Postoperative Management Beyond the Intensive Care Unit: Adults

Monitoring Graft Function

After transplant, graft function can be assessed in two ways, by clinical evaluation and laboratory monitoring. In the former, a well-functioning graft will process ammonia and other neurotoxins contributing to an altered state. Thus portosystemic encephalopathy, when present before transplantation, is reversed. Ammonia levels are not routinely checked post transplantation; instead, a daily assessment of mental status suffices. Patients with grade 4 encephalopathy (e.g., patients with fulminant hepatitis) may necessitate additional time to recover full neurological function because cerebral edema requires time to resolve.

With intact neurological function, patients can be weaned off the ventilator and extubated rapidly. Patients with portopulmonary hypertension and hepatopulmonary syndrome may require prolonged mechanical ventilation until fluid balance and oxygenation, respectively, improve. Weaning patients with hepatopulmonary syndrome completely off oxygen may take several weeks to months. Chapter 39 discusses portopulmonary hypertension and hepatopulmonary syndrome extensively.

Patients with hepatorenal syndrome or acute kidney injury will see an improvement in renal function in the presence of a well-functioning hepatic graft. As portal hypertension is reversed, the afferent arterioles of the glomerulus no longer vasoconstrict, allowing for improved renal blood flow and filtration. However, ascites or significant peripheral edema should not be expected to improve immediately. This may take days to weeks for complete resolution. Other risks of portal hypertension, such as bleeding gastroesophageal varices, should be eliminated as well.

From a laboratory perspective, graft function can be monitored by routine evaluation of liver function test results. Synthetic function is best gauged by a normalizing prothrombin time. Levels of the aminotransferases , aspartate aminotransferase (AST) and alanine aminotransferase (ALT), should peak within the first 24 to 48 hours after transplant, followed by a constant descent. This pattern is characteristic of preservation injury, which is the damage sustained by a graft during periods of cold and warm ischemia (discussed in Chapter 44 ). The degree of preservation injury affects the postoperative course and correlates with decreased graft and patient survival ( Fig. 71-1 ). A sudden and steep rise in AST and ALT levels suggests parenchymal injury and requires prompt initial assessment for vascular patency with Doppler ultrasonography.

The secretory function of the hepatic allograft is assessed by total bilirubin, alkaline phosphatase (AP), and γ-glutamyl transpeptidase (GGT) levels. Normally these canalicular enzymes follow a pattern of being “normal” for the first few (1 to 5) days after transplant, with subsequent elevations to a peak at day 7 to 14. This is thought to be secondary to reperfusion injury, in which biliary epithelial cells are damaged and slough, followed by a period of reparation. Elevations in AP and GGT levels with a secondary increase in AST and ALT may signify a graft rejection in which a liver biopsy classically shows bile duct epithelial injury and a mixed cellular portal infiltrate. Thus absence of canalicular enzyme elevation makes rejection unlikely. A progressive increase in total bilirubin level accompanied by elevations in AST, ALT, AP, and GGT suggests a biliary complication, such as a bile duct obstruction or leak.

Another indirect marker of hepatic function is the platelet count. Thrombocytopenia frequently accompanies cirrhosis because of splenic sequestration. With portal hypertension reversed, platelets are no longer trapped, resulting in an increase in circulating functional platelets. However, during the first postoperative week, platelets are consumed in the surgical wound, which may delay a rising platelet count. On occasion, a temporary rebound thrombocytosis is seen and treated with the addition of aspirin and/or hydroxyurea to reduce increased viscosity and the risk for clotting, leading to hepatic arterial complications.

The Wall Chart

What most transplant centers refer to as the wall chart was first developed by Thomas Starzl at the University of Colorado in Denver. Also known as a flowchart or flow sheet, the wall chart is a template on which essential information about a patient’s transplant, including donor and intraoperative and postoperative data, is written. The wall chart includes results from laboratory tests, microbial cultures, biopsies, and radiological examinations, among other information that can be tracked ( Fig. 71-2 ). Medications, including immunosuppressive agents along with their levels, are documented daily.

Although electronic health record software is becoming more sophisticated with the ability to reproduce test results and vital statistics chronologically, the wall chart allows any reviewing physician to swiftly become familiar with a patient’s clinical course and move forward with a treatment plan. Some centers are moving toward an electronic wall chart, which has the advantage of being viewed remotely. However, given the risk for information technology power failures, a securely stored tangible record has no equivalent.

Once the patient is discharged from the hospital, the wall chart follows the patient to the clinic setting, where it is constantly updated. After discharge from the clinic setting, outpatient laboratory test results and clinical updates are documented on the wall chart. Over a graft’s life span, a patient may accumulate multiple wall charts. From a historical perspective, reviewing a wall chart on a transplant recipient from 15, 20, or 25 years ago allows one to see the transformations that have unfolded over the years, from changes in immunosuppressive dosing and regimens to the drastic decreases in hospital stay after transplant.

Maintenance Immunosuppression

Thwarting the rejection response begins at the time of transplantation and may include the use of an induction agent. Following transplantation, drug levels are monitored and tailored to each patient: younger and healthier recipients may require a more aggressive immunosuppressive approach, whereas older and sicker recipients need a reduced immunosuppressive load. Specific therapies and side effects are discussed in depth in Chapter 91 .

Today’s standard immunosuppressive regimen includes a calcineurin inhibitor (CNI). Tacrolimus and cyclosporine levels are checked daily on immediate posttransplant recipients and tailored to a level generally between 8 to 12 ng/mL and 150 to 200 ng/mL, respectively. Dose adjustments are made when common side effects such as renal dysfunction and neurotoxicity are encountered. Six to eight weeks post transplantation, lower levels of the CNI are targeted. Although altered mental status immediately after transplantation may be attributed to the CNI or steroids, the most common cause of an altered state is sleep deprivation.

Sirolimus has been used increasingly at our center, as de novo therapy in recipients with malignancy and as conversion therapy in patients with renal dysfunction or in patients unable to tolerate the CNI. Sirolimus is initially dosed at 2 mg daily, and, due to its prolonged half-life of 2½ days, frequent trough level monitoring is not practical. Levels are initially checked weekly (during the inpatient stay) to a target level of 6 to 8 ng/mL, then checked monthly as an outpatient. Immediate side effects of sirolimus are uncommon. In the outpatient setting, however, laboratory abnormalities such as leukopenia, anemia, and hyperlipidemia are encountered. Clinically, oral ulcers, shortness of breath due to an atypical pneumonitis, and poor incisional wound healing may require conversion off sirolimus.

A complementary agent, mycophenolate mofetil (MMF), can be taken as CellCept or in its active form, Myfortic (enteric-coated mycophenolic acid [MPA]). Levels are not checked at our center. Pharmacokinetic studies have shown that MPA has twice the bioavailability when given intravenously than orally. Thus we have been trialing intravenous MMF as de novo immunosuppression with a delayed introduction of CNI. The most common of all side effects of MMF is gastrointestinal (GI) in nature and includes abdominal cramping, dyspepsia, diarrhea, and anorexia. These symptoms may ultimately lead to a full GI work-up, which usually has negative results. Dose splitting, dose reduction, or complete elimination of the agent usually resolves the symptoms. MPA is preferred by many centers because of its improved GI tolerability. In patients who do not tolerate either MMF or MPA, azathioprine can be used with excellent results.

The use of corticosteroids as maintenance therapy has diminished across transplant centers worldwide. Currently steroids are tapered off within 2 months on all our recipients except for those with autoimmune disease (i.e., primary sclerosing cholangitis [PSC], primary biliary cirrhosis [PBC], autoimmune hepatitis [AIH]), who stay on prednisolone at 5 mg daily for life to minimize the risk for disease recurrence. The role of steroids in the treatment of graft rejection remains first-line therapy. The long-term side effects of corticosteroids are well known and are summarized in detail in Chapter 97 .

Infection Prophylaxis

The Achilles’ heel of transplantation is infection. This holds particularly true in liver transplant recipients, whose number one cause of mortality at 1 year is sepsis or an infection-related source. To start, patients with cirrhosis are immunocompromised, and their risk for infection may be compounded by ongoing renal failure, malnutrition, preexisting medical conditions, and prolonged hospitalizations. As part of the reticuloendothelial system, an ailing liver no longer has the full capacity to fight off infection. Thus the classic signs of infection (fever, tachycardia, leukocytosis) may not be apparent in transplant candidates but should be aggressively addressed.

After transplantation the risk for infection remains and is principally due to the effects of immunosuppression. Collectively, upwards of 75% of all liver transplant recipients experience infection, with bacteria being the most common pathogen. Interestingly, bacteremia due to gram-negative organisms has become more prominent over the past decade, replacing gram-positive organisms as the more universal cause of early blood-borne infections after liver transplantation. This has resulted in an increasing number of multidrug-resistant gram-negative pathogens and limited options for treatment. For these reasons, an aggressive approach is taken when there is a high index of suspicion for infection. Chapter 78 addresses infections in liver transplantation in detailed fashion.

Successful management of infection starts with prophylaxis. For bacterial coverage, we use cefuroxime, a second-generation cephalosporin with broad gram-positive and good gram-negative coverage, postoperatively for 48 hours on low-risk patients. For patients who are at high risk for postoperative infection (e.g., intubated, on renal replacement therapy, recovered from recent infection, high Model for End-Stage Liver Disease [MELD] score), broader antibiotic coverage (meropenem and vancomycin) is used until the patient has stabilized.

Antifungal prophylaxis has been shown to reduce the rate of fungal infections following transplant. Our prophylactic agent of choice is low-dose amphotericin B, a fungicide, given intravenously for 10 days or until the day of discharge. However, for select high-risk recipients (bedded in the intensive care unit, treated infection within 1 month), liposomal amphotericin B (AmBisome) is used instead. Other centers may use fluconazole, a fungistatic agent, for prophylaxis. Because of competing mechanisms of action, caution must be taken when stopping fluconazole in the presence of a CNI.

Viral infections, namely cytomegalovirus (CMV), are a true cause of morbidity. One of the major advancements in the field of transplantation was the approval of ganciclovir in 1992 in the prevention of CMV infection. Although the incidence of CMV has declined since then, it remains the most common opportunistic infection after transplantation. Additionally, CMV causes a modulation of the immune system contributing to other complications such as allograft injury, superimposed infections, acute rejection, chronic rejection, and development of posttransplantation lymphoproliferative disease.

Antiviral therapy is a mainstay in the postoperative care of the liver transplant recipient. However, there is no universal approach to CMV prophylaxis. Some centers employ a prophylactic approach, in which all patients receive prophylaxis for a fixed period of time. Others use preemptive therapy, in which therapy is started at the onset of a CMV infection, whether by clinical suspicion or development of viremia. Yet another approach is selective prophylaxis on high-risk recipients (e.g., CMV-negative patients receiving liver allografts from CMV-positive donors). Regardless of the approach, it is interesting to note that the CMV status of blood bank donors is usually not known. Antiviral agents used for prophylaxis include acyclovir, valacyclovir, ganciclovir, and valganciclovir. At our center, all recipients receive intravenous ganciclovir (renally adjusted dose when necessary) for 10 days or fewer if discharged. After discharge, prophylaxis with valganciclovir (Valcyte) continues for 6 weeks in all recipients except for patients with autoimmune disease (AIH, PSC, PBC), who receive 6 months of valganciclovir.

Prophylaxis against Pneumocystis jiroveci pneumonia (PJP), formerly known as pneumocystis pneumonia, is universal and begins immediately after transplantation. Cases of PJP are essentially unheard of today while patients remain on prophylaxis. PJP infection carries a high mortality rate if left untreated and can still reach 30% despite appropriate therapy. Single-strength trimethoprim-sulfamethoxazole (Bactrim) is prescribed after transplantation for 1 year. Dapsone or monthly inhaled pentamidine are options for those unable to tolerate trimethoprim-sulfamethoxazole.

The development of a fever in a recipient following transplantation should be aggressively addressed. Fever, leukocytosis, focal symptoms, or clinical suspicion merits broad-spectrum antibiotic therapy until a workup has proven a conclusive result. Finally, consultation with an infectious disease physician familiar with the transplant patient population is an invaluable resource.

Gastrointestinal Complications

After a successful liver transplant, gastroesophageal varices are decompressed and should not be a source of GI hemorrhage. Patients experiencing upper or lower GI bleeding following transplantation should undergo a routine workup (i.e., endoscopy). GI bleeding may be due to the more common causes such as stress ulcers and hemorrhoids but may also be due to unusual causes such as a Dieulafoy lesion or a Mallory-Weiss tear.

A source of GI bleeding related to liver transplantation is hemobilia, which is a result of an abnormal fistulous communication between the biliary and arterial trees. It is usually iatrogenic in nature. Interventions such as transhepatic cholangiography and liver biopsies may cause a fistula. Eroding false aneurysms of intrahepatic arteries into biliary ductules can also lead to upper GI bleeding. When hemobilia is suspected, the patient should be taken urgently to the interventional radiology suite for a hepatic angiogram, and embolization with metallic coils or absorbable gelatin sponge (Gelfoam) can be used to stop further bleeding. Resulting blood clots in the biliary tree may cause duct obstruction, which can be treated endoscopically or surgically.

Dyspepsia (heartburn) is a common complaint after transplantation. Ulcer prophylaxis with a proton pump inhibitor is routinely started, and its dose or frequency may need adjustment to attain the desired effect. Other common GI disturbances after transplant include nausea, dysphagia, and diarrhea, which may have multiple causes. However, medications must be ruled out as the primary culprit. A common offender is MMF (previously discussed).

A not uncommon cause for diarrhea is colitis due to Clostridium difficile . Stools are typically numerous and watery, and the presentation may be accompanied by leukocytosis. In a recent analysis of hospitalized patients using a national database, the prevalence of C. difficile was greater for liver transplant recipients than for non-liver transplant recipients (2.7% versus 0.9%, P < .001), and C. difficile was also an independent risk factor for mortality in the liver transplant population. Other well-known risk factors for the development of C. difficile include the use of broad-spectrum antibiotics, altered intestinal flora from chronic lactulose or rifaximin use, and advanced age. C. difficile may be treated with either metronidazole or vancomycin. When there is an outbreak of C. difficile cases, hand-washing practices of all personnel and infection control measures should be revisited.

Another transplant-related cause of diarrhea is graft versus host disease, which usually includes other well-known symptoms such as fever and a skin rash. Discussed in Chapter 90 , the outcome is generally poor with the principal treatment being withdrawal of immunosuppression, allowing the recipient bone marrow to reject the offending donor marrow. Finally, diarrhea related to CMV colitis is not infrequently encountered. Diagnosis entails confirmation of viremia and biopsy-proven disease by colonoscopy. Treatment includes intravenous antiviral therapy until symptoms resolve and a negative polymerase chain reaction results are documented. Short-term maintenance treatment with an oral antiviral agent (e.g., Valcyte) is continued for 2 weeks thereafter.