Adult Liver Transplantation: Postoperative Critical Care Management

Introduction

• Liver transplant activity continues to increase globally, with now over 9,500 transplants performed annually in the United States.¹
• Patients requiring liver transplantation are often critically ill, requiring care in the intensive care unit (ICU) pre- and postoperatively; however, the median ICU length of stay (LOS) has decreased over time due to fast-tracking and evidence-based protocols, including utilization of a designated liver transplant anesthesia team intraoperatively.²
• Early liver recipient outcomes and survivability posttransplantation continue to improve globally, driven by the optimization of preoperative selection, intraoperative management, and postoperative care.³
• Postoperatively, renal dysfunction, respiratory complications, and altered mental status are the leading complications that contribute to increased ICU LOS.²
• The incidence of long-term morbidity and mortality following liver transplantation has been essentially unchanged, and longitudinal attention in recognizing longer-term complications such as metabolic syndrome, renal function, and malignancy may improve longitudinal outcomes of liver transplant recipients.³
• Please see the OA summary on anesthetic considerations for liver transplant. Link
• Please see the OA summary on surgical considerations for liver transplant. Link

Postoperative Hemodynamic Management and Goals^4,5

• In the patient requiring a liver transplant, systemic vasodilation and elevated cardiac output may persist or rapidly correct after transplantation, and additional factors can contribute to precipitous hemodynamic instability, such as third-spacing, blood loss, coagulopathy, infection, and reperfusion injury.
• Following a multidisciplinary handoff, the ICU team should rapidly assess and continuously monitor the patient’s cardiac, respiratory, neurologic, hepatic, and renal function through modalities such as invasive arterial blood pressure, electrocardiogram, central venous pressure, pulmonary artery and/or pulmonary wedge pressures as well as laboratory assessment (coagulation panel including viscoelastic hemostatic assays, blood counts, complete metabolic panels, arterial blood gas with lactate, immunosuppression levels, and cultures); point-of-care-ultrasound may also serve as a helpful modality in monitoring real-time hemodynamic status.
• To maintain adequate organ perfusion, mean arterial pressures are typically targeted to be above 70 mmHg. Careful fluid administration to optimize cardiac filling alongside vasoactive support may be utilized to facilitate this.
• Colloid solutions are generally preferred in liver transplant recipients to maintain oncotic pressure and intravascular volume while avoiding hypervolemia, which, in turn, can lead to pulmonary edema and right-sided heart failure; maintenance fluids are sometimes utilized to overcome the patient’s expanded extracellular fluid volume and increased vasomotor tone.
• Please see the OA summary on fluid responsiveness. Link
• Conversely, hypertension should be treated, avoiding hepatotoxic agents such as labetalol, hydralazine, or nifedipine.
• Oliguria can be expected within the first 24-48 hours posttransplantation, but it may also be a sign of renal dysfunction.

Immunosuppression and Infection Prevention^4,5

• Although varied by institution, the most common immunosuppressive regimens typically include a glucocorticoid, a calcineurin inhibitor, and an antimetabolite (such as mycophenolate, which is more commonly used in maintenance immunosuppression).
• Glucocorticoids have been the cornerstone in preventing acute rejection. Still, they are associated with deleterious side effects such as hypertension, fluid retention, hyperglycemia, adrenal suppression, electrolyte abnormalities, and gastric damage, so current investigations are examining reduced doses or even abstaining from corticosteroids in liver transplant recipients.
• Cyclosporine and tacrolimus are calcineurin inhibitors that have revolutionized transplant medicine, demonstrating decreased rejection and improved survivability, but may be nephrotoxic. With the administration of either of these agents, renal function and drug levels should be closely monitored. Sirolimus is frequently utilized as an alternative, as this agent is renal-sparing.
• Newer agents, such as daclizumab and basiliximab, are antibodies that inhibit IL-2 receptors and may be used to induce immunosuppression.
• Given the resulting immunocompromised state caused by immunosuppressive agents and surgical stress, liver transplant recipients are at a higher risk of infection from the donor liver, transfused blood products, previous infections in the recipient, and invasion by exogenous microorganisms or endogenous flora.
• Prophylactic antibiotics, which broadly target gram-positive cocci, gram-negative rods, and anaerobes, are recommended to be continued for 24-48 hours postoperatively.
• Cytomegalovirus (CMV) is the most common viral infection in liver transplant recipients, particularly when the donor is seropositive for the virus. In at-risk patients, ganciclovir or valganciclovir should be initiated.
• While more invasive opportunistic infections are rare in the first 48 hours following transplantation, antifungals should be considered if clinically indicated and are typically targeted towards Candida species, using agents such as fluconazole or amphotericin B.
• Delining should occur as early as feasible to avoid additional sites of infection.

Pain Control⁶

• Adequate analgesia control is paramount in accelerating recovery, improving morbidity and mortality, and reducing ICU LOS. Multimodal regimens that prioritize patient comfort over sedation should be emphasized to reduce surgical stress responses, minimize the need for prolonged mechanical ventilation, and promote early mobility.
• Postoperative pain in liver transplant recipients is typically not as severe as expected from a large abdominal incision due to a lack of nerve connections with the new donor liver, as well as increased plasma levels of endogenous opioid peptides, of which metenkephalin is significantly elevated in liver transplant recipients.
• Breakthrough pain should prompt evaluation for complications such as bleeding, infection, or ischemia.⁴
• Due to reduced hepatic blood flow, decreased enzymatic metabolism, and levels of plasma protein-bound drugs, analgesia provided in the immediate postoperative care period may be more potent, so long-acting opioids, if used, should be utilized with caution. Multiple pharmacodynamic and pharmacokinetic properties are altered in the critically ill postoperative liver recipient, so opioids are generally avoided postoperatively, especially morphine (due to prolonged respiratory depression) and meperidine (due to reduced seizure threshold).
• Immunosuppression (specifically cyclosporine and steroids) has also been shown to decrease inflammation levels and contribute to a slight analgesic effect.
• Acetaminophen in proper dosing (up to 1g per dose, 3 grams daily for adults) is well-tolerated postoperatively in liver transplant recipients, even those with poor graft recovery, and does not lead to sedating effects.
• Nonsteroidal anti-inflammatory agents should be avoided following liver transplantation as they have been shown to lead to liver cell damage, decreased platelet activity, increased gastric bleeding, and increased risk of renal dysfunction.
• If sedation is required, benzodiazepines should be avoided, and short-acting agents are recommended. Dexmedetomidine is generally well tolerated in the liver transplant recipient and has been shown to lead to reductions in narcotic requirements as well as in ICU and hospital LOS.^4,7
• Thoracic epidural analgesia may be considered preoperatively in patients with mild coagulopathy (INR < 1.4, aPTT <45 seconds, platelets > 70g/L, and a normal viscoelastic hemostatic assay) but should be managed postoperatively by an anesthetic expert as liver transplant recipients are more predisposed to significant complications; epidural placement immediately postoperatively is not recommended for establishing analgesia.

Nutrition and Glucose Management⁵

• In the immediate postoperative period, liver transplant recipients are at an increased risk of aspiration. They should remain nil per os with a nasogastric or orogastric tube until gastrointestinal mobility returns. Early introduction of enteral feeds should be preferred as malnutrition is associated with increased ICU LOS, morbidity, and mortality.
• As found in patients with end-stage liver disease, protein restriction can be dangerous in the liver transplant recipient and should be avoided.
• Critically ill patients, let alone transplant recipients, are frequently depleted of vitamins and micronutrients, which should be repleted; dietitian input is invaluable in the nutritional needs of these patients.
• Although enteral nutrition is preferred, total parenteral nutrition should be considered if gastrointestinal function is not restored within seven days.
• Hyperglycemia is a common postoperative finding due to surgical stress, corticosteroid use, and infection. To prevent graft rejection, surgical site infection, and mortality, insulin should be utilized to maintain blood glucose levels below 180 mg/dL.

Complications^5,8

• The list of both immediate and long-term complications is myriad and is further compounded by patient demographics, baseline liver disease, and advances in organ preservation such as normothermic abdominal organ perfusion and ex situ organ machine perfusion; the following is a list focused on the immediate and early complications observable in the intensive care unit.
• Markers of liver synthesis, such as the international normalized ratio (INR) and liver enzymes, should be monitored to detect complications directly related to transplanted liver dysfunction. Additionally, chemistries and blood counts should be closely monitored.

Early Allograft Dysfunction (EAD)

• The most severe form of EAD is primary nonfunction (PNF); PNF is a nonsurvivable complication, and early identification is imperative in allowing time for retransplantation.
• Secondary causes of graft dysfunction, such as thrombotic and nonthrombotic infarction, rejection, and cardiac etiology, must be ruled out; liver ultrasounds should be repeated to evaluate for any vascular source.
• Symptoms and laboratory findings include worsening hepatic encephalopathy, hemodynamic instability, hypoglycemia, renal failure, lactic acidosis, and coagulopathy.
• Plasma exchange can help maintain stability until retransplantation.
• Please see the OA summary on early allograft dysfunction for more details. Link

Small for Size Syndrome⁹

• Also known as small for flow syndrome, this condition occurs when portal flow is greater than 250 ml/min/100g or portal pressure exceeds 20 mmHg, which is more likely to occur with a living donor or split liver, as well as following extensive hepatectomy.
• Treatment is surgical through modulating portal flow by sacrificing the spleen with splenic artery ligation or embolization.

Rejection

• Rejection is classified into acute (within an hour), hyperacute (within the first 6 weeks), or chronic (greater than 6 weeks), with acute rejection being the rarest occurrence.
• Rejection may be T-cell-mediated or antibody-mediated, and diagnosis is confirmed through biopsy analysis.
• Empiric steroid boluses should be avoided; however, high-dose steroids can be considered in moderate to severe histology. Antithymocyte globulin, intravenous immunoglobulin, plasma exchange, or B-cell-depleting therapies may also be considered. Ultimately, rejection may require retransplantation.

Postreperfusion Syndrome

• Appearing as a distributive shock, postreperfusion syndrome typically peaks during intraoperative reperfusion but can linger in the ICU setting secondary to a significant inflammatory response.
• Treatment for postreperfusion syndrome is generally supportive with vasoactive agents; however, other etiologies of shock should be considered, especially given the comorbid nature of cirrhosis.

Pulmonary Complications¹⁰

• Generally, early extubation should be targeted to minimize the risk of ventilator-associated complications. Spontaneous ventilation at the conclusion of a liver transplantation is associated with improved early graft blood flow.
• Liver transplant patients may be at high risk for transfusion-related acute lung injury if they have received blood products, especially plasma.
• Special considerations should be taken for portopulmonary syndrome or portopulmonary hypertension (PPH), as these patients may experience hypoxia at baseline and may benefit from Trendelenburg positioning, nitric oxide therapy, and decreased positive pressure during ventilation. Patients with PPH may benefit from advanced hemodynamic monitoring such as a pulmonary arterial catheter.
• Please refer to the OA summaries on portopulmonary hypertension (Link) and hepatopulmonary syndrome (Link) for more detailed information.
• Extracorporeal membrane oxygenation should be considered in the event of failure of medical management.

Hepatic Artery Thrombosis (HAT)

• HAT is the most common vascular complication after liver transplantation, with an incidence as high as 9%. Risk factors include prolonged cold ischemia time, high blood transfusion, and low-volume centers.
• Aspirin is used as a prophylactic measure for HAT; thrombolysis or thrombectomy via an endovascular approach is the mainstay of treatment.
• Hepatic artery stenosis can present similarly to HAT.

Hepatic Artery Pseudoaneurysm (HAP)

• HAP is a rare but life-threatening complication that should be considered in patients with known fungal infection or pancreatitis and can be diagnosed and treated through angiography and stent placement.

Portal Vein Complications

• Portal vein stenosis or thrombosis are two complications that may disrupt venous outflow obstruction; care should be taken to correct hypercoagulable states, as this may also require surgical management.

Infection¹¹

• Given the immunosuppression that is needed to prevent rejection, patients who have received a liver transplant are at high risk for opportunistic infections, especially within the first 6 months of transplantation.
• In addition to more commonplace microbes, CMV, exhaled breath condensate, pneumocystis, and fungal infections should be considered in postliver transplant patients.

Neurological Complications¹²

• Neurological complications of liver transplantation include, but are not limited to, seizures, central pontine myelinolysis, worsening hepatic encephalopathy, cerebral vascular events, and central nervous system infections; these complications can occur at any perioperative time point and may also be a sequela of immunosuppressive agents.
• Neurological manifestations of underlying liver diseases should also be considered, such as Wilson’s disease.