Chapter 90. The Transplant Patient

• The critical care of the transplant recipient requires a multidisciplinary approach.
• Although some generalizations can be made regarding the management of all transplant patients, organ-specific considerations based on the particular allograft transplanted are often much more important.
• Risks and benefits of immunosuppressive therapy must be balanced in transplant recipients. Though immunosuppressive drugs are essential to prevent allograft rejection, they also increase the risk of infection and neoplasm.
• All immunosuppressive drugs have side effects and many have important drug-drug interactions that must be recognized by the intensivist.
• Rejection of the allograft can be divided into three broad categories: hyperacute, acute, and chronic rejection.
• Infections can reactivate in an immunocompromised recipient who has been previously exposed. Alternatively, a naïve recipient may acquire an infection following the transplant of an organ from a seropositive donor.
• Infections in transplant recipients can progress rapidly and hence must be promptly recognized and appropriately treated.
• Often immunosuppressive therapy must be adjusted or withdrawn in the presence of severe infection.

This chapter provides a practical approach to the critical care of patients following the most common solid-organ transplant procedures. Important scientific advances have greatly improved our understanding of transplant immunology. Therapies have been developed that markedly decrease the incidence and severity of allograft rejection, and this has resulted in dramatic improvements in the outcomes of transplant recipients (Table 90-1). The major causes of morbidity and death in these patients depend on the time since transplantation. Technical and bacterial infectious complications predominate in the early postoperative period. Chronic rejection remains the major cause of death overall in these patients, occurring months to years after transplantation (Fig. 90-1).

An organ that has been transplanted from one individual to another (of the same species) is called an allograft. Although some generalizations can be made regarding the management of all transplant recipients, organ-specific considerations dependent upon the type of allograft that has been transplanted are often much more important. Following a brief introduction covering important aspects of immunosuppressive therapy, allograft rejection, and infectious complications, this chapter has been divided into sections that focus on considerations specific to the organ that has been transplanted.

In this chapter we will not deal with the management of patients following bone marrow transplantation, which is discussed in Chapter 73. Furthermore, as most recipients of kidney transplants now are cared for in step-down units or transplant wards rather than within ICUs, we have chosen to only discuss this procedure when it is performed at the same time as pancreas transplantation.

The management of all transplant recipients involves a careful balance of the risks and benefits of immunosuppressive therapy. To avoid rejection of the allograft by the recipient's immune system, therapy with immunosuppressive agents is usually required. More than one agent is employed to allow for the targeting of different immunologic effector pathways (Fig. 90-2). As a consequence of the resultant modulation of the immune system's surveillance and response functions, the transplant recipient is placed at risk of developing infections and neoplasms.

Immunosuppressive therapy can be divided into three phases: induction, maintenance, and the treatment of acute rejection. The induction phase commences in the immediate postoperative period and involves intense immunosuppression which usually is continued for 2 to 4 weeks. Although practice at different centers varies, most regimens typically include the use of systemic corticosteroids in conjunction with a calcineurin inhibitor and a proliferation inhibitor (see below).1 These agents may be started intravenously, but are switched to oral formulations to minimize toxicity once the patient is tolerating and absorbing enteral medications and feeds. To avoid some of the renal toxicity associated with the calcineurin inhibitors, antithymocyte immunoglobulin or anti–interleukin-2-receptor antibodies (IL-2R Abs) may be substituted in the early postoperative period.

The maintenance phase follows the induction period and is heralded by a reduction in the intensity of immunosuppression. Typically the maintenance phase is comprised of the planned regimen that will be used to suppress the immune response to the allograft and thus prevent rejection over a more prolonged period. Most patients will be maintained on either oral prednisone and cyclosporine or tacrolimus, although it appears that in some patients receiving tacrolimus for maintenance the steroid component may be discontinued completely.2 Azathioprine or mycophenolate mofetil (MMF) are often used during the maintenance phase to permit dose reduction of the other immunosuppressive drugs in order to minimize side effects.

The remaining phase of immunosuppressive therapy is not planned but it is anticipated and involves the treatment of acute rejection. Despite improvements that have been made in immunosuppressive strategies, episodes of acute rejection still commonly occur in the postoperative period, typically between 1 week and 1 year following the operation. Early recognition and prompt treatment of acute rejection is essential if long-term graft function is to be preserved. Treatment involves an intensification of the immunosuppressive regimen, which is usually accomplished through the use of high-dose steroids, short courses of antithymocyte globulin, and increased doses of the other immunosuppressive therapies. Issues pertaining to acute rejection will be discussed in greater detail in the sections dealing with organ-specific considerations.

Calcineurin Inhibitors and Related Compounds (Cyclosporine, Tacrolimus, and Sirolimus)

The introduction of cyclosporine was one of the most revolutionary events in the field of transplant medicine,3 and the drug remains an important component of immunosuppressive regimens used by many institutions. Though in recent years some centers have switched to tacrolimus or sirolimus, two newer immunosuppressive agents, all agents in this class share several features. All provide effective inhibition of T-cell activation by interfering with a receptor on T cells that involves a calcium-dependent signal transduction pathway.

Cyclosporine binds to intracellular cyclophilin, and this complex interacts with calcineurin. Calcineurin is crucial for normal lymphokine gene activation, and its inhibition by cyclosporine consequently interferes with the production of interleukins-2, -3, and -4 (IL-2, IL-3, and IL-4), tumor necrosis factor-α (TNF-α), and other important mediators of inflammation. In turn, specific and potent inhibition of T-cell activation (especially CD4 cells) is achieved. It is important for the intensivist to understand the serious toxicities associated with the use of cyclosporine. The most frequently encountered problem is nephrotoxicity, and in many patients cyclosporine causes a rise in serum creatinine level and a reduction of glomerular filtration rate (GFR). The mechanism of this toxicity is felt to be related to vasoconstriction of the afferent glomerular arteriole.3 Neurologic complications may be encountered in up to 20% of patients, including tremor, paresthesias, headache, confusion, seizures, and even coma. Other complications include hypertension (which often requires treatment), hyperkalemia, tremor, hirsutism, gingival hyperplasia, and glucose intolerance. Cyclosporine is metabolized by cytochrome P450-3A4 (CYP450-3A4) enzymes. Thus it is important to remember that inhibitors of cytochrome P450 (e.g., erythromycin, fluconazole, diltiazem, and verapamil) will increase serum cyclosporine levels, whereas inducers of these enzymes (e.g., phenobarbital, phenytoin, rifampin, and trimethoprim) will decrease the serum levels (Table 90-2). Previously trough drug concentrations were used to guide therapy. However, more recent recommendations have focused on the use of peak cyclosporine levels to monitor the adequacy of immunosuppression.4 Ideally the dose of cyclosporine should be titrated using a biological assay or an assessment of the downstream effect of the drug on immune effector function. Such assays are under investigation.

Tacrolimus (formerly FK506) is a macrolide antibiotic with powerful immunosuppressive properties. Its mechanism of action is similar to cyclosporine, but the drug is more potent. Tacrolimus binds to a receptor known as FK-binding protein (FKBP), and suppresses calcineurin-dependent T-cell signaling.5 Two controlled trials comparing tacrolimus to cyclosporine in liver transplant recipients demonstrated that tacrolimus reduces the incidence of acute rejection, refractory rejection, and chronic rejection6–8 with similar patient and graft survival. However, the drug has important toxicities. As with cyclosporine, nephrotoxicity is the most troublesome side effect. Important neurotoxicity (seizures, tremor, psychoses, and coma) may also occur with its use. Both tacrolimus and cyclosporine decrease insulin secretion and can lead to hyperglycemia.9,10 Interestingly, however, in renal transplant recipients who were converted from cyclosporine to tacrolimus, there was an improvement in other cardiovascular risk factors such as blood pressure and lipid profile.11 The gingival hyperplasia and hirsutism commonly seen with cyclosporine do not occur with tacrolimus. Tacrolimus is also metabolized by CYP450-2A4 enzymes, and the clinician must be cognizant of the effects other drugs will have on its metabolism.

Sirolimus (rapamycin) is a drug related to tacrolimus that binds to FKBP. However, in contrast to tacrolimus it does not interfere with calcineurin activity and consequently does not interfere with the activation of cytokine genes. Its main effects are the inhibition of IL-2 production and the suppression of T-cell proliferation. Side effects include thrombocytopenia, hypercholesterolemia, and hypertriglyceridemia. Compared to cyclosporine and tacrolimus, the drug does not appear to have the same potential to cause renal failure. However, sirolimus may be associated with an increased risk of hepatic artery thrombosis and subsequent allograft loss12 in liver transplant recipients. There have also been reports of interstitial pneumonitis associated with sirolimus.13–16 Sirolimus is not recommended in the early postoperative period following lung transplantation, as it has been associated with bronchial anastomotic dehiscence.17,18

Proliferation Inhibitors (Azathioprine, Mycophenolate Mofetil)

The proliferation inhibitors block DNA and RNA synthesis by interfering with normal purine metabolism. Since lymphocytes are unable to salvage purine as efficiently as most other cells, these drugs effectively inhibit lymphocyte proliferation and clonal expansion.

Azathioprine is a purine analogue that is converted in the liver to 6-mercaptopurine and which compromises synthesis of DNA and RNA. Its most important side effect is marrow suppression, and the drug can cause a profound leukopenia. Other important toxicities include hepatotoxicity and rarely fulminant hepatic failure, acute pancreatitis, skin malignancies, and increased susceptibility to infections.

Mycophenolate mofetil (MMF) interferes with purine metabolism as a reversible inhibitor of inosine monophosphate dehydrogenase. It also blocks clonal expansion of B- and T-lymphocytes. Important side effects of MMF include marrow depression (especially leukopenia and thrombocytopenia) and diarrhea. Less common problems include esophagitis, gastritis, and gastrointestinal bleeding. MMF may have an advantage over azathioprine in preventing acute rejection.19

Both azathioprine and MMF are now used predominantly as an adjunct to corticosteroid therapy in the maintenance phase of immunosuppression. The major advantage of these drugs is that their use will often enable the doses of corticosteroids and even of the calcineurin inhibitor to be reduced, thus avoiding some of the potential dose-related toxicity associated with these other agents.

Antilymphocyte Antibodies

Antibodies directed against lymphocytes were first introduced as an immunosuppressive therapy as antilymphocyte globulin (ALG). This therapeutic agent was created by immunizing animals with human lymphocytes and subsequently purifying the antibody-containing globulin fraction. ALG is very effective at depleting lymphocytes in the peripheral circulation, and quickly became an important component of regimens used for induction of immunosuppression and for the treatment of acute rejection. However, it was subsequently largely replaced by OKT3, a murine monoclonal preparation directed against T lymphocytes which could be used in much smaller doses because of its increased purity. OKT3 binds to the CD3-ϵ chain present on all human T cells, and causes a rapid clearance of peripheral T cells. Interestingly, it initially causes activation of T cells and the subsequent release of several lymphokines, including IL-2, IL-6, γ-interferon, and TNF. Rabbit antithymocyte globulin and to a lesser extent equine antithymocyte globulin are currently the antilymphocyte antibody preparations used most frequently by most centers.1

The antilymphocyte preparations are used primarily in the induction phase, and they have been shown to have higher success rates than steroids for the treatment of acute rejection.20 When administered for this latter problem, prompt resolution of the rejection episode is usually observed. However, these preparations have significant toxicity. Fever is almost always observed at the time of infusion. Nonetheless, the importance of careful surveillance for infectious complications cannot be understated, as these therapies significantly attenuate the normal host immune response. The inflammatory response due to lymphokine production that is often seen with the initiation of therapy usually responds to corticosteroids, antihistamines, and acetaminophen.21 Serum sickness has been observed with repeated use of these preparations. Furthermore, when these agents (especially OKT3) are administered more than once, the patient may develop antibodies directed against the globulin preparation that can substantially limit its efficacy. Long-term use is also associated with increased risk of viral infections (particularly cytomegalovirus) and posttransplant malignancy. Other less common complications of therapy include seizures (especially when concomitant hypocalcemia is present) and the acute respiratory distress syndrome (ARDS), possibly due to increased pulmonary capillary permeability arising from lymphokine stimulation.

Systemic Corticosteroids

Systemic corticosteroids remain a key component of each phase of immunosuppression, and are received by over 95% of patients with pancreas, heart, lung, and heart-lung transplants.1 They have multiple effects on the immune response. Importantly, steroids block T-cell proliferation and IL-2 synthesis. The phagocytic function of macrophages is inhibited, and in high doses corticosteroids prevent neutrophil degranulation.

Though they effectively attenuate the immune response and help prevent allograft rejection, corticosteroids also significantly increase the recipient's susceptibility to infection. In particular, viral and fungal infections appear to be highly associated with the use of corticosteroids. An important consideration is that steroids can also mask the typical signs of infection. For example, patients on high doses of these medications may not present with signs of peritonitis despite having intra-abdominal infections. As transplant patients typically remain on steroids chronically, the possibility of adrenal suppression and even overt adrenal insufficiency must be considered if these medications are discontinued. Despite their widespread use and important role in most immunosuppressive regimens, corticosteroids are associated with many of the significant side effects encountered by transplant patients. Insulin resistance is common, and the use of oral hypoglycemic agents and often insulin may be required. Both cyclosporine and tacrolimus affect insulin release and can induce insulin resistance, and may contribute to the hyperglycemia.22–25 Increased sodium and water retention induced by steroids may aggravate posttransplant hypertension. Impaired wound healing has been well documented with the use of corticosteroids, and consequently these drugs may contribute to the development of postoperative surgical complications. Steroids are associated with increased risk of gastrointestinal hemorrhage, and thus most patients will be placed on routine stress ulcer prophylaxis, usually with either a histamine (H2)-antagonist or a proton pump inhibitor. Long-term use of steroids often leads to osteopenia, overt osteoporosis, and fractures. Aseptic necrosis is a dreaded complication of steroid use that can occur at any time following the institution of therapy. Skin changes and fat redistribution are common. Steroids are also associated with mood changes and rarely even frank psychoses. Because of the significant side effects associated with steroid use, most maintenance immunosuppressive regimens now include antiproliferation inhibitors such as azathioprine or MMF to facilitate the early reduction of the corticosteroid dose.

New Agents

Recently, there has been increased use of anti–interleukin-2 receptor antibodies (basiliximab, daclizumab) during the induction phase.1 Both agents bind to the α-chain of the IL-2 receptor, and competitively inhibit IL-2–induced proliferation of active T cells. The advantage of these compounds is that they are not associated with the toxicity produced by antilymphocyte preparations. Their use has been shown to decrease the rate of acute rejection following kidney26,27 and heart transplantation.28

Rejection of the allograft can be divided into three broad categories: hyperacute, acute, and chronic rejection. Hyperacute rejection is mediated by preformed antibodies directed against donor antigens, and occurs immediately following the transplant operation. Matching of donor and recipient major blood group type (A, B, O) essentially eliminates this class of rejection, which can have devastating consequences. Immunosuppressive therapy is generally ineffective at treating this cause of graft failure, and retransplantation of the organ may be the only possible recourse to prevent death.

Acute rejection is much more commonly encountered, occurring in 20% of kidney-pancreas transplants, 30% of liver transplants, and 40% of lung and heart transplants during the first year.1 Usually rejection does not manifest until the first several days following the transplant procedure. It occurs as the result of cell-mediated immunity, and it generally responds well to escalation of the immunosuppressive regimen.

Chronic rejection tends not to develop during the initial stay in the ICU, but patients may require ICU care as a result of the sequelae of the chronic inflammation and fibrosis that is the hallmark of this complication. Manifestations of chronic rejection are organ specific. In liver transplant recipients, it is characterized by the “vanishing-bile-duct syndrome,” whereas bronchiolitis obliterans is the scourge that faces lung transplant recipients and is the leading cause of late death in these patients. Premature and accelerated atherosclerosis of the coronary arteries characterizes chronic rejection in heart transplant recipients.

Prior to the transplant procedure, it is important to know whether or not the transplant recipient has been exposed to common infections that can cause serious morbidity in the postoperative period when immunosuppressive therapies are instituted. Patients are routinely screened for antibodies to cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes viruses, hepatitis B and C viruses, human immunodeficiency virus (HIV), Toxoplasma, and tuberculosis exposure via skin testing. These infections can reactivate in an immunosuppressed recipient who has been previously exposed. Alternatively, a naïve recipient may acquire an infection following the transplant of an organ from a seropositive donor.

Because of the considerable morbidity associated with these infections, most transplant patients will receive prophylactic therapy if they are seronegative for any of these agents. If not already done preoperatively, transplant recipients can be vaccinated with killed vaccines in the postoperative period. Vaccination still confers some protection despite the attenuated humoral response in these patients.

In the early posttransplant period, however, bacterial and fungal infections predominate and are a frequent cause of morbidity and mortality (see Fig. 90-1). Since the regimens used for immunosuppression are similar for all solid-organ transplants, the recipients of such transplants will be susceptible to similar infectious agents. Specifically, using relatively high doses of calcineurin inhibitors such as cyclosporine or tacrolimus in combination with high doses of corticosteroids places the recipient at high risk of early infectious complications. This intensity of immunosuppression amplifies the risk of infection faced by all critically-ill patients.

Opportunistic infections can develop through three general mechanisms. A virulent pathogen may be acquired from the environment (e.g., pneumococcal pneumonia, Aspergillus infections, etc), an endogenous but latent organism may become reactivated (e.g., tuberculosis, herpes viruses, etc.), or there may be invasion of an endogenous organism (e.g., Candida, enteric bacteria, etc.) into a normally sterile site. Several authors have proposed an approach that classifies the most likely infectious complications according to the time that has elapsed since the original procedure (Fig. 90-3).29,30

Infections Occurring in the First Posttransplant Month

In the first month after transplantation most infections will be similar to those encountered following any major surgery, including bacterial or candidal infections involving the lungs, urinary tract, surgical wound, or indwelling catheters. Consequently, efforts should be made to remove all vascular-access catheters and drains as soon as possible. As with any critically-ill patient, strategies to facilitate liberation from mechanical ventilation should be employed. The high level of immunosuppression during the induction phase significantly contributes to the development of infections during this time period, but usually the state of immunosuppression has not been of sufficient duration to allow many of the opportunistic infections that become so problematic in subsequent months to develop.31 Occasionally infections may be transmitted to the recipient by the allograft itself. The presence of bacteremia, fungemia, or active infection in a donor is generally considered a contraindication to organ donation given the associated high probability that infection will be transmitted to the host. Cultures obtained at the time of implantation (e.g., via bronchoscopic-guided lung lavage) may be used to guide treatment. Typically most centers employ prophylactic antibiotic strategies to empirically treat the microbes that are transplanted into the recipient. The choice of prophylactic antibiotics varies and usually reflects differences in the center's bacterial ecology. Parenteral, oral, topical, and inhaled medications are often used alone or in combination.

Similarly, any untreated infection that is present in the recipient at the time of the transplant may become a devastating problem following the initiation of immunosuppressive therapy. As a result, any active infection in a potential recipient is generally considered to be an absolute contraindication to transplant surgery.

Infections Occurring between 1 and 6 Months Posttransplant

Following the first month, the recipient is at risk for infections due to several viral infections that would normally be suppressed by an intact immune response. Particularly problematic are infections due to CMV, EBV, other herpes viruses, hepatitis B and C viruses, and HIV. Screening for these viruses is usually performed in both the donor and recipient prior to the transplant procedure, and pre-emptive therapy is often employed. Infection with HIV has traditionally been considered an absolute contraindication to transplantation. However, recently some experts have argued that asymptomatic HIV-positive patients should no longer be excluded from consideration for transplant of solid organs, citing the substantially improved survival of HIV carriers following the introduction of highly active antiretroviral therapy.32–34

The sustained immunosuppression used in the induction phase and early maintenance phase leads to an increased risk of opportunistic infections. Infections due to Pneumocystis carinii, Aspergillus, Listeria monocytogenes, and tuberculosis become important considerations. Most transplant programs routinely provide recipients with trimethoprim-sulfamethoxazole (TMP-SMX) to reduce the risk of Pneumocystis carinii infection. Should a transplant patient develop Pneumocystis carinii pneumonia, the treatment of choice is intravenous TMP-SMX. Pentamidine can be used as an alternative, but it is associated with a greater incidence of toxicity and side effects, and is generally considered to be less effective therapy. In patients who have a positive purified protein derivative tuberculosis skin test (>5 mm induration35) or who are at high-risk for reactivation of latent tuberculosis infection, prophylactic therapy with isoniazid for 9 to 12 months should be considered.35,36Aspergillus infections are most prob lematic for lung transplant recipients, but they can develop in any patient who has undergone solid-organ transplantation and is receiving chronic immunosuppressive therapy. The treatment of choice is amphotericin; liposomal preparations of amphotericin are available that are associated with less nephrotoxicity, but these are much more expensive. More recently caspofungin the first in a new class of antifungal agents (echinocandins) has been shown to be active against Aspergillus species.37–39 Although its role in treating immunosuppressed transplant patients has not been systematically evaluated, there is at least one suggestion that its antifungal effects (tested in vitro) may be enhanced in patients who are receiving concomitant calcineurin inhibitors.40Voriconazole, a newer azole anti-fungal agent, has demonstrated better outcomes and fewer side effects in comparison to amphotericin in patients with bone marrow transplantation.40a Experience in patients with solid organ transplantation is growing.

Infections Occurring More Than 6 Months Posttransplant

Severe infections occurring more than 6 months following the transplant procedure may necessitate ICU admission. Most commonly these infections are similar to those experienced by the general community and involve the respiratory tract.29 Other problems developing in this time frame include the progression of underlying infection with hepatitis B or C, CMV, EBV, and human papillomavirus. There is also a continued risk for the opportunistic infections that develop after the first posttransplant month (discussed above) during this time period, and careful surveillance for their occurrence must be maintained.

Infection Due to Cytomegalovirus

The most important and the most common viral infection for all solid-organ transplant recipients is CMV infection. Once an individual is infected by this herpes virus, they will be infected for life, though the virus generally remains in a latent or dormant phase. Recipients who are seronegative for CMV that receive an allograft from a seropositive donor are at greatest risk of developing symptomatic illness, including tissue-invasive disease from primary infection. Patients who are already seropositive for CMV prior to the procedure (indicating past exposure and latent infection) are at risk for reactivation following the initiation of immunosuppressive therapy. Superinfection by a new strain of CMV contracted from the allograft of a CMV-seropositive donor can also occur. Strategies to prevent CMV infection are usually based on the recipient's relative risk of developing infection, with those who are recipient-negative, donor-positive and recipient-positive, donor-negative (in the case of lung transplantation) receiving the more intense regimens.41 The monitoring of CMV antigenemia or viral load using polymerase chain reaction may be a component of these regimens, and may be used to guide duration of prophylaxis and provide evidence of infection or emergence of a resistant strain.42

The spectrum of disease caused by CMV infection among transplant recipients is quite variable.43 Infection can be completely asymptomatic or can be associated with an acute flu-like or mononucleosis-like illness characterized by fever and myalgias. The virus can cause bone marrow suppression and consequently leukopenia and thrombocytopenia. Infection of the allograft can cause organ-specific inflammation resulting in acute hepatitis, pneumonitis, myocarditis, nephritis, or pancreatitis, depending on the organ that was transplanted.31 Active CMV infection is also associated with the development of other opportunistic infections, likely due to CMV-mediated immune defects, and consequently it should be considered whenever an unusual infection (such as Pneumocystis carinii pneumonia or invasive aspergillosis) develops.29 Acute rejection has been associated with CMV infection. However, the role of CMV infection in contributing to chronic rejection is likely much more important. It has been associated with the development of bronchiolitis obliterans in lung transplant patients, the vanishing-bile-duct syndrome in recipients of liver allografts, and in premature and accelerated atherosclerosis of the coronary arteries following heart transplantation.29 Though posttransplant lymphoproliferative disease is usually associated with EBV infection, active CMV infection has also been implicated as a risk factor for its development.44–46

Treatment of CMV infection generally consists of intravenous ganciclovir for 2 to 4 weeks. Confirmation that CMV viremia has resolved should be sought before therapy is discontinued. In the near future ganciclovir use may be replaced or consolidated with the use of newer oral analogues, especially for long-term regimens.47,48 Occasionally a CMV isolate will be resistant to ganciclovir, and intravenous foscarnet must be used despite its increased toxicity.

Organ-Specific Infectious Considerations

Liver Transplant Recipients

Bacterial infections are frequent among liver transplant patients, and the source is most often intra-abdominal.49 Recognizing that overgrowth of pathogenic aerobic bacteria from the gastrointestinal tract may contribute to the development of many of these infections, some experts have recommended that oral selective bowel decontamination be started 3 days prior to the transplant operation.31 Though this approach may decrease the relative incidence of gram-negative infections in the first month, selective bowel decontamination has not been adopted by all transplant programs.50,51 Recent evidence suggests that this therapy only leads to a substitution for infections caused by gram-negative bacilli and Candida species with infections due to gram-positive organisms, and yet it is associated with a substantially increased cost.52

Transient biliary tree infection and subsequent bacteremia may occur following biliary tree manipulation (T-tube manipulation, cholangiography, etc). This has prompted many experts to advocate the use of pre-emptive systemic antibiotics around the time of such procedures.31

Liver disease resulting from hepatitis B or C infection remains one of the most common indications for liver transplant. The reactivation of these viruses in the recipient and resultant allograft infection remains a major challenge. Most patients who are seropositive for hepatitis B will receive hepatitis B immunoglobulin (HBIg) and lamivudine to suppress replication of the virus in the postoperative setting. These therapies are generally continued indefinitely, and have resulted in allograft and patient survival rates similar to those of patients not infected with hepatitis B.53 Recipients who are positive for hepatitis C virus prior to transplant have also been shown to have poorer graft and patient survival rates.54 However, no antiviral regimens have yet been shown to be effective at improving outcomes for these patients following orthotopic liver transplantation.55

Infections due to Candida are particularly common in liver transplant recipients, and the most common source is the gastrointestinal tract. Risk factors for these infections include concomitant CMV infection, retransplantation, the presence of choledochojejunostomy, and the use of OKT3 immunosuppression. The use of a regimen of oral selective bowel decontamination that includes an antifungal agent has already been discussed, and certainly this intervention decreases the incidence of candidal infections. There is evidence that the routine pre-emptive use of oral fluconazole (100 mg/d56 to 400 mg/d57) or liposomal amphotericin B 58,59 after liver transplant is effective at reducing the incidence of these infections. However, some have cautioned that routine prophylaxis may encourage the emergence of resistant candidal strains, and have suggested that only high-risk patients be targeted for therapy.60

Lung Transplant Recipients

Following lung transplantation, patients are at risk for all of the infections that plague individuals with a chronically immunosuppressed state. However, the incidence of infection in these patients is much higher than that reported for recipients of other solid organs, presumably due to the exposure of the allograft to the external environment.61,62 The development of CMV infection can cause significant morbidity and can increase transplant-related mortality, especially if new infection develops in a seronegative recipient who has received an allograft from a seropositive donor. Seropositive recipients can also be reinfected by a new strain of CMV, but these infections tend not to be as severe. Treatment consists of intravenous ganciclovir, and many centers will routinely use this agent as prophylaxis against CMV infection if either the donor or the recipient is seropositive.

Aspergillus is an organism that frequently colonizes the airways of lung transplant recipients, but may also lead to clinically important infections. Oral itraconazole or inhaled or intravenous amphotericin are usually effective therapies. In its most severe form, invasive aspergillosis and disseminated disease are associated with high mortality rates. The bronchial anastomosis is particularly vulnerable to infection with this organism, though the airways may become more diffusely affected, and mucosal edema, ulceration, and formation of pseudomembranes may occur.61 Patients with septic lung disease (cystic fibrosis or bronchiectasis) are a unique group and have a very high risk of early infection. These patients' airways are typically highly colonized. Despite efforts to sterilize the trachea and major bronchi in the perioperative period, secretions originating from these recipients' upper airways and proximal lower airways likely contaminate the transplanted lungs. Consequently most centers employ an antibiotic strategy to deal with these colonizing organisms, which are typically Staphylococcus aureus, nontuberculosis mycobacteria, Pseudomonas species, or enteric gram-negative bacilli. Owing to longstanding antibiotic pressure these organisms are often highly resistant to first-line agents, and can be difficult to treat if an infection becomes established. In particular Burkholderia cepacia is a dreaded colonizer that represents a major threat for some centers caring for cystic fibrosis patients.63 Indeed, patients with cystic fibrosis complicated by B. cepacia infection have a worse outcome than their counterparts without this infection.64,65Aspergillus lung infection may also be more common in patients transplanted for cystic fibrosis.66

Defining the etiology of new or progressive airspace opacities in the perioperative lung transplant period is a frequent dilemma. Airspace disease may represent reperfusion injury (see below), volume overload, acute lung injury, early rejection, or infection.67 Computed tomographic (CT) scanning of the chest and bronchoscopic sampling of the distal airways is often required to rule out an infectious cause. A trial of diuresis or placement of a pulmonary arterial flotation catheter may be required to evaluate the contribution of volume overload to the opacities. The role of lung biopsy in establishing the cause of radiographic worsening is controversial. Transbronchial lung biopsy may lack sufficient sensitivity in the perioperative setting.68 However, the utility of open lung biopsy (OLB) is variable,69,70 and hence it should be carefully considered if the etiology of the lung infiltrates remains uncertain. In one retrospective series of 48 open biopsies from 42 patients, 32 (67%) of the biopsies confirmed the clinicians' initial suspicions and prompted the initiation of “new therapy” in 30 (71%) of the patients.69 A new diagnosis was made following 14 of the biopsies (29%). Only two patients (4% of all OLBs) had a nondiagnostic OLB. Four biopsies (8% of all OLBs), including the two nondiagnostic OLBs, did not result in any change in therapy. Complications of the procedure were rare, though three (7%) patients developed an air leak which persisted more than 7 days. In contrast an earlier report of 38 biopsies (representing 32 patients) found that early open lung biopsies (performed <45 days after transplant) were not useful, and resulted in a change in therapy for only 1 of 11 cases.70

Heart Transplantation

Most heart transplant recipients will receive intravenous ganciclovir for 3 to 4 weeks as prophylactic therapy if they are seropositive for CMV before transplantation. If a seronegative recipient receives an allograft from a seropositive donor, they are given prophylactic therapy for 12 weeks following the procedure.71

Infective endocarditis is an infrequent complication following heart transplantation, usually developing on the supravalvular suture line. Antibiotic prophylaxis is generally recommended for heart transplant recipients prior to dental, gastrointestinal, or genitourinary tract surgery.72

Liver Transplantation

The Procedure

During orthotopic liver transplantation, the native organ is removed and replaced by a cadaveric liver. Extracorporeal venovenous bypass is often used during the procedure to decompress the systemic and splanchnic venous systems. Although this may help preserve hemodynamic stability during the operation and decrease intraoperative bleeding problems, potential complications include intraoperative air embolism73,74 and thromboembolism. The biliary tract will be reconstructed either by creating an end-to-end anastomosis of the donor and recipient common ducts (using a T-tube stent) or by connecting the donor's common duct to the recipient's jejunum. Anastomoses are created between the native and allograft cava (supra- and infrahepatic), portal veins, and hepatic arteries. Removal of the venous clamps leads to reperfusion of the organ, and this will often be associated with hemodynamic instability, coagulopathy, and electrolyte abnormalities (particularly hyperkalemia).

Recently, there have been a growing number of patients who undergo living-donor transplants. In Asia, almost all liver transplant procedures have involved living donors.75 In this procedure, the right hepatic lobe from a donor with a compatible blood type is implanted into the recipient following hepatectomy of the diseased organ. Along with an often substantially reduced waiting time for the procedure, living related transplants may also allow for better selection of healthy donors (and consequently donor organs) and a considerably decreased cold ischemia time. The elective nature of the procedure also enables potential recipients to be medically stabilized preoperatively. The major disadvantage is the small but significant risk of complications for the donor. Biliary complications may occur in up to 6% of donors,76 and other complications of abdominal surgery such as wound infection may develop; the reported mortality of donors following living-donor liver transplant is 0.28%.75 One study suggests that in the United States approximately 99% of living donors are genetically or emotionally related to the recipient,76 creating important ethical and psychosocial challenges.

Postoperative Considerations

Mechanical Ventilation

Most patients will require mechanical ventilation for the first 24 to 48 hours following the liver transplant procedure. Extubation should not be considered until there is evidence that the allograft is functioning properly and the patient's level of arousal is sufficient to allow for adequate airway protection. This latter consideration is especially important given that anesthetic agents and sedating medications may be cleared more slowly from the circulation by the newly transplanted liver. The need for reintubation in liver transplant patients has been associated with poorer outcomes and even increased mortality.77 However, there is mounting evidence to support the notion that attempts at early extubation of liver transplant recipients may reduce ICU utilization. Selection of suitable candidates seems crucial.78–82

Monitoring of Liver Function

The function of the new allograft should be assessed in the same manner that liver function is assessed in any patient. Coagulopathy is often present in the immediate postoperative period, but should correct soon after the transplant. The prothrombin time (PT) or International Normalized Ratio (INR) should be followed closely. Administration of fresh frozen plasma will interfere with the ability to monitor these parameters. Consequently some programs avoid the transfusion of coagulation factors unless necessitated by bleeding complications.

Glucose should be monitored frequently during the ICU stay as liver failure will often result in refractory hypoglycemia. Conversely, the use of corticosteroids may lead to insulin resistance and hyperglycemia, which should be treated appropriately. Bilirubin often remains elevated for many days following the transplant, but should be followed closely as abrupt changes may herald complications involving the biliary tree or the vascular supply to the liver. Serum lactate levels are frequently elevated immediately following the operation, but if the graft is functioning properly they should return to normal within a few days.

Serum transaminase levels (AST/ALT) are usually measured postoperatively; these usually rise in the first 2 to 3 days following the procedure, but then can be expected to normalize. Similar to changes in bilirubin levels, abrupt changes or progressive elevations of these enzymes may also signify complications and mandate further evaluation.

Fluids and Hemodynamics

Physiologic derangements following liver transplantation are common. Intraoperative blood and fluid loss may be considerable. The use of aprotinin during the operation has been advocated by some as a means to reduce blood loss.83–85 Interestingly, several studies also report decreased vasopressor requirements in patients who receive this therapy intraoperatively.86,87 Its use has also been associated with an improvement in renal function.88 However, this initial enthusiasm for aprotinin therapy needs to be tempered by concerns regarding a possible increased potential for thrombembolism.89,90

Following the operation, patients may lose significant amounts of fluid and protein via the abdominal drain, especially if massive ascites was present preoperatively owing to advanced cirrhosis and decompensated liver disease. These latter patients are at particularly high risk of developing intravascular volume depletion, and they must be monitored carefully and treated aggressively. Serial hematocrit determinations should be measured (usually every 4 to 6 hours) to ensure that significant bleeding is not present. It should be noted that the hyperdynamic circulatory state that characterizes liver dysfunction will often persist in the postoperative period, making interpretation of hemodynamic measurements difficult. An increased cardiac output with decreased systemic vascular resistance is often observed. Although aggressive fluid resuscitation is indicated to treat intravascular volume depletion, it should also be noted that patients are at particularly high risk of cardiopulmonary complications following liver transplantation.91 Electrolyte abnormalities, particularly hyponatremia, are often observed. Overly aggressive treatment of derangements of sodium can precipitate the osmotic demyelination syndrome (formerly called central pontine myelinolysis).

Particular care is required for the patient who has significant preoperative portopulmonary hypertension. These patients will often encounter pulmonary hemodynamic instability and may have increased cardiopulmonary mortality, especially if the preoperative mean pulmonary artery pressure is greater than 35 mm Hg.92 Invasive hemodynamic monitoring with a pulmonary artery catheter should be considered to guide therapy in these patients. Specific pulmonary vasodilators such as inhaled nitric oxide or nebulized prostaglandins may be required in the setting of right ventricular dysfunction in order to preserve cardiac output.

A system for classifying patients based on their anticipated need for fluid and electrolyte replacement has been proposed93 and advocated by several experts.94 Such an approach may be practically useful in that it creates a framework to understand the hemodynamic considerations for a given patient (Table 90-3). According to this classification, a patient with class I liver disease can be expected to have a normal postoperative response to intravenous fluid therapy. Patients with class II or III liver disease will have more ascites, leading to greater fluid and protein loss from the abdominal drain, and can be anticipated to need more fluids postoperatively and careful monitoring of electrolytes. Patients with class IV disease require the closest monitoring and may benefit from insertion of a pulmonary artery catheter to assist with the management of the portopulmonary hypertension and cardiac dysfunction that is often present.

Postoperative Renal Dysfunction

Following the liver transplant procedure renal dysfunction is frequently observed, and postoperative renal failure can be severe enough to require renal replacement therapy in up to one third of patients. However, kidney function generally improves, and only 5% of patients require chronic hemodialysis following liver transplant.95

The most common precipitant is intravascular volume depletion resulting in prerenal azotemia. However, nephrotoxicity due to the immunosuppressive drugs is also common. The development of hepatorenal syndrome occurs in 7% to 15%94,96 of patients with cirrhosis, and is commonly observed following orthotopic liver transplant. It is likely that strategies aimed at preventing hepatorenal syndrome are the most effective. Thus care should be taken to promptly treat bleeding insults and to avoid intravascular volume depletion. When CT scanning or other imaging techniques are being considered, the use of intravenous contrast dye should be avoided if possible. If intravenous contrast is required for proper imaging (and the benefits outweigh the risks of the test), consideration should be given to the use of acetylcysteine if renal function has not completely returned to normal, in order to protect the kidney from further insult and contrast nephropathy.97 Terlipressin (a long-acting vasopressin analogue) has been reported to be successful in improving urine output in cirrhotic patients with hepatorenal syndrome.98,99 The relative contribution of albumin coadministration to the success of this pharmacologic strategy has been evaluated and supports the notion that maintenance of intravascular volume is integral in the treatment of these patients.100 One study also advocates the addition of acetylcysteine to mitigate the potential ischemic nephropathy that may result from the vasoconstrictive effects of terlipressin on the kidney.99 The role of terlipressin in patients with established hepatorenal failure following transplantation has not been systematically evaluated. Indeed, in theory, liver transplantation should correct hepatorenal failure.101,102

Primary Graft Nonfunction

Primary graft nonfunction refers to a failure of the transplanted liver early in the postoperative period. The characteristics of this devastating complication include minimal bile output, refractory coagulopathy, progressive elevation of transaminases, acidosis, hypoglycemia, and cerebral edema. The incidence of this dreaded complication is likely only between 3% and 5%,103,104 but the associated mortality rate may be higher than 20%.105–107

Several considerations exist if the graft fails to work postoperatively. The possibility of vascular complications should be entertained and excluded with Doppler ultrasonography.108 Investigations to detect severe infection or acute rejection should be initiated. If all these tests fail to elucidate the cause of graft failure, primary graft nonfunction is the likely cause.

Vascular Complications

The incidence of vascular complications following liver transplant ranges from 8% to 14%.109,110 These develop most commonly on the first postoperative day, but may occur up to several weeks following the surgery.108 Thombosis is the most common early complication, and stenosis and pseudoaneurysm formation generally develop later in the patient's course.The presentation of hepatic artery thrombosis has been associated with hepatic artery reconstruction with an interposition graft to the supraceliac aorta.111 Despite reassurances, some concerns about an increased risk of hepatic artery thrombosis with the use of sirolimus remain.112 The clinical picture of this complication can vary from the asymptomatic rise in liver enzymes to fulminant hepatic failure. Urgent laparotomy and revision of the hepatic artery anastomosis is required if this complication develops, and unfortunately retransplantation is often necessary if hepatic necrosis has occurred.

Portal vein thrombosis develops less frequently and may present more insidiously. Ascites may be seen to develop or worsen, and variceal bleeding (usually from pre-existing varices) may ensue. Thrombectomy and anastomotic revision can be successful if this complication is diagnosed early.

Biliary Leaks

Biliary complications occur in approximately 15% of patients following orthotopic liver transplantation.113 Of these, bile leak is the most common early complication. Symptoms are nonspecific, and can include fever, abdominal discomfort, and signs of peritoneal irritation. Though ultrasound may demonstrate an intra-abdominal fluid collection, cholangiography will provide a definitive diagnosis. Endoscopic insertion of biliary stents can sometimes provide satisfactory results, but surgical repair of the leak may be required.

Biliary strictures and stones typically appear later in the postoperative period. Obstructions usually can be managed endoscopically114 or through the use of interventional radiology techniques, but surgical correction is sometimes necessary. Strictures typically develop at the anastomotic site, and are likely the result of local ischemia. These may present as cholestasis or possibly as overt cholangitis. Balloon dilation of the stricture with or without stent placement usually is successful treatment, but surgical revision and even retransplantation may be required.

Intra-Abdominal Infections

Intra-abdominal infections ranging from local abscess formation to overt peritonitis can occur following liver transplantation. Development of these complications should always lead the clinician to suspect that a leak has occurred from the biliary anastomosis or from the jejunojejunostomy; correction of these problems will often require laparotomy and surgical repair. However, abscesses can usually be treated with CT-guided drainage and subsequent serial CT scans to ensure that the collection has been adequately drained.

Rejection

Rejection of the hepatic allograft is usually not seen until about 1 to 2 weeks following the procedure, and most often manifests as fever, right upper quadrant pain, and reduced bile pigment and volume. However, the most sensitive marker of early rejection is a rise in serum transaminase (AST/ALT) levels and bilirubin. A rise in total white blood count may also develop. The most important consideration when elevation of these serum enzymes occurs early in the postoperative course is the exclusion of one of the various mechanical complications (such as vascular compromise, biliary obstruction, and primary graft nonfunction). After the biliary tree and vascular structures have been imaged using ultrasonography, a liver biopsy will help confirm the diagnosis of acute rejection. As is the case in any solid-organ transplant recipient, treatment of acute rejection should be aggressive and must be instituted promptly. For liver transplant recipients, therapy usually involves antithymocyte globulin and increased or pulsed doses of methylprednisolone.

The management of chronic rejection of the transplanted liver usually does not involve the intensivist, but occasionally these patients may require ICU admission. Chronic rejection of the liver presents clinically as progressive cholestasis and histologically with mononuclear infiltration of the allograft, vascular abnormalities, and fibrosis. These findings are most commonly seen as part of the vanishing-bile-duct syndrome; treatment is often unsuccessful and may require retransplantation.

Lung Transplantation

The Operation

While combined heart-lung transplantation is still performed for patients with Eisenmenger syndrome and complex congenital cardiac defects that cannot be easily repaired at the time of the lung transplant, most patients will undergo either bilateral or single-lung transplantation. Bilateral lung transplantation is the preferred procedure for patients with septic pulmonary disorders such as cystic fibrosis and bronchiectasis. In contrast, single-lung transplantation can be performed in patients with chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. The observation that right ventricular dysfunction generally improves in patients with pulmonary hypertension following single- or double-lung transplantation115 has obviated the need for performing combined heart-lung transplantation in this group of patients.

During single-lung transplantation, sequential anastomoses are performed to attach the donor and recipient mainstem bronchus and pulmonary artery. The donor left atrial cuff and pulmonary veins are then attached to the recipient's left atrium. In a similar manner, bilateral lung transplantation is performed as two sequential single-lung transplant procedures. Most patients can be supported intraoperatively through the ventilation of a single lung while surgery is performed on the contralateral side. Consequently, cardiopulmonary bypass is generally only required if profound hypoxia is encountered.

Complications

Ischemia-Reperfusion Injury

Since hyperacute rejection (due to ABO mismatch) has become extremely rare, the earliest serious complication of the lung transplant operation is ischemia-reperfusion (IR) injury (also called primary graft failure or pulmonary reimplantation response). IR injury is a syndrome of severe allograft dysfunction characterized histologically by marked alveolar damage which manifests clinically as severe pulmonary edema. The incidence of this complication ranges from 10% to 20%, depending on the reporting center and the definition used,116–118 and when severe, it is associated with a very poor prognosis; as many as 41% of affected patients may die.117 A recent study also suggests that IR injury may be associated with the development of bronchiolitis obliterans later in the patient's course.119 Most series of patients with IR injury demonstrate that recipients will develop pulmonary infiltrates on chest x-ray during the first 3 days following transplantation.120 When entertaining this diagnosis, it is essential that the clinician perform a careful evaluation to exclude other possible complications. Confirmation should be sought that a donor-recipient cross-match (hyperacute rejection) has not occurred, that bacterial pneumonia has not developed (negative cultures from bronchoalveolar lavage), and that pulmonary venous return is not compromised owing to technical problems with the left atrial anastomosis (transesophageal echocardiography should be performed to ensure adequate blood flow through pulmonary veins). Invasive monitoring with a pulmonary catheter will help exclude volume overload or cardiogenic pulmonary edema. Transbronchial biopsy may be required to rule out the possibility of acute rejection. Treatment of IR injury is similar to the management of ARDS. Extending the results of trials of mechanical ventilation in patients with ARDS we recommend that lung-protective ventilation strategies with low tidal volumes be employed, with the use of sufficient positive end-expiratory pressure (PEEP) to reduce the fraction of inspired oxygen to acceptable levels.121 Since IR is characterized by increased alveolar capillary permeability, care must be taken to provide judicious fluid management. Some success at attenuating the injury from IR has been observed with the administration of prostaglandin E1, though this may lead to hypotension owing to the effects of the drug on the systemic vasculature. Inhaled nitric oxide (NO) has been advocated as a means to both treat and prevent IR injury. Initial preclinical and uncontrolled clinical studies of inhaled NO suggest that administration prior to IR injury may improve graft function.122–126 However, a recent controlled study of NO administered 10 minutes after reperfusion failed to show any benefit in terms of graft function.127 NO has also been used to improve oxygenation and reduce pulmonary arterial pressures in patients with oxygenation and vasomotor dysfunction after lung transplantation.128–130 If inhaled NO is used for its pulmonary vasodilatory properties and to decrease ventilation/perfusion mismatch, it should be understood that these effects should be seen within minutes of the institution of this therapy. Daily measurements of methemoglobin levels are required. If one extrapolates from studies of NO use in acute lung injury, the effects of NO on lung function are likely short lived.131 Consequently the rationale for long-term use of NO is unclear. Furthermore, the benefit of therapy is often difficult to assess owing to the development of rebound during attempts to withdraw NO therapy.123 We often employ sildenafil to prevent such rebound associated with withdrawal of NO therapy in these patients.132

Following single-lung transplantation, IR injury will often compromise lung function in the allograft. To avoid exposing the native lung (which is often emphysematous and prone to hyperinflation) to potentially injurious high airway pressures and alveolar overdistention, independent lung ventilation is often used. If conventional ventilation is causing overexpansion of the native lung leading to an increase in its pulmonary vascular resistance, blood may be preferentially shunted to the compromised graft. Independent lung ventilation involves the use of a double-lumen endotracheal tube (avoiding intubation of the transplanted bronchus), and enables each lung to be ventilated with different airway pressures and tidal volumes. This strategy can dramatically improve ventilation-perfusion (V̇/Q̇) mismatch. In the extreme case, the native lung may become sufficiently overdistended to cause mediastinal shift and lead to hypotension as a result of compromised venous return or cardiac tamponade.133 Other measures that can ameliorate the V̇/Q̇ mismatch and other sequelae of native lung overexpansion include the positioning of the patient in a lateral decubitus position to direct the allograft superiorly (to preferentially perfuse the native lung) and the use of lower tidal volumes. The use of this latter strategy often comes at the expense of a mild respiratory acidosis. Rarely, lung reduction surgery performed on the native emphysematous lung may be required if the overdistension of this lung remains a problem.134,135

Airway and Mechanical Complications

Although the incidence of airway and other mechanical complications has decreased,136 it is important for the intensive care physician to have an understanding of these problems. Bronchial dehiscence is an infrequent yet potentially devastating complication. It may manifest within a few days of the operation and is usually heralded by persistent or large air leaks from thoracostomy tubes, but may present as pneumomediastinum with or without mediastinitis, pneumopericardium, or empyema. Usually the complication results from ischemia and necrosis at the anastomosis suture line. Although most cases can be managed conservatively by decompressing the large extrapulmonary air collections, bronchoscopic débridement and even bronchial stenting may be required to ensure airway patency. Complete dehiscence of the anastomosis mandates surgical correction or retransplantation.

Bronchial strictures leading to airway stenosis and compromise are sequelae of bronchial dehiscence and/or ischemia, but usually do not develop until several weeks following the transplant procedure. Strictures typically arise in the mainstem bronchus at or just distal to the anastomosis. Ischemic injury to the bronchi may also lead to bronchomalacia, which is characterized by weakened cartilage that is prone to (expiratory) dynamic collapse. Permanent stenting is the preferred approach to this problem. More commonly patients develop inspissation of secretions in the bronchi that cannot be cleared. This may manifest as areas of airspace disease on chest x-ray, atelectasis, or a worsening in oxygenation. In this setting, bronchoscopy is valuable to both establish the cause and clear the retained secretions.

Extracorporeal Membrane Oxygenation

Extracorporeal membrane oxygenation (ECMO) has been used with success to support patients with severe graft dysfunction resulting from ischemia-reperfusion injury. This therapy has generally been used only once conventional strategies to improve oxygenation have failed. Mechanical support is employed in some centers to treat patients with moderate to severe IR injury. ECMO employs a membrane with a large surface area through which oxygen and carbon dioxide may passively diffuse to equalize their respective concentration gradients in the patient's blood. This exploits the notion that resting the lung will allow time for the graft to overcome the initial IR insult. At present a systematic evaluation of this treatment is lacking and experience is restricted to case series and registry databases.137

Acute Rejection

Acute rejection may occur while the transplant recipient is being cared for in the ICU, and generally occurs within the first 100 days. The signs are nonspecific, and thus it is important to differentiate the bilateral airspace infiltrates that characterize this complication from those caused by infections. Other features are also unreliable discriminators, and include low-grade fever, impaired oxygenation, and leukocytosis. Findings on chest radiography other than alveolar infiltrates include nodular or interstitial opacities and pleural effusions; after the first month acute rejection is often undetectable radiologically.138 Routine bronchoscopy has become widely accepted as a means of differentiating infection from rejection. Bronchoalveolar lavage or protected-specimen brushing of the airways can exclude any important infection, whereas transbronchial lung biopsy (with at least five pieces of alveolated parenchyma, each containing bronchioles and more than 100 air sacs) can confirm rejection. Treatment of acute rejection entails the use of high-dose parenteral steroids (i.e., methylprednisolone 10 to 15 mg/kg daily), which usually provide a good response, though biopsy-proven rejection may persist in up to one third of patients.61

A detailed discussion of the problem of chronic rejection is beyond the scope of this chapter. However, intensivists may encounter these individuals who develop chronic airflow limitation (usually more than 6 months following the transplant) that is characterized histologically as bronchiolitis obliterans. Although aggressive immunosuppression is often employed, the prognosis for posttransplant bronchiolitis is still poor, with 2-year mortality rates approaching 40%.139,140 The definitive treatment remains retransplantation.

Heart Transplantation

The Operation

Although other variations have been described, the standard approach for heart transplantation involves the creation of four separate anastomoses between the recipient atria and great vessels and the atria and great vessels of the donor heart (the biatrial technique). There has been renewed interest in bicaval and pulmonary vein to pulmonary vein anastomoses, and the bicaval technique has now been recommended by many experts.141

The Immediate Postoperative Period

The care of the heart transplant recipient is similar in many respects to the care of patients who have undergone aortocoronary bypass and other cardiac operations involving cardiopulmonary bypass. The heart is denervated during the transplant procedure, and frequently a junctional rhythm develops, requiring atrial pacing and possibly isoproterenol infusion. Owing to this denervation, the transplanted heart will also have an altered physiologic response to stress. The heart becomes dependent on circulating catecholamines rather than direct sympathetic stimulation, and consequently increases in heart rate and contractility in response to stress will occur more slowly. Changes in cardiac output become much more dependent on changes in stroke volume, which are in turn mediated by changes in venous return. Sinus bradycardia is the most common dysrhythmia present following heart transplantation, and usually lasts less than a week. Isoproterenol is frequently used for both its chronotropic and inotropic properties, and is typically titrated to achieve a heart rate between 90 and 100 beats per minute. As already mentioned, temporary atrial pacing may be required. If the recipient's native atrial appendage and sulcus terminalis including the sinoatrial (SA) node are preserved during the surgical procedure, two P waves may be seen on the postoperative electrocardiogram (one from the donor heart and one from the recipient's SA node). Other atrial dysrhythmias are frequently seen and include atrial fibrillation and flutter in 15% to 20% of patients.142

Nearly all patients will have a pulmonary artery catheter in place for hemodynamic monitoring following the operation to help guide fluid and vasoactive management. Generally, the goal is to keep both the central venous pressure (CVP) and the pulmonary capillary wedge pressure (PCWP) <10 mm Hg if possible, though these goals should be individualized, and the management should be guided by the clinical picture and not purely based on hemodynamic measurements. Consequently intravenous fluids are used sparingly and aggressive diuresis is continued postoperatively. However, the denervated heart will not be able to respond acutely to hypovolemia with reflex tachycardia, and adequate preload must be present to maintain stroke volume and to preserve blood pressure. A decreased cardiac output can be supported with inotropes (dobutamine or milrinone), but transient support with intra-aortic balloon counterpulsation may be required. If the cardiac output acutely deteriorates, urgent echocardiography should be obtained to exclude the possibility of tamponade and to evaluate left and right ventricular dysfunction. Left ventricular function of the allograft may also be reduced and a restrictive physiology may be observed if there has been prolonged ischemic time and poor myocardial preservation. Other causes of ventricular dysfunction should be sought such as acidemia, hypovolemia, hypoxemia, and medications. Systemic vascular resistance can be decreased following the procedure, and should be supported with vasopressors.

Pulmonary Hypertension

If significant pulmonary hypertension was present before the transplant procedure, it may also persist in the postoperative period. This increase in right ventricular afterload can generate significant strain on the newly transplanted right ventricle (which is accustomed to pumping against a normal mean pulmonary artery pressure). Tricuspid regurgitation is often present following the transplant (especially if the biatrial technique was used), and this may be exacerbated by increased right ventricular strain. Through its effects as a pulmonary vasodilator, isoproterenol can often reduce the right ventricular afterload that is frequently present. However, when significant pulmonary hypertension persists postoperatively, intravenous nitroglycerine, nitroprusside, and prostaglandin E may be required. If vasodilators are used in this setting, systemic infusion of α-agonists such as norepinephrine or phenylephrine may be needed to support the systemic arterial pressure. Inhaled nitric oxide offers the advantage of reducing pulmonary vascular resistance while causing minimal systemic side effects and without increasing shunting.143–147 Routine measurement of methemoglobin level is required when nitrate-containing pulmonary vasodilators are employed. Recently, sildenafil, a cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 inhibitor has been used with success for persistent pulmonary hypertension, and to prevent rebound after withdrawal of inhaled NO.132 Owing to the expense associated with the use of inhaled NO, other inhaled therapies have been evaluated (NO donors and prostaglandin analogues) and appear to be of equal benefit.148–151 However, the half-lives of these medications mandate repeated dosing.

Right and Left Ventricular Assist Devices

Patients with failing hearts are frequently bridged to transplantation using mechanical cardiac assist devices. Both left (LVAD) and right (RVAD) ventricular assist devices are used.152,153 Preliminary reports suggest that although mechanical devices may be associated with more serious adverse effects, they may be superior to medical therapy alone in supporting the patient to transplantation.154 The role of ventricular assist devices in right ventricular failure or primary graft failure following transplantation is evolving. A report from New York reviewed one institution's experience with assist devices in 462 transplants. Of the 20 patients diagnosed with primary cardiac graft dysfunction, 11 received RVAD, 4 required LVAD, 3 received biventricular support, and 2 were treated with intra-aortic balloon counterpulsation.155 This group with primary graft dysfunction tended to have longer ischemic times and developed early noncardiac organ dysfunction, which was the primary mode of death in the nonsurvivors. Forty-five percent were weaned from mechanical support; the mean duration of support was 114.7 ± 207 hours (median = 54 hours). The 2-year survival in this group with primary graft dysfunction was 67% compared to 79% in the entire cohort. The authors reported that ventricular recovery within 96 hours was associated with better early survival.

Rejection

Though immunosuppressive regimens have improved the impact of episodes of acute rejection on graft function and overall survival among heart transplant recipients, this complication still is responsible for 7% of deaths within the first 30 days of the procedure.156 Most episodes of acute rejection are asymptomatic and are diagnosed on routine endomyocardial biopsy. When symptoms are present, they are often nonspecific and may include fever, malaise, hypotension, congestive heart failure, or reduced exercise tolerance and fatigue. Consequently, surveillance for rejection through the use of endomyocardial biopsy has become standard practice. When performed by an experienced operator, this procedure is associated with a morbidity of less than 1% and a procedure-related mortality of less than 0.2%.157,158 The most concerning complication of this procedure is cardiac perforation with acute pericardial tamponade or injury to the tricuspid valve. Typically biopsies (with multiple sampling) are performed 5 to 7 days following the transplantation and then twice weekly for the first 2 months.

Once rejection is diagnosed histologically, imaging to assess cardiac function should be obtained (two-dimensional echocardiography or multiple-gated acquisition).141 Mild rejection in the absence of cardiac dysfunction is usually treated conservatively with an increase in the dose of immunosuppressive agents. If moderate rejection or left ventricular dysfunction is present, the episode of rejection should be treated using high-dose pulsed steroids with or without cytolytic therapy (antithymocyte globulin or OKT3). Repeat endomyocardial biopsy should always be performed to assess the response to therapy.

Chronic rejection in the cardiac allograft typically manifests as aggressive and premature coronary artery disease. This complication usually develops months to years after the procedure, and usually will not involve the intensivist. In contrast to classic coronary artery disease, transplant-associated coronary artery disease is generally more diffuse, involving all the vessels of the heart including the arteries, veins, and great vessels. Because the allograft is denervated, classic angina only develops in a minority of patients, and coronary artery disease more typically presents with “angina-equivalent” symptoms such as dyspnea.

Kidney-Pancreas Transplantation

The Operation

Kidney-pancreas transplantation is almost exclusively performed on patients with end-stage kidney disease secondary to diabetes mellitus.

Postoperative Care

Following kidney-pancreas transplantation many patients will not require ICU admission, and can be extubated before leaving the recovery room. However, ICU admission may be necessary for these patients because of pre-existing medical problems, due to difficulties encountered during the operation, or owing to complications that develop in the postoperative period.

The most common initial complication following the transplant of a kidney is oliguric or nonoliguric acute tubular necrosis (ATN) resulting from ischemic-preservation injury to the renal allograft. Care must be taken in this setting to avoid hypovolemia which can lead to prerenal azotemia and exacerbate the ATN. Urine output following the transplant procedure is usually high (800 to 1000 mL/h) and should be associated with a decline in creatinine; a lower urine output in the immediate postoperative period may herald graft dysfunction. Fluid management can often be facilitated through the use of a pulmonary artery catheter for hemodynamic monitoring. If oliguria develops, the urinary catheter should be flushed to ensure patency, especially if hematuria has been observed. Duplex sonography or radionuclide renal imaging should be considered to exclude the possibility of vascular thrombosis. If these interventions fail to elucidate the cause of the oliguria, the most likely remaining explanation is ATN and ischemic-preservation injury.

Following combined kidney-pancreas transplantation patients are at risk of developing metabolic derangements, and are particularly prone to developing hyper- or hypoglycemia. Usually a continuous intravenous infusion of insulin is started intraoperatively and continued through the postoperative period. A glucose-containing maintenance infusion should also be used to protect against the development of hypoglycemia. Care should be taken to avoid mixing medications in glucose-containing solutions, as these will provide boluses of glucose that can aggravate the control of blood sugar levels.

Rejection

The diagnosis of rejection in recipients of pancreas transplants is often challenging. Overt hyperglycemia does not occur until approximately 80% to 90% of the allograft has been destroyed, and consequently by the time clinical evidence of rejection is present it is often too late for therapy to be effective. For this reason, diagnosis of pancreatic rejection is usually made by inference after diagnosing rejection in a kidney allograft. This likely explains the improved graft survival in recipients of combined kidney-pancreas transplants as compared to patients who only receive a pancreas transplant; in the former group rejection is likely diagnosed and treated at a much earlier stage. In contrast, rejection of a renal allograft is usually suspected when the serum creatinine rises by more than 10%. If another cause of renal dysfunction (such as prerenal azotemia, pyelonephritis, etc) is not readily apparent, kidney biopsy should be performed. This procedure is relatively safe and will enable treatment of rejection to be instituted early and promptly. Recent reports suggest that use of the renal arterial resistance index159 or DNA microarray profiling160 may become important methods for diagnosing rejection in the renal allograft in the future.161

The Development of Lung Infiltrates in the Transplant Patient

A frequently encountered problem following the transplant procedure is the development of lung infiltrates. Though pneumonia is common, there are a variety of other conditions that cause a similar appearance on chest radiography and must be considered. These include congestive heart failure, atelectasis, ARDS, aspiration, and transfusion-related acute lung injury. In the lung transplant recipient, IR injury or rejection of the allograft also have a nonspecific appearance on chest radiography. Thus it is important that the clinician have an approach to the patient who develops lung infiltrates.

Because pulmonary infections may progress rapidly in the immunocompromised host, empiric antimicrobial therapy should be started promptly if pneumonia is suspected. Usually the patient will have other signs of infection such as fever or leukocytosis, but these findings will not always be present, depending on the degree of immunosuppression. Usually there is increased quantity and purulence of sputum or secretions from the endotracheal tube. If possible, respiratory secretions should be cultured prior to the initiation of empiric antibiotics. Invasive tests such as bronchoalveolar lavage or protected brush specimen obtained through bronchoscopy may be useful to optimize culture yield and ensure that appropriate antibiotic therapy is chosen.162 If culture results are negative, the empiric antibiotics should be discontinued, as the continued use of inappropriate therapy may increase antimicrobial resistance.

Pneumonia in transplant patients may be caused by a variety of organisms, including gram-negative aerobes, fungi, Legionella, P. carinii, and viruses (especially CMV). Consequently, broad-spectrum therapy should be initiated when infection is suspected, but treatment should be changed to an appropriate agent with the narrowest spectrum of activity possible once susceptibilities of the causative organism are known. Initial therapy should have activity against Pseudomonas and other gram-negative organisms as well as gram-positive bacteria. Appropriate choices would include ceftazidime, piperacillin-tazobactam, or meropenem or imipenem. Consideration should be given to also including trimethoprim-sulfamethoxazole (TMP-SMX) to treat possible P. carinii, ganciclovir to treat CMV infection, and a macrolide to treat Legionella, if infection with any of these organisms is suspected.

The Transplant Patient with Decreased Level of Consciousness

A frequently encountered postoperative problem in the transplant recipient is the development of a decreased level of consciousness. When this occurs, a systematic evaluation is required to ensure that the etiology is correctly identified and appropriately treated. Distinguishing between structural problems and metabolic or drug-induced disturbances is often useful. Though the former are less common, the development of any localizing neurologic findings suggests a structural lesion and mandates CT or MRI examination. Stroke can occur in the perioperative period, and may be ischemic or embolic in nature. Perioperative cardioembolic stroke is more commonly seen following heart transplantation, and can be the result of intracardiac or aortic thrombosis. Intracranial bleeding usually occurs following hemorrhagic transformation of an ischemic infarct or a central nervous system infection. Liver transplant patients commonly develop coagulopathy, and this likely explains the relatively higher incidence of intracranial hemorrhage seen in this group.163 Air embolism has been described in liver transplant recipients,164–168 especially following venovenous bypass, and in cardiac and lung transplant recipients.73,74

Metabolic derangements leading to alterations in mental status are commonly encountered by transplant recipients. Electrolyte and glucose abnormalities are often present and should be corrected. However, care is required to avoid overly aggressive and rapid correction of sodium problems, which can precipitate central demyelination syndromes following treatment of hyponatremia or cerebral edema following treatment of hypernatremia. When present, renal failure and associated uremic encephalopathy may contribute to abnormal mentation. Hepatic encephalopathy is common in liver transplant patients and should be treated in the same manner as for all patients with liver disease. Hypoxia and hypotension can both cause a decreased level of consciousness, but are usually easily recognized.

Drug-induced depression of the central nervous system (CNS) is common. Clearance of the anaesthetic agents used during the transplant procedure may take longer in the transplant recipient, especially following liver or kidney transplantation. Narcotic analgesics, benzodiazepines, and other CNS depressants are frequently required following transplantation, and these agents may accumulate and lead to decreased arousal. Importantly, both cyclosporine and tacrolimus are associated with neurologic toxicity and can even lead to coma.169,170 Serum levels of these agents must be monitored carefully, and if no other explanation for the decreased level of consciousness can be found the drugs must occasionally be held or discontinued. The use of tacrolimus and cyclosporine has also been linked to the development of thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome, which can have neurologic manifestations.171–173 A very rare but potentially devastating complication of transplantation that leads to severe CNS depression is the hyperammonia syndrome.174–177 This syndrome is characterized by tremulousness progressing to seizures, coma, brain edema, and death. Severe elevations in serum ammonia will be present despite normal or only minimally elevated liver enzymes and normal indices of hepatic function. The syndrome appears to develop in individuals with abnormalities or deficiencies of enzymes in the urea cycle. Therapy consists of minimizing amino acid intake (especially parenteral), and treatments that enhance or increase elimination of nitrogenous waste products.176,177

Systemic infections can be associated with severe encephalopathy. However, when caring for a transplant patient, the intensivist must have a heightened suspicion for infections that involve the CNS. When these infections develop in the early postoperative period, they are usually related to nosocomial or donor-related organisms.178,179 Meningeal signs may be lacking in the transplant recipient, and so lumbar puncture with cerebrospinal fluid analysis should be considered if CNS infection is suspected and empiric therapy should be instituted promptly.

A rare but important cause of decreased level of consciousness or coma in the transplant recipient is nonconvulsive status epilepticus. Indeed, seizures may be the most common neurologic complication for all solid-organ transplant recipients.179 These may be precipitated by electrolyte and metabolic disturbances (especially of sodium and glucose), drugs (cyclosporine, tacrolimus, OKT3, antibiotics, etc) or drug withdrawal, CNS infections, or intracranial lesions (stroke, hemorrhage, abscess, etc). Evaluation should include CT scan and electroencephalogram, and treatment should be focused on correcting the underlying problem if possible, and treatment with benzodiazepines. Since many transplant patients are hypoalbuminemic, when therapy with phenytoin is employed it is necessary to calculate the unbound fraction of the drug to avoid potential toxicity. Valproate is not commonly used because of its potential for myelosuppression and hepatotoxicity.179

The very nature of transplant medicine mandates the adoption of a multidisciplinary approach to patient care. As such, one of the most important roles the intensivist can assume is to coordinate the management of the patient and to act as an intermediary between the numerous specialists and professionals involved in the case. The transplant surgeon and the transplant team will need to be frequently consulted and kept informed of changes in the patient's status in order for appropriate modifications to the immunosuppressive regimen to be made or surgical intervention provided if necessary. The needs of the transplant recipient are often quite complex, and the intensivist must frequently coordinate the involvement of other professionals, including dieticians, physiotherapists and occupational therapists, respiratory therapists, pharmacists, and nurses. It is usually the intensivist who will liaise with the patient's family and identify important psychosocial issues. Often the need to involve the social worker, psychiatrist, and chaplaincy is identified by the intensivist. Thus the critical care of the transplant patient requires the intensivist to be an expert in acute physiology and to have an understanding of the important medical issues facing the recipient, but also requires someone who can coordinate other professionals involved in the patient's care, and identify the medical and social needs of both the patient and family. It is only through such a multidisciplinary approach, coordinated by the intensivist, that transplant patients will achieve good outcomes.