due to the liver’s relative resistance to the humoral immune system, a positive crossmatch does not necessarily preclude liver transplantation. However, evidence does suggest that the presence of preformed donor-specific HLA-antibodies can increase the risk of acute cellular rejection and chronic rejection .
Unlike hyperacute rejection, which is B cell mediated, acute rejection is mediated by T cells. Acute rejection is usually seen within days or weeks of the transplant and occurs in 36–75 % of liver transplant patients. Acute rejection is characterized by mononuclear inflammation and active cell damage, and episodes refractory to antirejection medications (usually high-dose steroids) can progress to chronic rejection . Risk factors for the development of steroid unresponsive acute rejection include pre-liver transplant steroid administration, ABO incompatibility, recurrent rejection, low serum cyclosporine levels, and high liver function tests. A rising or persistent elevation of alanine aminotransferase (ALT) levels should prompt a biopsy to exclude rejection. Treatment options for a positive biopsy depend on the severity and include: optimization of maintenance immunosuppression for mild rejection, steroid pulses for moderate or severe rejection, and T cell depletion therapies for severe rejection.
GVHD occurs in 1–2 % of liver transplant recipients and is associated with an 85 % mortality rate. In the case of solid organ transplant, donor lymphocytes remaining in the parenchyma become detectable in the recipient weeks after transplant. These immunocompetent cells react against the different cellular antigens found in the host. A humoral response leading to hemolysis can also occur due to organ ABO incompatibility . GVHD is divided between acute (occurring within 100 days of transplant) and chronic (after 100 days) presentations. Risk factors associated with the development of GVHD include alcoholic liver disease, hepatocellular carcinoma, and diabetes mellitus. It has also been suggested that GVHD is more likely to occur in the setting of close HLA matching and autoimmune hepatitis. Symptoms usually develop 2–6 weeks posttransplant, and include fever, diarrhea, rash, and pancytopenia. Similar to treatment for acute rejection, treatment of GVHD includes administration of corticosteroids, increasing the current immunosuppressant regimen, or administration of medications for the antagonism of T cells. Mortality following the development of GVHD can be as high as 85 % . Prevention includes limiting recipient exposure to donor lymphocytes, such as graft irradiation or treatment with monoclonal antibodies, and limitation of blood products to those that have been leukocyte reduced and irradiated.
Aside from the medical complications discussed above, there are some posttransplant complications that occur secondary to surgical technique. Successful liver transplant services have close collaboration between the internists, surgeons, and intensivists. Complications that necessitate relisting the patient or urgent return to the operating room are discussed among the services and the risks and benefits are weighed carefully.
Primary nonfunction occurs in 4–8 % of deceased-donor liver transplants. Although uncommon, it is the most serious and life threatening condition in the immediate postoperative period and can be the most challenging for the transplant service. It is caused by reperfusion injury of the new liver, and results in irreversible graft failure. The diagnosis of primary nonfunction can only be made in the absence of technical or immunologic causes for graft dysfunction . The acute destruction of hepatocytes results in decreased bile production, coagulopathy, encephalopathy, hypoglycemia, lactic acidosis, and hemodynamic instability. Signs often are present intraoperatively, but correction of the metabolic disturbances will need to be aggressively continued in the intensive care unit. The risk factors for primary nonfunction are numerous, and include: prolonged cold ischemic time, increased donor age, donor hypernatremia, donor length of stay in the ICU, male recipients with female donors, reduced graft size, racial mismatch between donors, retransplantation, and hepatic steatosis [109–111].
The only treatment for primary nonfunction is early retransplantation, and primary nonfunction is the most common reason for early retransplantation . Without retransplantation, mortality is high. In addition to the complications from liver failure, cardiovascular, renal, and respiratory failure can often result from the release of vasoactive mediators from the nonfunctioning liver. Often times, removal of the failing graft can lead to a dramatic improvement in the patient’s clinical status. In the absence of an immediately available liver, a rescue hepatectomy with portocaval anastomosis can be performed with subsequent liver transplantation occurring 24–48 h following hepatectomy .