Critical Care Aspects of Liver Transplantation
Related Conditions
Rejection
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Allograft dysfunction
Anatomic complications
Infection
1. Description of the problem
What every clinician needs to know
This chapter covers four conditions: rejection, allograft dysfunction, anatomic complications and infection. Clinical features of these conditions overlap, rendering diagnosis challenging. High index of suspicion, monitoring of liver enzymes and coagulopathy, ultrasound, biopsy and close collaboration with a transplant surgeon and/or hepatologist are essential.
Clinical features
Rejection
Clinical features of rejection overlap with ischemia/reperfusion injury, obstruction, and other complications, and thus other conditions should be investigated and biopsy is required for diagnosis. A transplant surgeon or hepatologist should decide if biopsy is required.
Allograft dysfunction
Primary nonfunction presents as early graft failure with profound coagulopathy, liver enzyme elevation, and cholestasis. Ischemia/reperfusion/preservation injury and SFSS generally present with a less severe, but similar, clinical picture.
Anatomic complications
Vascular
Postoperative bleeding can be separated into medical and surgical bleeding. Medical bleeding is characterized by bleeding due to coagulopathy that can be treated without operative or invasive radiologic intervention. On ICU admission, the intensivist should inquire about intraoperative transfusion requirements, last hemoglobin, potential expected anatomic problems, and hemostasis at end operation.
The intensivist should also ask the surgeon if concern for vessel thrombosis would preclude aggressive coagulopathy correction. Serial hemoglobin checks, hemodynamic monitoring, and surgical drain output should be carefully monitored. Coagulopathy can be monitored using serial thromboelastography, or serial measurement of platelets, INR/PTT, and fibrinogen. If significant bleeding exists despite aggressive coagulopathy correction with restoration of normothermia and blood products (platelets, plasma, cryoprecipitate), then surgical bleeding is likely and the surgeon should be promptly notified. Determination of operative exploration, angiographic investigation and potential treatment, or observation is the surgeon’s decision.
Hepatic artery and portal vein thrombosis and stricture are key concerns. The hepatic artery supplies blood to the biliary system; consequently, hepatic artery complications can lead to biliary tree ischemia, with subsequent biliary leak, infection, and/or stricture. Thus, biliary complications mandate investigation of the hepatic artery. Hepatic artery thrombosis and stricture left untreated can lead to graft loss and death. Portal vein thrombosis and stricture are generally less severe than hepatic artery complications, but can lead to graft dysfunction and portal hypertension.
Biliary
Biliary complications are a major problem after liver transplant, with an overall incidence of about 15-20%. Complications range from anastomotic leak to stricture and obstructions. Upon arrival to the ICU, the intensivist should ask what type of anastomosis was performed, duct to duct or choledochojejunostomy. The most common biliary complication is stenosis, which is the result of either poor technique or ischemia. Recurrent cholangitis or abnormal liver function tests may indicate an obstruction to outflow. Often ERCP with balloon dilatation and stenting are successful; if no response, operative revision is the treatment.
Biliary leak is a feared complication, as bile peritonitis can be very painful to patients and can also cause problems with the arterial anastomosis. In a duct-to-duct anastomosis the most common site of leakage is at the T-tube exit site; it is usually self-containing, and no treatment is necessary. Some surgeons do not use T-tubes to avoid this complication. ERCP with stent placement can also be used to control a bile leak. If conservative measures are unsuccessful, operative repair is necessary. A potentially lethal complication of a choledochojejunostomy leak is mycotic rupture of the hepatic artery anastomosis.
Infection
Typical signs and symptoms of infection can be blunted in immunocompromised patients, but the general principles of infection management in the ICU still apply. The main difference is that infection in a liver transplant patient can present very subtly, and thus a high index of suspicion is necessary. Until proven otherwise, any change in mental status, vital sign, or liver enzymes should be considered infection until proven otherwise.
Differentiation between these four related conditions is important and difficult due to overlapping presentations. Early suspicion, diagnosis and treatment are key. Daily liver enzyme monitoring, liberal use of US, and early investigation of abnormalities are recommended. Supportive care until enhanced immunosuppression, retransplantation, SFSS liver regeneration, anatomic correction and sepsis care are completed is essential. As immunosuppressed patients often do not mount a febrile or leukocytosis response to infection, more liberal use of cultures and antibiotics is justified than in typical ICU patients. Consultation with an infectious disease physician experienced with transplant patients can be helpful in difficult cases.
2. Emergency Management
Rejection
Liver rejection can be acute or chronic; acute is more common. Acute liver rejection generally occurs in the first few weeks to months post-transplant. Chronic rejection generally presents as progressive graft deterioration.
Acute rejection can nonspecifically manifest as fever, tachycardia, altered mental status, right upper quadrant and flank tenderness or pain, hepatomegaly and increased ascites. Increased liver enzymes, international normalized ratio (INR) and lactate values usually precede symptoms.
Chronic rejection patients will generally present to the ICU with complications similar to cirrhosis patients (e.g. sepsis, encephalopathy) as well as immunosuppression side effects (e.g. neuro- and nephrotoxicity).
Clinical features of rejection overlap with ischemia/reperfusion injury, obstruction and other complications, and thus other conditions should be investigated and biopsy is required for diagnosis. A transplant surgeon or hepatologist should decide if biopsy is required.
Allograft dysfunction
Primary nonfunction is a devastating complication that presents in the early postoperative period and is characterized by early graft failure despite absence of anatomic or rejection complications. Patients rapidly become ill and often need retransplantation. Ischemia/reperfusion and preservation injury is believed to be the main mechanism. Less severe ischemia/reperfusion and preservation injury can be managed expectantly.
Small for size syndrome (SFSS) presents as postoperative liver dysfunction due to insufficient functional liver mass and is most seen with split liver grafts, such as with living donor transplants.
Anatomic complications
Liver transplant requires anastomosis of the donor and recipient hepatic artery, portal vein, and extrahepatic bile duct. Complications can be separated into two major categories – vascular and biliary. Vascular complications include postoperative bleeding, vessel thrombosis, and vessel stricture. Biliary complications include bile leak and biliary stricture.
Infection
Signs and symptoms of infection can overlap with those for rejection, immunosuppression can blunt traditional infection signs, infection alone can increase liver enzymes, and anatomic complications can lead to biliary infection, thus rendering diagnosis and management of infection challenging. Aside from the usual lower threshold for suspecting and empirically treating infection in all immunocompromised patients, as well as consideration of rare infections, the main additional concern in liver transplant patients is biliary sepsis. Consultation with an infectious diseases specialist with familiarity with transplants can be helpful.
Allograft dysfunction
Aggressive supportive care (e.g. correction of coagulopathy associated with bleeding, dialysis for renal failure and acidosis) for severe primary nonfunction may be necessary. Patients with primary nonfunction usually need to be retransplanted.
Anatomic complications
Aggressive supportive care (e.g. correction of coagulopathy associated with bleeding, dialysis for renal failure and acidosis) for severe primary nonfunction may be necessary.
Infection
General principles of infection and sepsis management apply, but given the narrower margin of error in immunocompromised patients, particular attention to detail is warranted. Early lactate measurement can help risk-stratify patients with “normal” blood pressure, early culture collection from every potential source (including ascites) is useful, and early empiric antibiotics are typically necessary in this infection-prone population.
3. Diagnosis
Rejection
Rejection does not usually require emergent management; however, early diagnosis is essential so appropriate rejection therapy can be started.
Allograft dysfunction
Severe liver dysfunction in the absence of rejection or anatomic complications strongly suggests primary nonfunction. Milder dysfunction suggests reperfusion/ischemia/preservation injury, or SFSS if the graft is known to be small.
Anatomic complications
Doppler US is the initial screening test of choice as it is noninvasive with good sensitivity. However, for definitive diagnosis of vessel thrombosis or stricture, invasive angiography or computed tomography angiography is often needed, and for biliary complications, endoscopic retrograde cholangiopancreatography (ERCP) is often necessary.
Infection
Traditional diagnostic methods and criteria still apply but are less sensitive in this population. Unique considerations are ascites infection, biliary infection and donor-transmitted infection.
Often in the early days after liver transplant, rejection, allograft dysfunction, and anatomic complications can be difficult to distinguish from one another. The laboratory derangements and clinical picture can overlap. When the LFT values start to increase or plateau and do not continue to decrease, the first step is often an abdominal US with Dopplers to assess the liver vessels. This is the easiest test to obtain and is noninvasive. If this is abnormal or inconclusive and a biliary complication is suspected, a magnetic resonance cholangiopancreatograph (MRCP) can be obtained next, with a cholangiography (either via T-tube if present, or percutaneous transhepatic) if the MRCP is abnormal but inconclusive. If a vascular complication is suspected, CT angiography or conventional angiography would be the next diagnostic test.
With the availability of advanced scanners, MRI, MRA, MRV, and MRCP increasingly are used to better define the postoperative biliary tree and to evaluate hepatic vascular anatomy and patency. Many complications can be temporized or corrected by using interventional radiologic techniques. Some can be treated using ERCP. With a combination of these tools, many patients can be spared the morbidity and potential mortality associated with repeat operation or retransplantation.
Rejection
Rejection should always be considered with most complications. Often the LFT values either plateau or begin to increase. A positive cross-match to the donor is supportive of this diagnosis as well. An ultrasound can be obtained first as it is noninvasive, but the gold standard is a liver biopsy.
Allograft dysfunction
In primary nonfunction, there are severe metabolic derangements and LFT values do not decrease. The lactate level also rises, and mental status changes or failure to wake up after surgery occur since the liver is unable to metabolize anesthetics.
In ischemia/reperfusion injury, the patient may exhibit encephalopathy and other organ dysfunction (usually renal) and LFT values that stay elevated. A US to rule out vascular compromise can be done; findings of ischemia/reperfusion injury on US could include loss of diastolic flow and congestion.
Anatomic complications
Often the laboratory abnormalities associated with an arterial stenosis or thrombosis are increasing levels of hepatocellular enzymes ALT and AST. An increase in the bilirubin and gGTP values suggests a biliary tree complication. An abdominal US with Dopplers should be the initial diagnostic test.
Infection
Fever and an elevated white blood cell count may not be present due to immunosuppression. A high degree of suspicion and often empiric cultures and antibiotics are necessary.
As noted in the previous section, the major complications can overlap in presentation.
4. Specific Treatment
Rejection
Biopsy is necessary to confirm diagnosis, using consensus pathology criteria.
Differential diagnosis is broad and includes any condition that could adversely affect the transplanted liver, including primary allograft dysfunction, anatomic complications and infection, as discussed separately.
Allograft dysfunction
Severe primary nonfunction requires retransplantation. Equivocal data exist for prostaglandin infusions. Expectant management and supportive care can be used for less severe forms of reperfusion/ischemia/preservation injury, as well as for SFSS.
Anatomic complications
Vessel stricture and thrombosis are sometimes amenable to angiographic treatment but operative repair is usually necessary. Similarly, biliary strictures are sometimes amenable to ERCP with stenting but operative repair is often necessary. For refractory cases, retransplantation is the last resort.
Infection
As with any immunocompromised patient, empiric antibiotics should be administered based on past antibiotic use, local antibiograms and suspected primary source. As a general principle, broad-spectrum antibiotics (e.g. vancomycin + piperacillin/tazobactam) should be given first, with narrowing of the spectrum once cultures are available. This is often difficult to do in “culture-negative” sepsis; in such cases, a short course (e.g. 7 days) can be considered.
For refractory cases, consult transplant ID, consider CT scan of chest and abdomen, consider fungal or viral infection if only bacterial coverage given.
5. Disease monitoring, follow-up and disposition
Rejection
One or two courses of high-dose corticosteroids will effectively treat most cases of acute rejection. A poor-quality biopsy specimen and presence of other conditions that can harm graft function should trigger consideration of alternative diagnoses. Follow-up in a transplant center is mandatory.
Rejection
Increased immunosuppressive therapy is the initial therapy for acute rejection. It should be directed by a transplant surgeon or hepatologist, and varies by transplant center. Intensivists need to be familiar with immunosuppression side effects. High-dose corticosteroids are generally the first-line therapy and carry the expected side effects of increased infection susceptibility, GI bleed, hyperglycemia and altered mental status.
Hepatitis C patients require different and/or lesser therapy as corticosteroids can accelerate hepatitis C progression and death. OKT3, thymoglobulin, and other drugs can be used in steroid-refractory cases, with retransplantation as the last resort. Chronic rejection often requires retransplantation.
Allograft dysfunction
Severe primary nonfunction requires retransplantation. Patients with less severe dysfunction may recover with time; however, patients are more susceptible to multi-organ dysfunction and sepsis complications and are often cholestatic for prolonged periods of time. Overall prognosis is dependent on many variables, including donor age and quality of organ, degree of reperfusion injury, recipient age and other organ dysfunction. Close monitoring and support for other organ dysfunction is necessary. In some cases where the patient has failure to thrive due to continued allograft dysfunction, retransplantation is necessary.
Anatomic complications
Prognosis depends on the severity of allograft damage resulting from the vascular or biliary complication, and the reversibility of the complication.
Infection
With proper resuscitation, antibiotics and source control, most acute infection episodes can be successfully treated, with the exception of multi-drug-resistant organisms. The difficulty is keeping these patients infection-free after resolution of the acute episode.
Biopsy quality is key. An inadequate sample may yield false-negative results for rejection. US also has false negatives, and invasive testing such as angiography and ERCP may be necessary to confirm the diagnosis of anatomic complications. Severe sepsis and septic shock have up to a 50% culture-negative rate, but a poor response to adequate empiric antibiotics and negative results despite comprehensive microbiologic testing suggest infection may not be primary pathology.
Follow-up in a transplant center is mandatory for all critically ill liver transplant patients who recover and leave the ICU.
Pathophysiology
Rejection
Mechanisms of rejection are complex but include mismatched human leukocyte antigen and T-cell native immunity.
Allograft dysfunction
Reperfusion/ischemia/preservation injury is the believed primary mechanism for primary nonfunction, although certain donor conditions (e.g. persistent hypernatremia prior to harvest, high percentage of steatosis) lead to an increased incidence of primary nonfunction. SFSS is due to inadequate functional liver mass.
Anatomic complications
Complete thrombosis of the hepatic artery (HAT) is usually a dramatic complication that can lead to acute massive necrosis, formation of central bilomas secondary to intrahepatic duct necrosis, multiple biliary strictures or intermittent bacteremia. Factors that determine whether a liver can survive in HAT are not known, but the presence of collateral circulation is usually associated with a more benign course.
Portal vein stenosis or thrombosis (characterized by rapid graft dysfunction with massive ascites) can be from technical errors, steal syndrome, or anastomotic stricture or twist. The rapid dysfunction is due to ischemia of the graft. Biliary strictures are either technical in nature or due to ischemia, either from manipulation during the donor or recipient surgery or arterial (primarily the right hepatic artery) compromise (the primary source of blood flow to the biliary system).
Infection
Immunosuppression renders these patients more prone to infection, as do invasive lines, intubation and lengthy operative time.
Epidemiology
Rejection
Acute rejection occurs in approximately 20% of liver transplants; it mostly occurs in the first month.
Allograft dysfunction
Primary nonfunction occurs in approximately 4-10% of cadaveric liver transplants. The incidence of milder forms of dysfunction may be increasing due to use of extended-criteria (marginal) organs. SFSS occurs most frequently with low graft-to-recipient weight ratios.
Anatomic complications
Vascular complications occur in approximately 10% of adult liver transplant patients, and biliary complications in approximately 15-20%.
Infection
Even with proper prophylaxis, almost all liver transplant patients will at some point develop infection. The type of infection varies with time from surgery.
Prognosis
Rejection
Prognosis is good for most episodes of acute rejection, as most respond to corticosteroids with no long-term sequelae. Prognosis is poor for chronic rejection without retransplantation.
Allograft dysfunction
Severe primary nonfunction carries a very poor prognosis without retransplantation. Prognosis for less severe allograft dysfunction depends on the degree of liver insufficiency. Meticulous critical care provides the opportunity for the allograft to recover/regenerate.
Anatomic complications
Prognosis depends on the severity of allograft damage resulting from the vascular or biliary complication and the reversibility of the complication.
Infection
Overall prognosis varies with the severity of infection (i.e. uncomplicated infection to septic shock). With proper resuscitation, antibiotics and source control, most acute infection episodes can be successfully treated, with the exception of multi-drug-resistant organisms. The difficulty is keeping these patients infection-free after resolution of the acute episode.
What's the evidence?
Caiado, A. “Complications of liver transplantation: multimodality imaging approach”. RadioGraphics. vol. 27. 2007. pp. 1401-17..
Eghtesad, B, Kadry, Z, Fung, J. “Technical considerations in liver transplantation: What a hepatologist needs to know (and every surgeon should practice)”. Liver Transplantation. vol. 11. 2005. pp. 861-71.
Kemmer, N, Secic, M, Zacharias, V, Kaiser, T, Neff, GW. “Long-term analysis of primary nonfunction in liver transplant recipients”. Transplant Proc. vol. 39. 2007. pp. 1477-80. (Analysis of 58,576 cadaveric liver transplants from 1990-2004)
Tucker, ON, Heaton, N. “The 'small for size' liver syndrome”. Curr Opin Crit Care. vol. 11. 2005. pp. 150-5. (Good review written from a critical care perspective.)
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