Liver transplantation can provide a cure for acute liver failure and many devastating types of end-stage liver diseases (ESLD). In the past, patients who suffered from liver diseases would die, as humans cannot survive without a liver. Thomas E. Starzl, MD, performed the first liver transplantation in 1963, on a 3-year-old boy who later died from uncontrolled bleeding secondary to coagulopathy from ESLD.1 Four other pioneer patients also died within 23 days due to ischemia-reperfusion injury and cellular rejection.2 In 1967, Starzl's first survivor lived for 18 months, quite an accomplishment since during the 1970s, 1-year survival rate after a liver transplant was 30%.3,4 Today, the 1-year survival rate is 80% to 82% and the 5-year survival rate is 60% to 68%.5,6 As orthotopic liver transplantation becomes a more standard approach of care, clinicians must be aware of postoperative care and complications of this procedure. This article describes an evidence-based approach to managing patients with complications after liver transplantation.
Liver transplant surgery has an average operative time of 9 hours with a postoperative stay in the ICU of about 3 days.7 A multidisciplinary care team, including surgeons, anesthesiologists, intensivists, physician assistants (PAs), nurses, and pharmacists, work in collaboration to provide needed postoperative care. Because the acute postoperative period is a critical time, close patient monitoring and care is important. The immediate postoperative period is when the most life-threatening complications can occur, thus the need for accurate and timely diagnosis is critical.
This article discusses the orthotopic approach, the most commonly performed method, and postoperative complications associated with liver transplantation. Specific surgical techniques are beyond the scope of this article. In orthotopic surgery, the diseased liver is removed and replaced with the donor liver via vessel anastomosis (Figures 1 and 2).
Transplanted livers fall into two basic types:
- Whole deceased liver. The deceased donor's entire liver is transplanted into the patient. Deceased donor livers can be further subdivided into donation after cardiac death or donation after brain death.8,9
- Living donor. Only a partial graft (left or right lobe) can be donated from a living person.
Complications can occur in patients no matter the source of the transplanted organ.
Doppler ultrasound screening lets clinicians evaluate the postoperative vascular anatomy and evaluate graft function and anastomoses for patency. This screening should be done within 24 hours of surgery to look for postoperative complications. Ultrasound is the diagnostic screening test of choice because it is cost effective, portable, rapid, and accurate.10
Resistive indices are measured on ultrasound to determine arterial blood flow to the liver. Normal findings are a rapid systolic upstroke and resistive index between 0.55 and 0.8.5,6 Although a slightly elevated resistance index may be noted in up to half of all patients, clinicians must differentiate between normal postoperative resistance or a catastrophic hepatic arterial thrombosis.
Frequently monitor the patient's postoperative laboratory values, which can give crucial evidence of graft function and overall patient status (Table 1). Using physical examination, ultrasound screening, and laboratory values, clinicians can detect many different types of postoperative complications.
Hepatic artery thrombosis
The most common and serious complication, hepatic artery thrombosis has an overall national incidence of about 4% in patients who have had a liver transplant.5 The biliary tree relies entirely on blood supply from the hepatic artery; therefore, thrombosis causes rapid necrosis of the transplanted liver.11,12 Necrosis can quickly lead to complete graft failure that mimics acute liver failure. Hepatic artery thrombosis has an overall mortality of 33%.5
On ultrasound screening as described earlier, suspect thrombosis if the patient has a resistive index less than 0.5, slowed systolic acceleration time (greater than 0.08 seconds), and no flow within the hepatic arteries.2,11
Treatment depends on the size and severity of the thrombosis and includes observation, revascularization, or retransplantation.5 Most patients will ultimately require retransplantation to prevent mortality. Due to the catastrophic effects of this diagnosis, the liver transplant surgeon must be notified immediately after the discovery is made and often the patient is immediately relisted for a new transplant.
Hepatic artery stenosis
The second most common vascular complication, hepatic artery stenosis presents in a slower, more indolent course, occurring even weeks postoperatively.12 On ultrasound screening, findings can mimic hepatic artery thrombosis. Treatment involves stenting the stenotic artery. Untreated stenosis can lead to hepatic artery thrombosis, graft dysfunction, and death.5,12
Portal vein thrombosis
The most common venous complication of liver transplantation, portal vein thrombosis has only a 2% incidence.6,10 Unlike hepatic artery thrombosis, portal vein thrombosis usually has an insidious onset and can be asymptomatic in some patients.6 The patient may have an anastomotic leak; variceal hemorrhage; graft dysfunction with abnormal liver values; and clinical signs of ascites, sepsis, or hemodynamic instability. Screening for portal vein thrombosis is done with ultrasound, which will reveal a thrombosis and lack of blood flow. Treatment involves fibrinolysis or surgery for direct thrombectomy.6,11,13
About 4% of patients develop postoperative bile leak after liver transplant; about 30% of patients who received living donor transplants develop this complication due to smaller graft size.10,13 Bile leaks, especially undetected ones, can lead to graft loss and death. Bile leaks can cause bilomas, an encapsulated collection of bile, which require surgical correction or interventional radiologic procedures with percutaneous drain placement.13 Patients with bile leaks or bilomas may appear septic with elevated serum bilirubin values and increased white blood cell counts. Diagnosis is made by ultrasound, which directly reveals the leak or biloma formation. Treatment in the early postoperative period is often done surgically to make a Roux-en-Y choledochojejunostomy or by stenting the biliary duct with endoscopic retrograde cholangiopancreatography (ERCP).14
Primary graft nonfunction
In this complication, the transplanted liver fails to function for no obvious reason in a patient with an uneventful and uncomplicated surgical course and no vascular abnormalities. Primary graft nonfunction often leads to patient death. Clinical manifestations are very similar to those seen in acute liver failure and severely critically ill patients. The symptoms can include coma, hemodynamic instability, acid-base imbalance, persistent hypothermia, severe coagulopathy with little to no intrinsic factors (sometimes requiring numerous corrective measures and often continuous transfusions), severe thrombocytopenia, complete renal dysfunction, hyperbilirubinemia, and markedly elevated liver transaminases.10,13 Prompt treatment is critical and most patients are immediately relisted for a new transplant.
Complications often occur after liver transplantation because of the patient's condition that required the transplant as well as the long and invasive surgery.
Assess the patient's neurologic status frequently in the acute postoperative period. Encephalopathy from previous acute liver failure can prolong a patient's return to baseline neurologic status.14 Immunosuppressive agents, essential for graft survival, often have neurologic adverse effects including altered mental status, seizure activity, encephalopathy, and posterior reversible encephalopathy syndrome. Very rarely, patients may develop cerebrovascular complications such as ischemic stroke or intracranial hemorrhage.15
If a patient has an abnormal neurologic examination, consider CT or MRI to look for intracranial pathology, such as infarct, hemorrhage, infection, or posterior reversible encephalopathy syndrome. An electroencephalogram (EEG) can be performed if an underlying seizure is highly suspected. Treatment of impaired neurologic status is directed toward the underlying cause and may require a neurologic consultation.
Postoperative pulmonary complications can be caused by several factors. Recipients may require ongoing support through mechanical ventilation. Medications such as rocuronium and midazolam are metabolized by the liver, and metabolism can be delayed until the transplanted liver is fully functioning.16 Patients also may need ventilator support if they have preexisting pulmonary hypertension or hepatopulmonary syndrome along with pulmonary edema, large pleural effusions (especially right-sided as this is common after liver transplantation), atelectasis, or hypoxia. With large volumes of fluids and blood products needed during surgery or for postoperative resuscitation, patients may develop ventilation-perfusion mismatch from shunting caused by fluid shifts and may need respiratory support. Other pulmonary complications include pneumothorax, diaphragm dysfunction, pulmonary embolus, and transfusion-related acute lung injury (TRALI).17-19
Infectious pulmonary complications may contribute to respiratory problems. Sputum change, leukocytosis, and fever should prompt an evaluation.19 Infectious causes are usually from pneumonia, often from Gram-negative bacilli, but occasionally from methicillin-resistant Staphylococcus aureus or cytomegalovirus (CMV) causing pneumonitis.18
With patients' predisposition to these pulmonary complication, reintubation may be required. Additional causes of respiratory failure include encephalopathy, surgical bleeding, hemodynamic instability, and acute respiratory distress syndrome (ARDS). Up to 80% of patients who develop ARDS after transplant die.18
Hemodynamic parameters are often difficult to manage postoperatively because many types of liver failure cause a hyperdynamic cardiac state and vasodilation.14 These physiologic disruptions can cause hemodynamic instability with high cardiac output and low systemic vascular resistance.13,14 Clinically, the patient will present with tachycardia and hypotension. The treatment is identical to hypovolemic shock and patients require aggressive IV fluid administration and may require vasopressors.20,21 Fluid resuscitation and hemodynamic stabilization are crucial to prevent cardiovascular collapse and end-organ damage.
Patients also may develop new-onset dysrhythmias, typically atrial fibrillation (AF).21 The treatment of AF depends on the patient's hemodynamic stability and is typically electrical or chemical cardioversion.
The patient's surgical scar should be examined postoperatively for sources of infection or bleeding. Closely monitor indwelling drains: sudden changes in fluid output volume, fluid consistency, and fluid appearance may reflect worsening clinical status, bleeding, infection, or bile leaks.10
Starting immediately after surgery, perform abdominal examinations frequently. This examination can change rather quickly, often due to surgical bleeding. A soft abdomen is reassuring, but a distended and tense abdomen can be signs of abdominal hypertension or compartment syndrome, which can lead to severe overall decreased organ perfusion and death.22-24 Nutrition, although of utmost importance for healing postoperatively, usually is addressed after patient is stable.
A functioning renal system produces adequate urine output and provides metabolic clearance. Renal dysfunction can be caused by a preexisting hepatorenal syndrome or a postoperative hemorrhage or hypovolemia that causes decreased renal perfusion and AKI.2,14 In patients whose liver graft function suddenly decreases, renal function often abruptly decreases as well, as in hepatorenal syndrome. AKI occurs in 40% to 70% of patients after liver transplant; 8% to 17% of these patients require renal replacement therapy.25 Consultation with a nephrologist may be needed if the patient needs hemodialysis or continuous renal replacement therapy. In patients with hemodynamic instability, continuous veno-venous hemodiafiltration often is used because fluid shifts are more gentle and patients are less likely to have abrupt hemodynamic fluctuations.10,25
After transplant, patients are at increased infection risk because of the immunosuppressants needed for graft vitality. Bacterial infections are most commonly caused by Gram-negative bacteria such as Enterococcus, Stenotrophomonas, Ochrobactrum, Acinetobacter, Enterobacteriaceae, and Pseudomonas. Patients also are at risk for infection with Gram-positive bacteria such as Staphylococci. Treatment begins with broad-spectrum antibiotics that are narrowed based on the bacterial susceptibilities. Up to 50% of Gram-negative bacteria can progress to multidrug-resistant variants, which increases risk of patient mortality and graft rejection.26
Immunosuppressed patients are at high risk of contracting Pneumocystis jiroveci pneumonia, formerly known as Pneumocystis carinii pneumonia, so all patients are offered prophylaxis with sulfamethoxazole and trimethoprim after liver transplant.13
Transplant patients also are at higher risk for postoperative fungal infections, specifically from Candida.27 Fungal prophylaxis with fluconazole or itraconazole is given but has not been shown to reduce all-cause mortality and is not a standard of care.28
Patients with active CMV are at increased risk of Candida infections.29 CMV is the most common viral infection seen in liver transplant patients in the acute postoperative period.30 True viremia is detected by a simple blood test using polymerase chain reaction. Prophylaxis is preferred over preemptive therapy by most transplant institutions.31 Valganciclovir has been shown to be extremely efficacious against CMV infection.13,31,32
The endocrine system often is disrupted by the high-dose immunosuppressant drugs used in the acute postoperative period. Patients can develop corticosteroid-induced hyperglycemia and may even progress to corticosteroid-induced diabetes.33 Glucose monitoring and treatment is crucial to prevent further complications. Treatment typically is intermittent injections of insulin using a sliding scale or continuous insulin infusion.
The hematologic system is a direct indicator of liver graft function. If the graft is not functioning properly, the patient may develop coagulopathy, thrombocytopenia, and platelet dysfunction.13 Transfusion may be indicated for patients who are hemodynamically unstable or hemorrhaging; however, be careful not to overcorrect and cause thrombosis at the anastomoses. Massive transfusion is appropriate and critical for life-sustaining support in patients with rapid hemorrhage and shock. Provide packed red blood cells, fresh frozen plasma, platelets, and cryoprecipitate if indicated. Notify the surgeon immediately, as patients may require emergency surgery.34,35
Immunosuppression is essential for graft vitality, function, and protection against cellular rejection. Patients typically are prescribed a specific combination of immunosuppressive medications. The most standard combination is a calcineurin inhibitor (most commonly tacrolimus, less often cyclosporine), an antimetabolite (most commonly mycophenolate, less commonly azathioprine), and a corticosteroid.10,21,36,37 These agents, specifically tacrolimus, mycophenolate, and corticosteroids, typically ensure the best possibility of graft survival.7,38
Tacrolimus is the most commonly used calcineurin inhibitor in patients after liver transplant due to its extremely powerful immunosuppressive effects.37 Compared with cyclosporine, tacrolimus has a much better graft survival rate (80% to 85% after 1 year) and fewer adverse reactions.37,38 However, overdose may occur at any dosage. Common adverse reactions include nephrotoxicity (oliguria, AKI) that can progress to full renal failure, and neurotoxicity (changes in mental status, simple tremors, seizures, coma, and posterior reversible encephalopathy syndrome).15,25 Uncontrolled hypertension and dysglycemias (hyperglycemia or hypoglycemia) also may occur.39
Cyclosporine, an older calcineurin inhibitor, often is used for immunosuppression if tacrolimus is contraindicated.21 This drug has a 1-year patient survival rate of 70% to 75%.21 Cyclosporine poses a significant risk of nephrotoxity, so monitoring patients for oliguria and AKI is extremely important.
Mycophenolate and azathioprine, drugs known as antimetabolites, interfere with DNA synthesis and cell cycle production.21 Mycophenolate is used more frequently than azathioprine due to more specificity against lymphocytes.21 The drug also acts as a purine inhibitor when metabolized in the liver.21 The most well-known adverse reaction to mycophenolate is bone marrow suppression. Closely monitor patients' complete blood cell counts.
Sirolimus can be used if the patient has contraindications to tacrolimus, cyclosporine, and other immunosuppressive agents. This drug is used less often because of its increased adverse reactions, including renal dysfunction, hepatic artery thrombosis, and liver graft dysfunction.21,36
IV methylprednisolone is started in high doses and tapered down to low-dose oral prednisone that is continued in the acute postoperative period. The most adverse reactions to corticosteroids are hyperglycemia and corticosteroid-induced diabetes.40
With immunosuppression comes increased risk of malignancy. Medications that prevent rejection can contribute to oncogenesis in transplant recipients. This is particularly a concern in liver transplant, as this is the only solid organ in which primary malignancy can be treated with transplantation and recurrence is possible.41
Skin, hematologic, and solid-organ are common de novo cancers after transplant. In a recent single-center study by Rademacher and colleagues, the incidence of malignancy was 16.5% after liver transplantation. The risk at 10 years was 12.9% and 23% at 25 years.42 In this study, solid-organ tumors were the most common, followed by skin cancer and hematologic malignancies. The researchers found that cyclosporine use was associated with a higher solid-organ tumor rate compared with tacrolimus (HR 1.53, P = .03). Additional risk factors included smoking (HR 1.92, P = .001) and increased recipient age (HR 1.03, P = .001). With this increased risk, clinicians must educate patients on the risk and provide appropriate screening recommendations for these malignancies.42
Liver transplantation offers a cure to life-threatening acute liver failure and ESLD. Liver transplantations are extremely complex vascular surgeries with multisystemic involvement and require a multidisciplinary team approach. Healthcare providers must be aware of the complications of this surgery and be able to recognize complications and intervene appropriately to reduce further complications, sustain graft vitality, and decrease patient morbidity and mortality.
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