Many patients who undergo liver transplantation (LT)—probably the majority—spend some time in the intensive care unit (ICU) during the postoperative period. The expectations for an immediate postoperative ICU stay have changed markedly as the specialty has progressed. In a state-of-the-art review published in 1994, the authors reported an expectation of 36 hours of postoperative mechanical ventilation and an average 6-day ICU stay for routine cases.1 Nowadays, in many units, the expected ICU stay for such cases is less than 24 hours, and selected patients in some institutions bypass the ICU altogether and instead move to a postoperative recovery unit and then receive floor care.2 The achievement of reduced ICU utilization in the immediate post-LT period requires a proactive approach to recovery from anesthesia and, in particular, to weaning from mechanical ventilation to extubation. Also, a considerable number of patients require ICU management in the postoperative period because of preexisting conditions, adverse intraoperative events, or posttransplant complications. In this review, we discuss 4 topics germane to the ICU management of the post-LT patient and cover issues that frequently arise in this setting. Infectious complications are frequent in the posttransplant population and are the leading causes of death within the first year.3 Acute kidney injury (AKI) and renal failure are common in the early period after LT both as continuations of pretransplant morbidity and as results of the procedure. All patients who are transferred from the operating room while they are intubated require weaning from mechanical ventilation; for some, this may be a prolonged process. Finally, the timely identification of the poorly functioning graft and appropriate management thereof are critically important.
The majority of patients who undergo liver transplantation (LT) spend some time in the intensive care unit during the postoperative period. For some, this is an expected part of the immediate posttransplant recovery period, whereas for others, the stay is more prolonged because of preexisting conditions, intraoperative events, or postoperative complications. In this review, 4 topics that are particularly relevant to the postoperative intensive care of LT recipients are discussed, with an emphasis on current knowledge specific to this patient group. Infectious complications are the most common causes of early posttransplant morbidity and mortality. The common patterns of infection seen in patients after LT and their management are discussed. Acute kidney injury and renal failure are common in post-LT patients. Kidney injury identification, etiologies, and risk factors and approaches to management are reviewed. The majority of patients will require weaning from mechanical ventilation in the immediate postoperative period; the approach to this is discussed along with the approach for those patients who require a prolonged period of mechanical ventilation. A poorly functioning graft requires prompt identification and appropriate management if the outcomes are to be optimized. The causes of poor graft function are systematically reviewed, and the management of these grafts is discussed. Liver Transpl 17:511–527, 2011. © 2011 AASLD.
Infections are leading causes of critical illness, morbidity, and mortality after LT.3-5 It has been estimated that more than half of patients will develop an infection during the first year after LT, and many of these infections will require care in the ICU.3-5 The risk of infection is generally determined by the intensity of the exposure to infectious agents (in the hospital environment and community settings) and the net state of immunosuppression. These infections occur most commonly during the first 6 months after LT when patients are also highly susceptible to potentially serious outcomes from these infections as a result of the intensity of their immunosuppression.3-5
Immediate Posttransplant Period
Infections during the posttransplant period generally follow a characteristic temporal pattern that may be predicted by the time to onset of the disease.4 During the first month after LT, most infections are related to surgical issues and hospitalization.4 Bacterial and fungal wound infections, urinary infections, bloodstream infections, pneumonias, and Clostridium difficile–associated diarrhea are common during this period.
The complexity of LT surgery with potential breaks in areas of high microbial loads (ie, the gastrointestinal tract), the exposure to infectious pathogens during prolonged hospitalization, the presence of indwelling urinary and vascular catheters, and the occasional need for prolonged ventilatory support predispose LT patients to nosocomial bacterial and fungal infections during the first month.4 Prolonged and complicated surgical procedure and the volume of blood loss directly correlate with the risk of infection and mortality after LT.6 The urgent nature of some LT procedures (eg, those for fulminant hepatic failure) lessens the time available for optimally preparing patients for LT, and this may further increase their risk.4 Fulminant hepatic failure per se is particularly associated with an increased risk of opportunistic viral and fungal superinfections.4 Abdominal re-exploration surgery (for retransplantation, abdominal bleeding, biliary leaks, and vascular thrombosis) and the type of biliary anastomosis (eg, choledochojejunostomy) increase the risk of bacterial and fungal infections as well.4
The risk of infections after LT is reduced by standard perioperative antibacterial prophylaxis (eg, cefotaxime; Table 1). No single agent is widely recommended for peritransplant antibacterial prophylaxis, although third-generation cephalosporins are preferred. Others have also used oral selective bowel decontamination (which is a solution containing a combination of nonabsorbable antimicrobials such as colistin, gentamicin, and nystatin) in order to reduce the infection risk after LT, although the benefits of this practice are debated because of the inconclusive results of clinical studies.7 Indeed, a recent meta-analysis has shown that the use of oral selective bowel decontamination is associated with an increased incidence of cholangitis and bacterial infections and with longer hospital stays.8 Despite prevention efforts, infected bilomas, intra-abdominal abscesses, and surgical site infections caused by drug-susceptible and drug-resistant bacteria (eg, Staphylococcus aureus, coagulase-negative Staphylococci, Enterococci, gram-negative bacilli, and anaerobic organisms) and fungi (eg, Candida albicans) may occur.3-5, 9-12 The clinical manifestations of these infections vary widely and include fever, leukocytosis, erythema, purulence, drainage, and dehiscence of surgical wounds; in severe cases, these infections can lead to bacteremia and sepsis, which would require care in the ICU. These early-onset infections often lead to prolonged hospitalization, which further increases the risk of nosocomial and ventilator-associated pneumonias, catheter-associated urinary tract and bloodstream infections, and antibiotic-related C. difficile–induced diarrhea.3-5, 9
|Pathogen or Syndrome||Prevention||Treatment|
|HSV||Acyclovir, 400 mg twice daily||Acyclovir, 5 mg/kg intravenously every 8 hours or Acyclovir, 400 mg by mouth 3 times a day or Acyclovir, 800 mg by mouth twice daily or Valacyclovir, 500 to 1000 mg twice daily|
|CMV||Antiviral prophylaxis: Valganciclovir, 900 mg by mouth once daily or Ganciclovir, 1 g by mouth 3 times a day/Preemptive therapy: Valganciclovir, 900 mg by mouth twice daily||Ganciclovir, 5 mg/kg every 12 hours or Valganciclovir, 900 mg by mouth twice daily Second line: Foscarnet, 60 mg/kg intravenously every 8 hours (or 90 mg/kg every 12 hours)/Third line: Cidofovir, 5 mg/kg every week for 2 weeks and then every 2 weeks|
|Influenza||Vaccination (preferred)/Oseltamivir, 75 mg by mouth once daily||Oseltamivir, 75 mg by mouth twice daily|
|C. albicans||Fluconazole, 200 to 400 mg by mouth once daily or Lipid formulation of amphotericin B, 3 to 5 mg/kg/day for 4 weeks or until resolution of risk factors||Fluconazole, 200 to 400 mg by mouth or intravenously once daily or Echinocandins (caspofungin, anidulafungin, or micafungin) or Other triazoles (voriconazole or posaconazole) or Amphotericin B product|
|A. fumigatus||Lipid formulation of amphotericin B, 3 to 5 mg/kg/day or Echinocandin (caspofungin, anidulafungin, or micafungin) or Voriconazole, 200 mg by mouth twice daily||Voriconazole, 6 mg/kg every 12 hours (2 doses) and then 3 to 4 mg/kg every 12 hours or Voriconazole, 200 mg by mouth twice daily (adjusted according to levels) or Echinocandins (caspofungin, anidulafungin, or micafungin) or Amphotericin B product (deoxycholate, liposomal amphotericin B, Abelcet, or amphotericin B lipid complex)|
|P. jirovecii||Trimethoprim-sulfamethoxazole, single or double strength once daily||Trimethoprim-sulfamethoxazole, 15 to 20 mg/kg/day for the trimethoprim component in 3 to 4 divided doses Possible switch to oral therapy with clinical improvement to complete 21 days of treatment|
|C. neoformans||None routinely provided||Amphotericin B liposome, 3 to 4 mg/kg/day or Abelcet, 5 mg/kg/day plus 5-Flucytosine, 100 mg/kg/day for 2 weeks and then Fluconazole, 400 to 800 mg by mouth once daily for 8 weeks and 200 mg by mouth once daily for suppression for 6 to 12 months/Isolated pulmonary cryptococcosis: Fluconazole, 400 mg by mouth once daily|
|H. capsulatum||Itraconazole, 200 mg by mouth once daily only in at-risk individuals||Mild to moderate disease: Itraconazole, 200 mg by mouth twice daily/Moderately severe or severe disease: Amphotericin B product, 1 to 2 weeks or until a favorable response and then Itraconazole, 200 mg by mouth twice daily|
|C. immitis||Fluconazole, 200 mg by mouth once daily in at-risk individuals||Mild to moderate disease: Fluconazole, 400 to 800 mg daily (preferred) or Itraconazole, 200 mg twice daily Meningeal disease: Amphotericin B product or Fluconazole, 800 mg daily/Moderately severe or severe disease: Amphotericin B product|
|Bacterial infections||Perioperative prophylaxis (eg, cefotaxime, ceftriaxone, or cefepime) Oral selective bowel decontamination (controversial) Fluoroquinolones (for subacute bacterial peritonitis)||Guidance by culture results and the antimicrobial susceptibility pattern Removal of affected foreign devices such as urinary catheters and indwelling vascular catheters|
Herpes simplex virus (HSV) reactivation disease is the most common opportunistic viral infection during this early period, although antiviral prophylaxis (with acyclovir or ganciclovir) has markedly reduced its incidence.13 If left untreated, a reactivated HSV infection can progress from limited orolabial ulcerative lesions to disseminated multiorgan infections (eg, fulminant hepatitis) with high morbidity and mortality rates. Latent or unrecognized active infections involving the donor or recipient liver (eg, Histoplasma capsulatum, Coccidioides immitis, Cryptococcus neoformans, Toxoplasma gondii, and Mycobacterium tuberculosis) can manifest with severe atypical disease during the early period after LT.3-5, 14-16
The prevention of infections is essential in the management of all LT recipients. Table 1 lists the various methods for the prevention of infections after LT. Surveillance cultures or other methods such as polymerase chain reaction are used to identify infections before their clinical manifestation. Surveillance using rectal swab and stool specimens can be employed to identify colonization with drug-resistant bacteria such as vancomycin-resistant Enterococci in an effort to interrupt nosocomial transmission.10 However, surveillance cultures of biliary fluids are generally discouraged because they are often colonized by multiple organisms.
The early administration of effective empirical antimicrobial therapy is crucial in the management of infections after LT, and for this, knowledge of the local antibiogram profile of the hospital is essential.10 Initially, a broad-spectrum antibacterial therapy is recommended for the treatment of bacterial sepsis and other infectious syndromes requiring admission to the ICU. Resuscitation and hemodynamic management should follow the guidelines for early goal-directed therapy, which are discussed in detail in the accompanying review of critical care for the pretransplant patient.17 Adjuvant therapies such as recombinant human activated protein C may occasionally be used in transplant patients with septic shock.18 These infections should be treated aggressively with antimicrobial therapy that is tailored to the offending microorganism and guided by susceptibility tests once they are available3, 10, 12, 19 because these infections have been associated with poor allograft and patient survival.20 Likewise, it is important to control the source of the infection, and thus the drainage of infected fluid collections (eg, infected hematomas and abscesses), the debridement of surgical infections, and the removal of infected vascular and urinary catheters are essential components of therapy.3, 10, 12, 19
Opportunistic Infection Period
Opportunistic infections generally occur during the second to sixth months after LT when the net state of immunosuppression is most intense.15, 21-24 The most common opportunistic infection is cytomegalovirus (CMV).23, 25, 26 The risk of CMV infection is highest among CMV-seronegative recipients of liver allografts from CMV-seropositive donors [CMV donor-positive/recipient-negative (D+/R−) mismatching].23, 25, 26 The use of lymphocyte-depleting agents (eg, anti-thymocyte globulin), mycophenolate mofetil, and alemtuzumab further increases the risk of CMV23, 25, 26 as well as other opportunistic infections such as human herpesvirus 6, C. neoformans,16Aspergillus spp.,27 and Pneumocystis jirovecii.28 Patients with CMV disease commonly present with fever and myelosuppression (CMV syndrome), and in less than half of cases, tissue-invasive CMV disease may occur and involve any segment of the gastrointestinal tract (causing abdominal pain, nausea, and diarrhea) or the liver allograft (causing transaminitis).26 If CMV hepatitis occurs, it may be confused with rejection or drug toxicity. One of the most morbid and fatal manifestations of CMV disease, which often requires admission to the ICU, is CMV pneumonia, which is characterized radiographically by a diffuse interstitial pattern. The treatment of CMV disease is listed in Table 1. Because of the common occurrence of CMV infection and its overall negative impact on allograft and patient survival, CMV prevention is standard practice after LT.26 The 2 major approaches to preventing CMV disease after LT are antiviral prophylaxis and preemptive therapy.25, 26 Generally, it is recommended that CMV D+/R− liver recipients receive prophylaxis with a ganciclovir-based regimen for at least 3 months after transplantation.25, 26 CMV prophylaxis is also administered to patients receiving lymphocyte-depleting agents (eg, anti-thymocyte globulin) for acute rejection.25, 26 In patients with a low to modest risk of CMV disease, a preemptive approach is recommended: patients are monitored for CMV by polymerase chain reaction or pp65 antigenemia, and if CMV is detected, antiviral therapy (usually with valganciclovir) is provided (Table 1).25, 26
Fungal pathogens commonly cause opportunistic infections during this period after LT.11, 15, 16, 27 After LT, Candida species are the most common fungal pathogens that cause clinical illness (in the form of urinary tract infections, bloodstream infections, and abscesses).11 Invasive aspergillosis, most commonly due to Aspergillus fumigatus, is the second most common opportunistic infection27 and is more commonly observed among liver recipients with underlying fulminant hepatitis, those with profound immunosuppression, and those with epidemiological exposures (eg, close proximity to construction sites).27 Other risk factors for the occurrence of opportunistic fungal infections after LT are retransplantation, renal failure [particularly when renal replacement therapy (RRT) is required], and reoperation involving the thoracic or abdominal cavity.27 Infections due to endemic fungi (eg, H. capsulatum and C. immitis)15 and C. neoformans,16 all of which have been transmitted occasionally through transplanted allografts, may occur during this period. Cryptococcosis often presents as meningoencephalitis with symptoms that include fever, neck stiffness, headache, seizures, and mental status changes, although it may occur as isolated pulmonary cryptococcoma or nonhealing cellulitis.16 The prevention of fungal infections consists of the use of antifungal drugs in targeted populations (eg, those with clinical variables putting them at high risk); however, this practice is not uniform across transplant centers (Table 1). Because of the risk of invasive fungal diseases, particularly with candidiasis, fluconazole or other antifungal agents are recommended for liver recipients who require retransplantation or reoperation, those whose surgery is prolonged or who experience profound blood loss, and those who require RRT.11, 27 This approach is supported by a meta-analysis demonstrating that fluconazole reduced invasive fungal infections (mainly due to C. albicans) by 75%.29 Some centers also administer prophylaxis with fluconazole or other triazoles, echinocandins, or amphotericin B to patients with fulminant hepatitis.11, 27 Nonetheless, this is not a widely accepted practice, and there is no standard practice that is widely accepted by many transplant centers.29
Another opportunistic fungus that is traditionally found during this period is P. jirovecii (previously known as P. carinii).28 The estimated incidence of Pneumocystis infections is 5% to 10%, but the widespread use of trimethoprim-sulfamethoxazole prophylaxis during the first 6 months after LT has virtually eliminated this infectious complication.28Pneumocystis infections are now presenting as late-onset pneumonia characterized by severe hypoxemia and diffuse interstitial pulmonary infiltrates in patients who have completed trimethoprim-sulfamethoxazole prophylaxis or who have discontinued prophylaxis because of adverse toxicities. The use of trimethoprim-sulfamethoxazole may also reduce the incidence of other infections (eg, nocardiosis) that typically present as pulmonary nodules and brain abscesses.24 The recommended treatment for opportunistic infections is listed in Table 1. In addition to the pathogen-specific antimicrobial therapy, a reduction in the degree of pharmacological immunosuppression should be regarded as a major component of the treatment of opportunistic infections.
Late Posttransplant Period
Beyond the sixth month after LT, the level of immunosuppression in the majority of patients has been reduced to minimal levels. As a result, patients are no longer at high risk for opportunistic infections. Community-acquired infections such as viral respiratory diseases (influenza, parainfluenza, and respiratory syncytial virus) and bacterial pathogens (eg, pneumococcal pneumonia, staphylococcal and streptococcal cellulitis, gram-negative bacterial urinary infections, and sepsis), however, may occur, with severe cases requiring care in the ICU.10, 12, 30 LT patients with biliary complications may present with hepatic abscesses, which may be complicated by bacteremia and sepsis.31
In the minority of liver recipients, such as those with poor allograft function, recurrent chronic hepatitis, or recurrent acute or chronic rejection and those who remain on intense immunosuppression, the opportunistic infections that characteristically occur during months 1 to 6 may still occur.4, 32 A common opportunistic infection during this period is herpes zoster, which typically manifests as a painful monodermatomal or multidermatomal vesicular eruption, although it can disseminate and cause multiorgan failure if it is left untreated.33 Epstein-Barr virus–related posttransplant lymphoproliferative disorder may occur at any time, although it often peaks between 6 to 12 months and 2 to 4 years after LT.22 Late-onset CMV disease may also manifest during this period, especially in CMV D+/R− LT recipients who received a prolonged course (3-6 months) of antiviral prophylaxis; its symptoms can include gastroenteritis, intestinal bleeding, and pneumonia.23, 25, 26
The occurrence of AKI in patients undergoing LT is associated with reduced patient and graft survival not only in the perioperative period but also in the longer term,34-36 with reports of 10% progressing to end-stage renal failure.37 AKI reduces patient survival and leads to increased health care costs because of increased intensive care and hospital stays.34-36 Furthermore, increasing evidence supports the fact that even relatively minor deteriorations in renal function not requiring RRT are associated with inferior patient and renal outcomes in the longer term; this underlines the importance of the early identification of at-risk individuals and the need to identify preventative strategies.34, 35
Incidence, Definition, and Detection of AKI
AKI post-LT is not an infrequent problem and has been reported to occur in 9% to 78% of cases.34, 38-40 This marked variability in the reported incidence rates can be predominantly attributed to the different underlying etiologies and definitions of AKI used.
Definitions of AKI have varied, and only relatively recently has a consensus definition based on the Risk, Injury, Failure, Loss, and End-Stage Kidney Disease (RIFLE) criteria (Table 2)41 been introduced. This staging system has been modified by the Acute Kidney Injury Network (AKIN) to define AKI as a rise in serum creatinine levels within a 48-hour time frame and also stresses the importance of a relatively small rise in serum creatinine levels (Table 2).42 More recently, the Kidney Disease: Improving Global Outcomes group has taken elements from both the RIFLE and AKIN definitions; this group uses the AKIN definition but also allows the definition of AKI to include a doubling or greater increase of serum creatinine levels within a 7-day period rather than the 48-hour AKIN time frame.43 When AKI is defined as at least a doubling of serum creatinine levels or the need for dialysis (RIFLE grades I or F or AKIN stages 2 or 3), the incidence of AKI is approximately 9% to 48%.34, 38, 40, 44 In addition to using changes in serum creatinine, both RIFLE and AKIN criteria use urine output to stage AKI because changes in serum creatinine may not accurately reflect dynamic changes in renal function.45
|AKI Stage||Serum Creatinine Criteria||Urine Output Criteria|
|Risk (AKIN-1)||Serum creatinine ≥ 0.3 mg/dL or ↑ Serum creatinine ≥ 150%-200% above the baseline||<0.5 mL/kg/hour for >6 hours|
|Injury (AKIN-2)||↑ Serum creatinine > 200%-300% above the baseline||<0.5 mL/kg/hour for >12 hours|
|Failure (AKIN-3)||↑ Serum creatinine > 300% above the baseline or Serum creatinine ≥ 4.5 mg/dL with an acute rise ≥ 0.5 mg/dL||<0.3 mL/kg/hour for 24 hours or anuria for 12 hours|
These newer consensus definitions of AKI in the LT population have been recently validated by studies in which an increasing severity of renal dysfunction (RIFLE grades R-F or AKIN stages 1-3) correlated with reduced patient survival.39 A major shortcoming has been the fact that creatinine is a relatively poor biomarker of renal function because changes in serum creatinine levels tend to lag behind dynamic changes in renal function. There are also some specific considerations when serum creatinine is used to diagnose AKI post-LT. The commonly used colorimetric Jaffe reaction methodology yields a falsely lower creatinine estimation with increasing bilirubin levels. In addition, patients with cirrhosis have a lower creatine production rate because they often exhibit malnutrition with muscle wasting; therefore, the use of serum creatinine levels can lead to an overestimation of renal function. During the LT operation, large volumes of fluids may be administered and result in a dilution of creatinine immediately after the operation; the levels may be further lowered if hemofiltration has been used perioperatively.46 Postoperatively, creatinine levels may then increase from this artificially lowered baseline; this can be compounded by an increased hepatic creatinine generation rate with improved liver function and concomitant steroid therapy. Other traditional markers of kidney injury, such as serum urea, fractional sodium excretions, and the presence of casts on urine microscopy, are insensitive and nonspecific for the diagnosis of AKI in patients with liver disease.47 As such, there has been a search for more reliable biomarkers of renal function to alert the clinician to impending AKI. Current biomarkers fall into 3 main categories: (1) markers of kidney function similar to creatinine (typified by cystatin C), (2) markers of inflammatory response severity made by the individual in response to the insult (including neutrophil gelatinase-associated lipocalin, liver-type fatty acid binding protein, and urinary interleukin-18), and (3) markers of kidney damage (eg, kidney injury molecule 1, a number of urinary enzymes including glutathione S-transferase P and c-glutathione S-transferase, alpha-1-microglobulin, alpha-1-acid glycoprotein, N-acetyl-β-D-glucosaminidase, and albumin). These biomarkers are most useful in patients with normal preexisting renal function, but they have been somewhat disappointing in clinical practice.48 Although both plasma and urine neutrophil gelatinase-associated lipocalin levels have been associated with AKI post-LT,44 rather than specifically denoting renal injury, they are more in keeping with the general insult. An increasing number of adult patients with some degree of preexisting chronic kidney dysfunction are now going forward to LT, and in this group, the current biomarkers of AKI are less helpful. Therefore, larger multicenter, prospective studies are required to evaluate the role of the currently available panel of biomarkers.
Etiology and Risk Factors
Clearly, the etiology of AKI post-LT can be multifactorial because these patients are frequently critically ill in the perioperative period. Renal insults can occur during septic episodes or periods of hemodynamic instability and hypovolemia due to intraoperative blood loss, and this can result in prerenal failure or ischemic injury.40, 49
Intraoperative Factors Associated With AKI in LT Recipients
A host of intraoperative variables have been implicated in AKI; they either cause de novo injury or lead to further declines in preexisting renal dysfunction. Most studies have been single-center and retrospective; they have typically excluded patients with fulminant liver failure, retransplant patients, living donor LT patients, and patients experiencing severe renal dysfunction or receiving dialysis before transplantation; and they have been limited to the immediate postoperative period.
Hypotension during surgery has consistently been shown to adversely affect renal function.38, 44, 50 Hypotension may occur during various stages in the intraoperative period and may vary in both severity and duration; its causes include vasodilatation at anesthesia induction, hemorrhaging, inferior vena cava (IVC) clamping, and reperfusion of the transplanted liver. Cirrhotic cardiomyopathy, pretransplant beta-blockade, and autonomic polyneuropathy may also contribute.
Conventional LT involves total hepatectomy with resection of the retrohepatic IVC, which causes interruption of the venous return during the anhepatic phase and both reduced renal flow51 and renal venous hypertension.52 Venovenous bypass should, in theory, preserve venous return and reduce renal venous hypertension, but studies have yielded conflicting results in terms of its protective effect on renal function.53, 54 The newer cava-preserving piggyback technique necessitates only partial clamping of the recipient IVC with maintenance of the venous return and a lower renal venous pressure. This has been reported to reduce renal injury.55, 56 The modified piggyback technique, which incorporates a temporary portocaval shunt, has also been reported to reduce the incidence of early renal failure after transplantation.57
Most retrospective, observational studies using multivariate analysis have demonstrated an association between the quantity of transfused blood and blood products and the development of AKI during LT.34, 58 This may in part reflect the severity of intraoperative hypotension and hypovolemia caused by excessive hemorrhaging.
Overall, there are no definite treatment options for the prevention of intraoperative AKI.
Aiming for a low central venous pressure in association with isovolemic hemodilution has been reported to reduce the requirement for blood products59 and consequently the incidence of AKI.60 The use of more physiologically balanced intravenous solutions has been reported to reduce the incidence of AKI after cardiac surgery in comparison with 0.9% saline,61 but there are no comparable data for LT.
Numerous drugs, including N-acetyl cysteine, nitric oxide, prostanoids, dopamine, and diuretics, have been administered during LT in an attempt to reduce AKI, but none of these have been effective.44, 62-64 Fenoldopam, a D1 receptor agonist, has shown promise in cardiac surgery65; however, it has not been evaluated in LT.65 The use of terlipressin in the management of patients with preoperative hepatorenal syndrome has been reported to lead to a reduction in postoperative AKI.66 Postoperative hyperglycemia has been reported to be a risk factor for developing AKI,67 and a recent study has also suggested that intraoperative hyperglycemia may be associated with an increased risk of early AKI post-LT44; however, whether this can be influenced by tight glucose control is unknown.
Intraoperative venovenous hemofiltration has not been shown to have a proven benefit in reducing postoperative AKI,68 although hemofilters designed to remove small water-soluble solutes have been used69 instead of combinations of high-permeability membranes with adsorption columns, which could potentially remove cytokines and other inflammatory mediators.
Immediately after the operation, the risk of developing AKI depends primarily on the aforementioned factors, the severity of the liver disease, the preoperative renal function,64 and the postoperative liver function. Furthermore, several studies have reported an increased risk of AKI associated with poor graft function or primary nonfunction (PNF)63 postoperatively.51, 64 Elevated intra-abdominal pressure is well established as a risk factor for AK; however, there has been no formal evaluation of whether there is a critical threshold post-LT.70 Major causes of late postoperative AKI (ie, after the first 3 days) include bacterial infections, retransplantation, and exploratory surgery for delayed hemorrhaging and surgical leaks.44 However, the single most important cause of renal injury remains drug-induced toxicity. Calcineurin inhibitors are the mainstay of immunosuppressive regimens for LT recipients. Unfortunately, cyclosporine and tacrolimus can lead to renal injury.71 Indeed, AKI post-LT due to calcineurin inhibitors has been reported to increase almost 3-fold the odds ratio for developing chronic kidney disease within 10 years.72 Therefore, several studies have looked for differences between cyclosporine and tacrolimus; they have reported no difference in renal function in the long term,73 although tacrolimus is more likely to result in glucose intolerance.74 Thus, many LT centers delay the administration of these drugs after surgery, and to reduce the subsequent risk of chronic kidney disease, the doses of these agents used today are much lower than those prescribed historically.75 Although the initial use of interleukin-2 receptor antibodies followed by delayed calcineurin inhibitor introduction resulted in an early reduction in renal impairment, renal function was no better after 4 months76 or after 12 months.77
This has led to the increased use of other immunosuppressives, including mycophenolate mofetil and the mammalian target of rapamycin inhibitors; however, studies to date have not shown any superiority of mammalian target of rapamycin inhibitors,78 and the combination of immunophilins and sirolimus often leads to increases in creatinine levels and renal glomerular proteinuria.79 Nephrotoxic antibiotics (aminoglycosides) should be avoided.
It is now becoming more recognized that after recovery from AKI, surviving patients have an increased mortality risk, particularly within the first year, and also an increased risk of developing progressive chronic kidney disease. The risk of developing chronic kidney disease is greatest for those patients with preexisting chronic kidney damage and for those patients who develop AKI post-LT (particularly by immunophilin toxicity).72
Initiation of Renal Support
The initiation of RRT remains a clinical decision; fluid overload and electrolyte disturbances are the most common trigger factors (Table 3),80 and they are followed by metabolic acidosis rather than urea and creatinine levels per se.81 Although the current consensus from retrospective and observational studies suggests that the early initiation of RRT for AKI is associated with improved patient survival, this remains to be confirmed by adequately powered prospective, randomized trials.
|Refractory hyperkalemia > 6.5 mmol/L|
|Serum urea > 30 mmol/L|
|Refractory metabolic acidosis (pH ≤ 7.1)|
|Refractory electrolyte abnormalities: hyponatremia or hypernatremia and hypercalcemia|
|Urine output < 0.3 mL/kg for 24 hours or absolute anuria for 12 hours|
|AKI with primary graft nonfunction or multiple organ failure|
|Refractory volume overload|
|End organ damage: pericarditis, encephalopathy, neuropathy, myopathy, and uremic bleeding|
|Creation of intravascular space for plasma and other blood product infusions and nutrition|
The choice of the renal replacement modality should be guided by each patient's clinical status, the medical and nursing expertise, and the available modalities. Apart from peritoneal dialysis, a number of intermittent and continuous modalities are available for use (Table 4). Although continuous modes of RRT [ie, continuous renal replacement therapy (CRRT)] have been reported to offer superior cardiovascular stability in comparison with conventional intermittent hemodialysis,82 studies have failed to confirm a survival advantage of one modality over others. More recently, hybrid therapies (ie, prolonged intermittent RRT) have been introduced, and these potentially have benefits in comparison with conventional intermittent hemodialysis. However, patients with AKI post-LT are prothrombotic and have an increased risk of CRRT circuit clotting, and anticoagulation is often required.83 Systemic anticoagulation with heparin can increase the risk of hemorrhaging, whereas citrate is a regional anticoagulant.84 Although citrate is metabolized by the liver, the low concentrations that return to the patient during CRRT can usually be readily metabolized, even by patients with delayed graft function.
|Modality||Use in Hemodynamically Unstable Patients||Solute Clearance||Volume Control||Anticoagulation|
|Intermittent hemodialysis||No||High||Moderate||Possible without|
|Prolonged intermittent RRT||Possible||High||Good||Possible without|
WEANING FROM MECHANICAL VENTILATION
Although mechanical ventilation is essential for the support of patients with respiratory failure, optimal patient outcomes can be achieved only with early weaning and extubation. The risks of prolonged mechanical ventilation include infection (ventilator-associated pneumonia), muscle deconditioning, and tracheal injury. Surprisingly, muscle deconditioning can be identified as early as 18 hours after the initiation of mechanical ventilation. There is evidence that an increasing duration of mechanical ventilation is associated with increased mortality.85 The majority of the data discussed in this review come from clinical trials of general ICU patients and not specific populations of patients who have undergone LT. Weaning from mechanical ventilation is defined as that period in which the patient transitions from full ventilatory support to spontaneous ventilation. There are now extensive data showing that an organized, protocolized approach to ventilator weaning can significantly reduce the duration of mechanical ventilation, the length of the ICU stay, and complications associated with mechanical ventilation. Patients should be evaluated for their readiness to wean as soon as their underlying cause of respiratory failure has been stabilized. The most important innovation in improving weaning from mechanical ventilation has not been technological but rather has been organizational: placing the responsibility for ventilator weaning on bedside providers such as nurses and respiratory care practitioners has been recognized to greatly improve outcomes. With respect to weaning, physicians tend to be only intermittently available to each patient, whereas bedside providers are continuously present. In recognition of this issue, Ely et al.86 randomized 300 patients to either traditional physician-led weaning (the control group) or protocol-driven weaning managed by the bedside nurses and respiratory care practitioners (the intervention group). For the intervention group, the time to weaning, the duration of mechanical ventilation, and the cost of ICU care were significantly decreased, and there were significantly fewer complications. There were no differences in the mortality rates, the length of the ICU or hospital stay, or the total costs. Kollef et al.87 found similar benefits in a trial of protocol-directed weaning versus physician-directed weaning.
Ultimately, patients may fail in single or multiple attempts at weaning. Those who fail in multiple attempts at weaning, those whose mental status continues to be poor, and those who experience prolonged respiratory failure are candidates for tracheostomy.
Early Extubation and Weaning in LT Patients
The LT population presents a unique challenge, yet studies suggest that many patients may be suitable for early postoperative extubation. In a single-center study, Neelakanta et al.88 retrospectively compared 18 patients who were extubated immediately after the operation to 17 patients who underwent delayed extubation (which was defined as immediate extubation in the operating room). Successfully extubated patients had actually received more intraoperative crystalloid, had a lower pH, and had higher arterial carbon dioxide tension in comparison with those patients who were not immediately extubated. In a retrospective study from 2 centers, Mandell et al.89 reported that 41 of 173 patients were extubated immediately at the conclusion of surgery, and only 2 patients required reintubation. To qualify for early extubation, patients needed to have good donor liver function, to have received fewer than 10 units of packed red blood cells, and to have an alveolar-arterial oxygen gradient less than 150 mm Hg. For patients who were successfully extubated early, the length of the ICU stay was reduced, and the costs were substantially lower. More recently, Biancofiore et al.90 retrospectively studied 168 patients who had undergone orthotopic liver transplantation (OLT; 181 procedures in all). One hundred fifteen patients (64%) were extubated within 3 hours of surgery, and 19 more patients were extubated within 8 hours. They identified risk factors for delayed extubation (Table 5). After examining LT procedures between 1999 and 2004, they updated their data: they found that 207 of 354 patients (58.5%) were extubated immediately at the end of sugery.91 They also reported that in the last 2 years of the study, 82.5% of their patients were extubated at the end of surgery. The best predictor of extubation success was a Model for End-Stage Liver Disease (MELD) score less than 11. Anesthetic management may also contribute to the success of early extubation. In a randomized study, the use of short-acting anesthetic and analgesic agents instead of longer acting agents was associated with significantly shorter times to extubation.92
|Severity of liver disease before surgery (Child-Pugh)|
|Duration of graft ischemia|
|Duration of surgery|
|Primary graft dysfunction|
|Intraoperative blood requirements|
|Body temperature on ICU admission|
|Need for inotropes or vasopressors|
Weaning From Prolonged Mechanical Ventilation
Although the majority of post-LT patients are candidates for early weaning and extubation, this is not possible for some. Weaning for these patients should follow the best practices identified for all ICU patients. Among the identified parameters (Table 6), the best studied has been the frequency/tidal volume ratio. Yang and Tobin93 found that rapid shallow breathing, as measured by the frequency/tidal volume ratio, was the most accurate predictor of failure to wean from mechanical ventilation, and its absence was the most accurate predictor of success. When the frequency/tidal volume ratio was measured to be greater than 100 breaths/minute/L, failure was likely.
|Maximal inspiratory force|
|Frequency/tidal volume ratio|
The specific techniques used for weaning assessment have been studied. Esteban et al.94 compared 4 methods of weaning patients from mechanical ventilation in a randomized, prospective, multicenter study involving 546 patients. They found that once daily spontaneous breathing trials (SBTs) were superior to intermittent mandatory ventilation and pressure support ventilation methods and were just as efficacious as multiple SBTs. On this basis, they recommended that all mechanically ventilated patients be weaned with once daily SBTs.
Most ICU patients require sedation to tolerate mechanical ventilation, yet there is increasing evidence that sedation results in an increased duration of mechanical ventilation. The same organizational issues that limit the evaluation of patients for ventilator weaning affect the sedation process. Likewise, it is difficult for patients to tolerate SBTs if they are oversedated. Kress et al.95 randomized 128 ICU patients to daily sedation interruption (the intervention group) or the usual physician-led treatment (the control group). Daily sedation interruption led to a significant reduction in the duration of mechanical ventilation (from 7.3 to 4.9 days) and reduced the length of the ICU stay (from 9.9 to 6.4 days). Studies by Kress and Girard have demonstrated that protocol-driven ventilator and sedation weaning can result in a reduced duration of mechanical ventilation without additional costs or complications. These authors recently collaborated on a randomized, prospective trial combining paired sedation and ventilator protocols.95, 96 They randomized 336 patients to either a combination of daily sedation interruption and an SBT or routine sedation management with a daily SBT (the control group). The combination of the 2 interventions led to significant reductions in the duration of mechanical ventilation, the length of the ICU and hospital stays, and the 1-year mortality. The findings of the aforementioned trials suggest that the current standard of care in any ICU should include both daily SBTs and daily sedation interruption.
Noninvasive Mechanical Ventilation
In appropriate patients, noninvasive positive pressure ventilation (NIPPV) has a number of advantages over traditional mechanical ventilation with translaryngeal intubation. Again, most experience has involved medical patients with respiratory failure, whereas less is known about the use of NIPPV in patients undergoing major abdominal surgery. With NIPPV, the risk of ventilator-associated pneumonia is greatly reduced because there is no endotracheal tube serving as a conduit for oral secretions into the lung. In addition, these patients may be able to ambulate more successfully and usually require lower doses of sedatives and analgesics. Contraindications for NIPPV include an altered mental status (AMS) and an inability to tolerate a tight mask fit. A recent meta-analysis by Burns et al.97 examined 12 clinical trials enrolling 530 patients. They found that weaning with NIPPV resulted in reduced rates of mortality (relative risk = 0.55, 95% confidence interval = 0.38-0.79) and ventilator-associated pneumonia (relative risk = 0.29, 95% confidence interval = 0.19-0.45). The majority of studies examined patients with chronic obstructive pulmonary disease who had failed in at least 1 attempt at extubation. Another important study by Squadrone et al.98 demonstrated that continuous positive airway pressure was highly effective in preventing reintubation in laparotomy patients with postoperative hypoxemia. The application of NIPPV to post-LT patients has not been specifically studied; however, the use of NIPPV may allow the more expeditious extubation of those not ready for conventional early weaning.
POORLY FUNCTIONING ORGAN GRAFTS
The growing gap between the number of allografts appropriate for transplantation and the number of patients awaiting LT has prompted aggressive donor utilization; simultaneously, increasingly moribund, decompensated recipients are undergoing transplantation.99 The early identification and appropriate management of poorly functioning liver grafts in an often tenuous postoperative population have thus become critical aspects of post-LT care. Although there is no concrete definition of the poorly functioning graft, the spectrum ranges from organ dysfunction with slow engraftment in the early postoperative period to the complete absence of hepatic function. Here the causes of graft dysfunction in the early postoperative period are systematically classified, and the approaches to management are summarized.
Signs of early graft dysfunction can be considered with respect to (1) hepatocellular dysfunction (biochemical, metabolic, and synthetic), (2) extrahepatic organ dysfunction (neurological, metabolic, cardiovascular, and renal impairment), and (3) sequelae of portal hypertension. Unless dramatic presentations such as coma and shock occur, the signs and symptoms of poorly functioning allografts can be insidious and difficult to ascribe to graft malfunction. A systematic approach to diagnosing and managing graft dysfunction is facilitated by the classification of complications into 1 of 2 main categories: technical and nontechnical (Fig. 1). Technical complications are almost uniformly anastomotic, whereas nontechnical complications generally are due to immunological causes, suboptimal donor-recipient matching, or cryptogenic causes, which ultimately may in turn result in technical complications.
Hepatic Artery Thrombosis (HAT)
Early HAT, occurring in 3% of adult cases, is the most common technical complication after LT100 and the most common complication requiring retransplantation.101 The most dramatic manifestation is fulminant hepatic ischemic necrosis with a rapid onset of hepatic decompensation characterized by progressive sepsis, fever, AMS, hypotension, and coagulopathy. Although they are not specific for HAT, laboratory values often demonstrate transaminitis and leukocytosis. These findings should lower the threshold for suspicion, but physicians should not rely on them as the sole diagnostic tests. Because the sole blood supply to the bile duct is the hepatic artery, biliary dehiscence with peritonitis may be seen with a delayed diagnosis. The absence of these signs does not exclude HAT. Although many centers use duplex Doppler ultrasound for diagnosis, operative exploration is considered by many the gold standard because of both the diagnostic sensitivity and the expediency of treatment (a revision of the arterial anastomosis or the creation of an aortic conduit), with the second best alternative being selective celiac angiography. Multiphase, multislice computed tomography and magnetic resonance angiography have evolved to provide a reported concordance of 95% with operative findings.102 The high rate of renal dysfunction in LT recipients and the potential operative delay make contrast imaging a less attractive diagnostic option.
Although interventional strategies such as catheter-directed thrombolysis have been applied with some success,103 the best treatment for early HAT is operative arterial reconstruction. If significant parenchymal necrosis has been sustained, retransplantation may be necessary, often through an aortic conduit, to prevent liver failure and death. Patients for whom HAT is diagnosed within 1 week of their first transplant meet the United Network for Organ Sharing (UNOS) criteria for high priority for emergent retransplantation.104
Portal Vein Thrombosis (PVT)
The incidence of early post-LT PVT is approximately 0.5% to 15%, with the higher incidence occurring in pediatric recipients.105 Symptoms include transaminitis, ascites, intestinal congestion, systemic inflammatory responses due to bacterial translocation, and gastrointestinal bleeding, and PVT may progress to acute liver failure with an emergent need for retransplantation. Duplex Doppler ultrasound is also used diagnostically; computed tomography and magnetic resonance imaging have less sensitivity for PVT versus HAT. If PVT is left untreated, the mortality rate approaches 100%.106 Although immediate operative thrombectomy may allow graft salvage, emergent retransplantation may be necessary according to the extent of viable tissue. Interventional thrombolysis is mentioned only to be discouraged because of the tenuous nature of the anastomosis and the risk of reocclusion.107
Hepatic Vein Thrombosis (HVT)
HVT occurs infrequently and is usually associated with techniques resulting in hepatic venous outflow compromise and thus causing an acute Budd-Chiari effect (eg, piggyback grafting, which may narrow the entrance into the recipient IVC).108 Recipients with underlying hypercoagulability are predisposed to this complication. Acute transaminitis, severe abdominal pain, worsening jaundice, hepatomegaly, and ascites should prompt an immediate investigation. The diagnosis is again made with Doppler ultrasound and/or operative exploration. The treatment depends on the degree of parenchymal damage. Retransplantation will be required in cases of massive necrosis. Percutaneous interventional procedures may be warranted in the most stable individuals or alternatively in very unstable patients intolerant of laparotomy. There is no UNOS provision for priority for patients with PVT or HVT.
Regardless of the management strategy, most clinicians employ long-term anticoagulation after revision or retransplantation for vascular thrombosis.
Although patients with nontechnical complications may present with vascular occlusion, these complications are by definition the results of nonvascular events. Nontechnical early allograft dysfunction may be attributable to immunological complications or a graft of insufficient quality to support a particular donor recipient match: initial poor function (IPF) or PNF may result.
Donor Quality and Recipient Matching
A systematic analysis was undertaken by Feng et al.99 to determine factors affecting graft survival. The donor risk index (DRI) model, which incorporates the donor's age, cause of death, race, graft type (whole versus partial), cold ischemia time, and height, can be used to determine the predicted outcome of a specific graft. When the DRI and the recipient's condition are considered together, experienced clinicians may be able to accurately predict the risk of graft failure. Many agree that grafts with DRI scores exceeding 1.8 have a higher than average risk of failure,109 particularly for recipients with high MELD scores. Early signs of dysfunction with grafts from high-DRI donors should be aggressively evaluated. Operative exploration should be used liberally and early to ascertain whether retransplantation is warranted. In fact, many surgeons have found that in patients expected to have a challenging perioperative course because of either recipient factors alone or specific donor-recipient combinations, the preemptive practice of a planned re-exploration 24 to 48 hours after LT is an effective way of ruling out potentially lethal complications.110 The recipient is packed with temporary closure and stabilized in the ICU with warming measures, product resuscitation, and RRT (if necessary) before he or she returns to the operating room for graft re-evaluation and LT completion.
In addition to DRI factors, other donor, procurement, and recipient parameters are known to affect function.
The incidence of macrovesicular hepatic steatosis in the cadaveric donor pool has been reported to be 24% to 45%.111 Although macroscopic and microscopic changes may be minimal, functional alterations exist. In addition, associated aortic and mesenteric atherosclerotic disease may alter graft perfusion during procurement. Such changes pose no overt threat to the donor's hepatic function and reserve, but they may result in post-LT graft dysfunction because of the physiological stress of procurement and cold storage. That said, the literature supports the implantation of grafts with up to 30% macrosteatosis.112, 113
Ischemia/Reperfusion (I/R) Injury.
Intragraft proinflammatory markers such as the intercellular adhesion molecule P-selectin are up-regulated as a result of metabolic changes seen with neutrophil activation after I/R, and they have been correlated with the degree of transaminitis and graft dysfunction.114 Studies examining the effect of the inhibition of P-selectin activity on immediate graft function are underway; the results are pending. Graft dysfunction due to I/R injury is suspected on the basis of circumstances surrounding procurement and reimplantation and can be confirmed by biopsy. Sequelae are usually self-limited.
Warm Ischemia Time.
A prolonged time to graft vascularization after the graft's removal from cold storage can result in unintended rewarming along with hepatocellular ischemia and graft swelling. Totsuka et al.115 noted that reperfusion times in excess of 45 minutes, particularly in combination with prolonged cold ischemia times, result in irreversible graft injury.
Small-for-Size Syndrome (SFSS).
Experience with SFSS has developed with the increasing use of living donor allografts.116 SFSS is characterized by graft dysfunction in the setting of suboptimal-volume allografts with hepatic dysfunction ranging from mild isolated cholestasis to irreversible graft failure leading to retransplantation or death. SFSS is now known to be relevant to whole organ and reduced size deceased donor grafts as well. Although its exact mechanism is unknown, SFSS appears to result from portal hypoperfusion and inadequate hepatocellular regeneration.117 The liver volume required to avoid SFSS is characterized by a graft-to-recipient weight ratio of 0.8.118 For recipients of grafts with marginal graft-to-recipient weight ratios who have hepatic dysfunction, operative exploration may be necessary to ensure graft viability.
Large-for-Size Syndrome (LFSS).
LFSS is usually seen in pediatric recipients of partial grafts and is a result of graft dysfunction due to vascular thrombosis or necrosis due to insufficient graft inflow. The clinical manifestations are identical to those described previously for portal and arterial vascular occlusion. Fukazawa et al.119 noted that the use of grafts with body surface area ratios > 1.4 resulted in the highest and most significant hazard ratio for graft failure. Re-exploration with splenic artery ligation may remedy the problem; however, retransplantation may be necessary.
Requirement for RRT
In addition to its proven role as an independent risk factor for IPF and PNF,118 recipient renal failure can confound the assessment of graft dysfunction because of associated platelet dysfunction, encephalopathy, and acidosis.
IPF and PNF
Early graft dysfunction that progressively improves (IPF) and the early failure of an organ that never demonstrates engraftment (PNF) are extreme entities on a spectrum of nonfunction that may be due to the aforementioned factors or unidentifiable causes. PNF is the most dramatic manifestation and is universally lethal without retransplantation. Approximately 4% of LT grafts meet the criteria for PNF, and PNF accounted for nearly 40% of retransplant cases in a published series.120 Interestingly, this figure has not changed with an increasing number of LT procedures being performed in recipients with high MELD scores.121 In the most extreme cases, allograft hepatectomy with a native portocaval shunt in anticipation of impending retransplantation within the next 12 to 24 hours improves the patient's physiology and may be required to save the patient. Recipients meeting the UNOS PNF criteria (Table 7) receive the highest priority for immediate retransplantation. All other cases of early graft dysfunction are defined as IPF by default. Although IPF grafts eventually function, they have a higher than expected rate of graft failure as early as 3 months post-OLT.123 Although risk factors can be identified in the majority of patients with PNF or IPF, the exact pathophysiology in most cases is unknown.120 Furthermore, such factors can also be present with a normally functioning graft. The key to distinguishing IPF from PNF is close clinical observation with a low threshold for operative exploration and relisting.
|Within 7 days of implantation/AST level ≥ 3000 and one or both of the following:|
|INR ≥ 2.5|
|Acidosis, (arterial pH ≤ 7.30 or a venous pH of 7.25 and/or a lactate level ≥ 4 mmol/L)|
|Anhepatic candidate because of allograft failure|
Early Immunological Complications
Hyperacute Rejection [Antibody-Mediated Rejection (AMR)].
Hyperacute rejection is a rare entity after LT. It is the result of the deposition of circulating, preformed antibodies present at the time of transplantation into the allograft sinusoids and vascular endothelium, with the activation of complement and the coagulation cascade culminating in thrombosis and hemorrhagic graft necrosis.124 The use of ABO-incompatible grafts accounts for 60% of these cases.124 Perioperative risk reduction strategies include plasma exchange, intravenous gamma globulin (IVIG) and B cell–depleting therapy, and splenectomy.125 In the absence or failure of one or more of these therapies, recipients may develop signs of acute liver failure (coma, renal failure, transaminitis, and coagulopathy), often within hours to days of LT. Despite attempts at medical salvage with the aforementioned maneuvers, expeditious retransplantation is the only durable option for recipients with acute liver failure.
Acute Cellular Rejection (ACR).
ACR is diagnosed in 25% to 50% of recipients within the first 6 months after transplantation,126 but it is rarely seen early unless the immunosuppression is subtherapeutic. Thus, maintaining the appropriate degree of scrutiny of serum aminotransferases allows the early detection of ACR. Particularly specific for hepatic injury is a rising or plateaued alanine aminotransferase (ALT) level; if this is left untreated, increasing aspartate aminotransferase (AST) and bilirubin levels may follow. For a previously functioning graft, if a normalizing aminotransferase trend reverses and technical complications have been excluded, ACR should be high in the differential diagnosis. Biopsy will confirm the diagnosis, and the treatment is based on the severity. Options include the optimization of maintenance immunosuppression for mild ACR, steroid pulses and tapering for moderate or severe ACR, and T cell depletion therapies for severe or refractory episodes.127, 128 Patients receiving depleting therapies should receive prophylaxis against CMV viremia/infection. Notably, intragraft edema associated with severe ACR may result in secondary HAT.129
Because of the technical challenges and attendant increased blood loss, both of which can magnify the impact of the aforementioned risk factors, recipients undergoing second or third retransplant operations have progressively higher rates of early graft dysfunction and loss.130
In summary, technical and nontechnical complications may arise in the early post-OLT period and should be evaluated expeditiously. Subtle extrahepatic organ dysfunction, transaminitis, coagulopathy, and progressive hepatic dysfunction with coma and renal failure represent a spectrum of clinical manifestations of all of the complications reviewed herein. Supportive management with hemodynamic support, RRT, and factor resuscitation when indicated with fresh frozen plasma, cryoprecipitate, recombinant factor VII, and desmopressin should be applied, but determining the need for retransplantation is of paramount importance. Experience allows clinicians to best determine whether imaging and catheter-based procedures will provide outcomes equivalent or superior to the outcomes of planned early reoperation, remediation of technical complications, or even a temporary anhepatic state with retransplantation for the salvage of failing grafts.