Chapter 52: Posttransplantation Care

This chapter discusses early postoperative care, early recognition and management of complications, antimicrobial prophylaxis, and immunosuppressant drugs and their side effects in the management of the posttransplant liver, kidney, pancreas, and small intestine recipient.^{1,2,3,4,5,6,7,8} Indications for transplantation and preoperative management are not discussed in this chapter.

There are 3 major types of liver transplantation (LT): cadaveric orthotopic LT (OLT), where a whole organ is transplanted from a deceased donor (most common); cadaveric OLT by split LT, where the recipient receives 1 lobe of the liver from a deceased donor; and live donor OLT, where the donor undergoes either a right or left hepatic lobectomy. In the case of split or living donor liver transplants, adult recipients usually receive the larger right lobe; children are ordinarily transplanted the smaller left lobe.

OLT requires surgical anastomosis of the hepatic artery, portal vein, bile duct, and inferior vena cava from donor to recipient, and postoperative complications are often related to dysfunction at these anastomotic sites.

Recovery in the Immediate Postoperative Period

Most of the patients after LT, even after an uncomplicated operating room course, are monitored in the ICU. Uncomplicated cases usually transfer to an inpatient liver transplant unit within 24 to 72 hours but complicated cases may require ICU care for weeks. Fifteen percent to 20% of liver transplant patients are taken back to the operating room during the transplant admission. The main reasons for reoperation include postoperative bleeding, vascular and biliary complications, and intraabdominal sepsis.

In the ICU, frequent hemodynamic assessments are commonly performed using vital signs and noninvasive monitoring (eg, ultrasonography). A preexisting pulmonary artery catheter is utilized if placed intraoperatively for more hemodynamically challenging cases or those with pulmonary hypertension. Vital signs, intake, output, physical changes in drain output, bile production (if a biliary drain [eg, T-tube] is present), abdominal drain (eg, Jackson–Pratt) output, and any signs of postoperative bleeding are recorded hourly. The initial postoperative level of liver biochemistries, that is, alanine transaminase (ALT), aspartate aminotransferase (AST), and bilirubin, may not correlate with liver function in the first day or first 2 days after transplant. Therefore, most centers rely on the serial assessment of international normalized ratio (INR) and lactate along with complete blood count, arterial blood gas, electrolytes, glucose, blood urea nitrogen, and creatinine as well as the liver biochemistries (ALT, AST, bilirubin, and alkaline phosphatase) analyzed every 6 hours within the first 2 days. The clinical picture (eg, hemodynamics, renal function, and neurological status) also provides important information about graft function.

Increased INR is usually not treated with fresh frozen plasma (FFP) because it may mask allograft dysfunction and potentially increase the incidence of hepatic artery thrombosis (HAT) or portal vein thrombosis. Thrombocytopenia is also very common after LT, however platelet transfusions are also avoided because they may increase the chances of HAT. If there is significant bleeding, FFP and platelet transfusions may be indicated but the decision to transfuse should be made in concert with the transplant surgeon.

Assessment of Liver Graft Function

Graft edema, any unusual or discolored appearance of the allograft in the operating room, inability of the patient to raise the core body temperature, hemodynamic instability, hypoglycemia, dramatic increases in potassium, prothrombin time or INR, and lactate all signal inadequate allograft function. Inadequate urine output or acute kidney injury is also common in this setting, but may be caused by factors other than graft dysfunction such as acute tubular necrosis (ATN) or immunosuppressive drugs such as cyclosporine or tacrolimus.

Doppler ultrasonography (DUS) is routinely done on the first postoperative day to assess patency of the hepatic arteries and portal veins to rule out HAT, stenosis, or portal vein thrombosis. DUS also assesses for fluid collections, hematomas, and abscesses. As the hepatic artery supplies blood to the biliary ducts, HAT is associated with bile leaks. Follow up DUS is performed if the initial findings are equivocal or there is a sudden deterioration in graft function or elevation of LFTs.

Split cadaveric and live donor lobe transplants may be associated with initially higher ALT and AST due to raw liver surfaces as well as more prolonged lactate and INR elevation due to smaller liver mass relative to recipient size. Elevated INR may also occur in standard cadaveric OLT when the overall liver mass is small. Recipients of split and living donor transplants often become hypophosphatemic and require rigorous phosphorus supplementation due to the metabolic needs of regenerating liver tissue.

Recognition and Management of Early Complications

Medical Complications

Sepsis—The risk of infections is increased after LT and bacterial infections are more common than fungal infections. Deep surgical space infections and biliary leaks are common sources of infection. All potential sites for infection should be explored and, if possible, eliminated (catheters, hematomas, or fluid collections suspicious for abscess).

Respiratory Complications—Patients that are critically ill prior to LT are at increased risk for prolonged mechanical ventilation due to debilitating conditions and concomitant loss of muscle mass. Those with liver graft dysfunction, extrahepatic organ dysfunction, or sepsis are also more likely to require prolonged ventilator support. Transient severe pulmonary edema may occur due to systemic inflammatory response syndrome (SIRS) or sepsis, or much less commonly transfusion-related lung injury. Although pneumonia is possible early after LT, pulmonary infiltrates are usually due to noncardiogenic pulmonary edema from systemic inflammation or sepsis originating from the abdomen. Patients intubated postoperatively for more than 7 to 10 days should be evaluated for tracheostomy.

Hepatopulmonary syndrome (HPS) is defined by the triad of liver dysfunction or portal hypertension, abnormal gas exchange, and evidence of pulmonary vascular shunts resulting in hypoxemia. Patients with HPS have an increased length of stay in the ICU (median 4 days) and hospital (median 39 days). LT may be curative, however, the median time to cessation of oxygen is 4.5 months in some series. Right pleural effusions are common after liver transplant due to operation near the right diaphragm, but do not usually cause respiratory failure. Postoperative right pneumothorax may occur less commonly.

Cardiovascular Complications—Liver failure typically results in a hyperdynamic circulation with elevated cardiac index and low blood pressure. A patient receiving a transplant before severe liver failure is manifest, for example, hepatic tumors or living-related donor recipients, may not have a hyperdynamic circulation. If present prior to LT, the hyperdynamic state does not resolve immediately after LT and may persist for weeks or longer. Mild to moderate portopulmonary hypertension in the setting of high cardiac output (CO) usually resolves with successful LT.

The majority of low CO states in the ICU after LT are caused by volume loss usually from bleeding, third spacing, and/or a stunned myocardium due to SIRS or sepsis. Dynamic left ventricular outflow tract obstruction due to decreased LV preload in the setting of inotropes is also a potential cause of low CO post-LT. Rarely, low CO may be caused by an acute myocardial infarction. Other causes of low CO after LT include cirrhotic cardiomyopathy or cardiomyopathies associated with alcohol, hepatitis, or hemochromatosis, although these should have been screened out during the preoperative work up.

Management of hemodynamic instability includes treatment of the causative factors. Central venous pressure measurement is a poor guide for intravascular volume and adequate resuscitation both in the ICU and in the operating room. No relationship between CVP and liver graft outcome has been demonstrated subsequent to an uncontrolled observational study to the contrary. The use of CO trending and mixed venous blood gases via a pulmonary artery catheter (often present in the immediate postoperative period after intraoperative placement), and or serial echocardiography, coupled with lactate trends are helpful to guide hemodynamic management. Although there are no randomized control trials to support the use of colloids over crystalloids after LT, albumin 5% is preferred for volume resuscitation after LT due to hypoalbuminemia and to limit positive fluid balance.

Hypertension may develop posttransplant and is more common in patients with preexisting hypertension. Hypertension can be caused or exacerbated by immunosuppressive drugs such as tacrolimus, cyclosporine, and steroids. The treatment may include diuresis in the setting of fluid overload or the addition of antihypertensive agents.

Renal Dysfunction—The incidence of acute renal failure after LT varies widely in the literature, ranging between 27% and 67%. The most important risk factor for postoperative renal dysfunction is pretransplant renal dysfunction (ie, hepatorenal syndrome or ATN). Most kidneys recover with time and only a small percentage of patients develop chronic kidney failure. Management of renal failure in the posttransplant period includes renal replacement therapy and judicious use of immunosuppressants, particularly, nephrotoxic calcineurin inhibitors (ie, tacrolimus or cyclosporine) or a calcineurin inhibitor-sparing protocol (eg, mycophenolate mofetil, steroids, monoclonal antilymphocyte antibodies) at the discretion of the transplant team. In hemodynamically unstable patients and particularly those with primary nonfunction or poor early graft function, continuous veno-venous hemofiltration is the preferred modality for renal replacement and should be started as early as feasible to maintain metabolic homeostasis during this critical time of multiorgan dysfunction.

Neuropsychiatric Complications—Neuropsychiatric complications occur in up to 30% of liver transplant patients and often require prolonged management in the ICU. Complications include encephalopathy (delirium), tremors, myoclonus and less commonly seizures (including nonconvulsive status epilepticus), meningitis, ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage.

Delirium is common after LT. Treatment with antipsychotic medications may be required (eg, haloperidol or risperidone). It may be due to preexisting hepatic encephalopathy, postoperative liver graft dysfunction, renal failure, sepsis, or side effects of immunosuppressive medications such as steroids and calcineurin inhibitors (see later under Immunosuppressive Drugs). If there are no focal deficits and the patient is hemodynamically and or respiratory unstable, computed tomography (CT) imaging may be postponed or avoided. However, if the patient exhibits focality or seizures, emergent CT should be performed. Ischemic stroke, subarachnoid, and subdural hemorrhages are uncommon but possible. Central nervous system infections such as meningitis and brain abscess are unusual but possible in these immunocompromised patients.

Surgical Complications

HAT occurs in less than 2% to 3% of patients after LT. Thirty percent develop signs of acute hepatic necrosis with high transaminases, sepsis, mental status changes, and coagulopathy, but may the presentation be more subacute with progressive biliary infections and hepatic dysfunction. Suspicion of HAT should be immediately investigated with DUS and potentially confirmed by an arteriogram or exploratory laparotomy depending on the level of surgical concern. HAT within the first week after OLT is an indication for relisting for retransplantation. Portal vein thrombosis is also diagnosed by DUS. If the diagnosis is made during the ICU stay, the patient may undergo thrombectomy depending on the degree of occlusion and collateral circulation.

Biliary complications remain frequent after LT varying between 1.6% and 18% and include bile leaks, bilomas, and strictures. Early bile leaks should be suspected in any patient with constant abdominal pain, or unexplained fever or sepsis after liver transplant. Most leaks occur from the biliary anastomosis and present early. Many require abdominal washout and surgical repair, although endoscopic stenting may be successful. Late bile leaks (after 30 days) are rare, however late strictures are the most frequent cause of biliary complications after LT and are often associated with recurrent cholangitis. Treatment of anastomotic strictures usually requires endoscopic stenting; intrahepatic strictures are more complex and may lead to retransplantation.

Nutritional Management

In uncomplicated liver transplants an oral diet can be started within the first 1 to 2 days after surgery. A protein-rich diet is recommended, as the liver patient needs 1.5 to 2 g protein per kg body weight per day. If oral intake is not sufficient, postpyloric feeding through a tube should be considered. Parenteral nutrition should be initiated only if tube feeding is not possible due to intestinal complications and prolonged nothing by mouth (NPO) (eg, > 3-7 days) is anticipated. Both steroids and calcineurin inhibitors may cause hyperglycemia and this will be even more pronounced in patients with preexisting diabetes mellitus. Hypoglycemia may be a sign of liver graft dysfunction or excess insulin dosing.

Early Postoperative Management

Intensive care unit observation is usually not required after renal transplant except under special circumstances involving hemodynamic or respiratory instability.⁹ Once the patient is stable hemodynamically and has recovered from anesthesia, transfer to the floor is initiated. Volume status needs to be monitored closely. Additional evaluation includes a full electrolyte panel, complete blood count, chest X-ray, and an electrocardiogram. The intraoperative anesthetic record, blood loss, volume replacement, and the operative report should also be reviewed to identify intraoperative events or complications with potentially adverse sequelae. Voluminous urine output after surgery is a sign of good graft function. A brisk large volume diuresis following graft revascularization may be due to preoperative volume overload, osmotic diuresis in previously uremic patients, intraoperative mannitol or furosemide, or vigorous intraoperative intravenous crystalloid or colloid fluid administration.

In low urine output states, the Foley catheter should be irrigated to rule out obstruction and to flush out blood clots. Evaluation of the kidney by ultrasound to determine blood flow, patency of the renal vessels, and for evidence of urinary tract obstruction is important. The absence of blood flow to the allograft or tract obstruction (eg, ureteral torsion) requires urgent evaluation by the surgical team for possible reexploration. Fluid replacement should equal urine output with 1/2 normal saline because the sodium concentration of the urine from a transplanted kidney is about 60 to 80 mEq/L. Patients who are anuric or oliguric should receive conservative fluid management and diuretics if intravascularly volume repleted or volume overloaded. Renal replacement therapy is necessary if there is inadequate recovery of renal function.

Assessment of Graft Function

Immediate Graft Function—In patients with immediate graft function the serum creatinine commonly decreases by 1.0 to more than 4.0 mg/dL daily. These patients are usually discharged on postoperative day 4 or 5 following successful Foley catheter removal and voiding trial.

Slow Recovery of Graft Function—Patients with slow recovery of graft function are generally nonoliguric and experience a slow decline in serum creatinine. The level typically decreases by 0.2 to 1.0 mg/dL daily. Attention must be given to fluid management. These patients usually do not require dialysis unless complicated by hyperkalemia or fluid overload. Patients who are at high risk for obstruction such as diabetics with neurogenic bladder or male patients with benign prostatic hypertrophy may require a Foley catheter for a longer time period of monitoring.

Delayed Graft Function—The incidence of delayed graft function (DGF) ranges from 10% to 60% and can often be anticipated based on recipient and donor factors. Unless these patients have adequate residual urine output from the native kidneys, most patients are oliguric or anuric and will require temporary dialysis support for volume, hyperkalemia, or uremia. Donor factors for DGF include age (< 10 or > 50), donor macrovascular or microvascular disease, prolonged used of vasopressors, donation after cardiac death, nephrotoxic agents, and prolonged ischemia time. Intraoperative factors include hemodynamic instability and prolonged rewarming time (anastomotic time). Recipient factors include diabetes, age, male gender, African American race, peripheral vascular disease, duration of dialysis before transplant, and early high-dose calcineurin inhibitors.

Surgical Complications

Surgical complications after renal transplantation have an incidence of 5% to 10% and remain an important cause of graft loss.

Graft Thrombosis

Graft thrombosis may be arterial or venous and usually occurs within the first 24 to 72 hours. The incidence ranges from 0.5% to 5%. Renal artery thrombosis may present with sudden cessation of urine output and the diagnosis is made by DUS which shows the absence of arterial inflow and nonperfusion of the transplant kidney. Renal artery thrombosis is a catastrophic complication and almost invariably results in graft loss. With renal vein thrombosis, the clinical presentation includes a sudden decrease in graft function, hematuria, pain, and swelling over the graft. Diagnosis is confirmed by DUS. Urgent exploration and allograft thrombectomy is required.

Renal Artery Stenosis

The incidence of renal artery stenosis ranges from 2% to 10%. The presentation is later, from a few months to 2 years posttransplant with sudden onset of refractory hypertension associated with peripheral edema and graft dysfunction. The anastomotic site is the most common location. Initial screening is performed with DUS and may be followed by magnetic resonance angiogram or CT angiogram. The gold standard for diagnosis remains the arteriogram. The treatment is percutaneous transluminal angioplasty with or without stent placement.

Urological Complications

Urological complications after kidney transplantation have an incidence of 2% to 10%. They may present either as a urinary leak or urinary obstruction. Symptoms and signs include pain and swelling over the graft, fever, decreased urine output, an elevated serum creatinine, and urine draining from the skin incision. Urinary leaks usually occur early after transplantation. Analysis of fluid drainage from the wound will typically demonstrate an elevated creatinine concentration compared to the serum creatinine. Small leaks can be managed by placing a Foley catheter for bladder decompression. Open operative repair and drainage is usually required for larger leaks. Obstruction of the urinary tract often presents with findings similar to acute allograft rejection with a fall in urine output, tenderness over the graft, and fever. Ultrasound confirmation of hydronephrosis is required for diagnosis. Treatment includes percutaneous nephrostomy, balloon dilation of the stricture, and stent placement. If endoscopic techniques fail to resolve the obstruction, open surgical repair is indicated.

Only 1 of 10 pancreas transplants are isolated, that is, only pancreas, and these few are performed in complicated diabetics without nephropathy. The majority of pancreas transplants are simultaneous pancreas–kidney transplants in patients with diabetic nephropathy. A pancreas transplant may also be done subsequent to a successful kidney transplant. Occasionally a pancreatic transplant is performed simultaneously with small bowel transplantation.

In terms of exocrine drainage, currently most pancreas transplants are enteric drained rather than bladder drained.

Pancreas Transplant Care

Early Assessment of Allograft Function

The appearance and texture of the pancreas on completion of the procedure is essential because pancreatitis and allograft edema are common at the time of reperfusion. In this setting, osmotic diuretics are frequently administered to decrease edema and improve microvascular perfusion. A similar strategy is used with intestinal allografts to limit edema and bowel distention. The failure of an allograft to respond to intraoperative interventions aimed at reducing edema is a signal to maintain close surveillance of allograft function perioperatively. Donor risk factors associated with intestinal allograft thrombosis include increased donor age, hemodynamic instability, catecholamine requirements, and acidosis.

Support of the Transplanted Pancreatic Allograft

Optimal support for the pancreatic allograft focuses on the detection and prevention of rejection and thrombosis, the 2 most common causes of pancreatic graft failure.

Although never scientifically validated, prophylactic anticoagulation involving low-dose systemic heparin in the operating room with dose escalation through the first week (due to decreasing bleeding risks) after transplantation, supplemented with aspirin therapy, is routine.

Pancreatitis and pancreatic ischemia typically present as abdominal pain, peritonitis, ileus, and fever. Serum amylase and lipase correlate poorly with the severity of allograft pancreatitis, with posttransplant hyperamylasemia observed in greater than 30% of recipients; however, trend analysis is helpful. In particular, a sudden increase in amylase and lipase with a change in exogenous insulin requirements is predictor of graft ischemia or necrosis. The use of DUS is sensitive in the diagnosis of thrombosis. The “gold standard” for confirming rejection remains a pancreas graft biopsy. Any form of pancreatic rejection is treated aggressively.

Pancreas transplants with exocrine drainage via the bladder have the advantage of closer monitoring for rejection via urine analysis, however more complications occur including urethritis (greater in males), bladder infection, and acid-base abnormalities, specifically metabolic acidosis due to loss of bicarbonate in the urine.

Small Bowel Transplant Care

There are fewer serum markers and radiologic modalities to guide the management of intestinal transplant recipients. In this population, clinicians only have physical examination, ostomy output, laboratory analysis for hyperkalemia, metabolic acidosis and lactate, and endoscopy. Appropriate volume resuscitation is challenging because volume depletion occurs secondary to inflammation and poor fluid absorption from the transplanted intestine in addition to ileostomy losses. These patients are malnourished with low albumin levels. In some cases, the intestinal graft may become very edematous and the transplant surgeon may request fluid restriction and diuresis. Albumin 5% or 25% for fluid resuscitation is preferred in these transplants when volume limitation is the goal. Managing the fluid status requires a clinical assessment of systemic perfusion and a hemodynamic assessment of the intravascular volume. Cardiac and pulmonary ultrasound and lactate trends can help to guide fluid management.

Rejection usually occurs within the first month posttransplant. In many centers, serial endoscopy and biopsy are performed twice a week for the first month. After the first month, endoscopies are performed less frequently. The treatment of rejection involves bolus doses of corticosteroids and intensification of the baseline immunosuppressive regimen. Plasmapheresis may be initiated within 24 hours of transplant to reduce intestinal graft rejection in patients with high levels of donor specific circulating antibodies. The effectiveness of plasmapheresis in this setting is under investigation.

Intestinal transplant recipients typically have malnutrition and protein deficiency that results in low oncotic pressure and further loss of intravascular fluid. If anticipated to be NPO for more than about 3 days, total parenteral nutrition is resumed postoperatively. Once anastomotic integrity is established, enteral feeds are initiated and advanced gradually as tolerated. Most patients continue to need supplemental intravenous fluids and electrolytes due to stoma loss during the first posttransplant year.

Posttransplant Lymphoproliferative Disease

Posttransplant lymphoproliferative disease develops in up to 30% of the recipients of intestinal transplant and is usually associated with Epstein–Barr virus (EBV) infection. Treatment principles include a substantial decrease in the immunosuppression regimen and antiviral therapy.

The risk of infection after transplantation changes over time (Figure 52–1), with modifications in immunosuppression, also depending on the type of organ transplanted. It can be difficult to differentiate rejection or noninfectious inflammation from infection as no assays can accurately distinguish between these entities. Currently, the clinician assesses a recipient's risk of infection while considering the risk of allograft rejection, the intensity of immunosuppression, and other factors that may contribute to infection. Prophylactic strategies are based on the patient's known or likely exposures to infection according to the results of serologic testing and epidemiologic history. The risk of infection in the transplant recipient is a continuous function of the interplay between these factors. Prophylactic antimicrobial regimens vary depending on the transplant center and the type of transplant. All patients receive usual antibacterial surgical prophylaxis and trimethoprim–sulfamethoxazole (Bactrim) prophylaxis against Pneumocystis jirovecii. Antifungal prophylaxis is given depending on the organ transplanted, previous infection, and risk factors such as renal failure. Specific antiviral prophylactic regimens are determined by prior history of viral infections in the recipient and the organ donor. The major risks are herpes virus infection or reactivation, particularly cytomegalovirus (CMV) and EBV, hepatitis C virus (HCV) and hepatitis B virus. There is a very high risk of infection in seronegative recipients receiving an organ from a seropositive donor.

Early Posttransplantation Period

The first month after transplant is a vulnerable time for nosocomial bacterial infections including multidrug-resistant organisms related to complicated surgery. Venous and urinary catheterization and intubation add to the risk, as sicker patients tend to have more invasive devices for longer time periods. Opportunistic infections are generally absent during the first month after transplantation because the full effect of immunosuppression is not yet manifest. Unexplained early signs of infection, such as hepatitis, pneumonitis, encephalitis, rash, and leukopenia, may be donor-derived. Therapy may be empiric or determined by antimicrobial susceptibility data.

Intermediate Posttransplantation Period

The full effect of immunosuppressive medications typically manifest in months 1 to 6 posttransplant. This is when opportunistic infections tend to be most common. Viral pathogens and allograft rejection are responsible for the majority of febrile episodes that occur during this period. Trimethoprim–sulfamethoxazole prophylaxis generally prevents most urinary tract infections and opportunistic infections such as P jirovecii pneumonia, Listeria monocytogenes infection, Toxoplasma gondii infection, and infection with sulfa susceptible nocardia species. Infection due to endemic fungi, aspergillus, cryptococcus, Trypanosoma cruzi, or strongyloides may occur. Herpes virus infections are uncommon with antiviral prophylaxis. However, other viral pathogens, including polyomavirus BK, adenovirus, and recurrent HCV have emerged.

Late Posttransplantation Period

Beyond 6 months posttransplant, most stable patients are on reduced doses of immunosuppression and therefore have decreased risk for opportunistic infections. CMV, EBV, herpes simplex virus, and hepatitis viruses remain a concern, but more commonly transplant patients are infected with seasonal respiratory and gastrointestinal viruses, community-acquired pneumonias and urinary tract infections during this period. In those who require a higher level of immunosuppression, the risk for opportunistic infections may be as high as during the 1 to 6 months posttransplant period. This includes an increased risk for infections with P jirovecii, nocardia, varicella, and aspergillus.

Immunosuppression protocols vary from center to center and the transplant team determines the immunosuppressive regimens that are used posttransplantation. The intensivist should be familiar with the agents given, what levels to monitor, and the side effects and how they relate to the critical care management. The goal of immunosuppression is to prevent graft rejection while minimizing infection and other side effects. The current initial (ie, for induction) immunosuppression regimens used in solid organ transplants usually consists of a corticosteroid, a calcineurin inhibitor, and an antiproliferative agent. Monoclonal antibodies to lymphocyte receptors may also be used for induction, acute steroid resistant rejection or to reduce calcineurin inhibitors. In patients with corticosteroid intolerance, antiproliferative agents can be increased to reduce corticosteroid use. When renal toxicity is a concern, for example, pretransplant renal failure in a liver transplant patient, corticosteroids and antiproliferative agents may be preferentially used over calcineurin inhibitors.

Corticosteroids

Corticosteroids (eg, methylprednisolone and prednisone) decrease inflammatory proteins and are a cornerstone of immunosuppression. Side effects relevant to postoperative critical care management include mood changes, encephalopathy, hypertension, gastritis, hyperglycemia, hypokalemia, metabolic alkalosis, myopathy, and increased risk of infection.

Calcineurin Inhibitors

Cyclosporine and tacrolimus (Prograf, FK-506) are interleukin-2 (IL-2) inhibitors. They initially require daily monitoring of drug trough levels. The target levels vary with the overall immunosuppressive regimen, the type of transplant, underlying graft function, associated organ function, and the presence of infection. Nephrotoxicity and neurotoxicity remain the most important adverse side effects. Cyclosporine is associated with less neurotoxicity than tacrolimus. Neurotoxic side effects include tremors, headaches, dysarthria, neuropathies, delirium, cognitive impairment, somnolence, seizures, posterior reversible encephalopathy syndrome, and coma. Hypomagnesemia increases neurotoxicity and magnesium replacement with the avoidance of hypomagnesemia is important in patients receiving calcineurin inhibitors.

Antiproliferative Agents

Mycophenolate mofetil (Cellcept) and azathioprine (Imuran) are antimetabolite purine synthesis inhibitors. They are not nephrotoxic or neurotoxic. Side effects include myelosuppression with leukopenia and thrombocytopenia and gastrointestinal symptoms including vomiting, ileus, and oral ulcers. Azathioprine is usually not used as a first-line agent but may be substituted in patients who do not tolerate mycophenolate because of gastrointestinal side effects.

Sirolimus (Rapamune) inhibits IL-2 postreceptor, downstream in the signal cascade, preventing proliferation of T lymphocytes and reducing antibody production. It lacks the neurotoxicity and nephrotoxicity of the calcineurin inhibitors and is a long-term alternative to tacrolimus or cyclosporine in patients with renal dysfunction as a result of calcineurin toxicity. It is avoided in the early posttransplant period due to delayed wound healing and should be avoided in patients with nonhealing wound infections. Other adverse effects include bone-marrow suppression and it has been associated with an increased incidence of HAT after LT.

Monoclonal antibodies (eg, basiliximab) block IL-2 receptors on activated T-lymphocytes thwarting their multiplication and expansion. They have minimal side effects compared to muromonab-CD3 (Orthoclone OKT-3), a monoclonal antibody to T cell CD3 receptors that first activates T cells, causing systemic inflammation, before removing T cells from the circulation thus having significantly more side effects including fever, headache, nausea, and noncardiogenic pulmonary edema.

The maturation of solid organ transplantation as a clinical entity has brought new challenges for intensivists managing these patients. The relaxation of recipient criteria combined with expansion of the donor pool has resulted in sicker patients receiving transplants. Donor factors, recipient comorbidities, and intraoperative events play a critical role in determining the postoperative course.