Chapter 59. Anesthesia for Kidney, Pancreas, or Other Organ Transplantation

1. The 5-year survival of patients on chronic hemo- or peritoneal dialysis is only 30%. In contrast, the 5-year survival following transplantation for end-stage renal disease is 70%. Therefore, transplantation is considered the treatment of choice for patients with renal failure.

2. Living related kidney transplant is associated with fewer episodes of acute and chronic rejection than cadaveric organ transplant.

3. Cardiac events related to coronary artery disease and autonomic nervous system dysfunction are the most common causes of morbidity and mortality in the first year following kidney or pancreas transplant.

4. Significant hypotension upon induction of general anesthesia is common in recently hemodialyzed patients. Diabetics with autonomic neuropathy are at increased risk for severe hypotension and bradycardia during induction of general anesthesia.

5. According to the most recent ACC/AHA guidelines for those receiving β-blocker therapy, these drugs should be continued in patients preoperatively, or initiated in patients with a positive stress test. The evidence also favors perioperative β-blockers in high-risk patients (more than 3 risk factors: high-risk surgery, ischemic heart disease, congestive heart failure, cerebrovascular disease, insulin-dependent diabetes mellitus, renal failure—creatinine >2.0 mg/dL). Use of β-blockers in low- and intermediate-risk patients is not supported by current available data.

6. Patients with long-standing diabetes often develop stiff joints due to glycosylation of the connective tissue that results from elevated blood sugars. The inability to oppose the palms of the hands is 1 sign in a diabetic patient that stiff connective tissue may be present. Patients with stiff joints may be difficult to intubate and may require an awake, fiberoptic intubation.

7. Adults and children who receive hematopoietic stem cell transplantation (HSCT) are at risk for complications, including respiratory failure or acute graft versus host disease. Acute graft versus host disease is the most important complication that significantly influences clinical outcome. HSCT recipients are at risk for airway complications during the first 2 months of transplantation.

8. Due to the high incidence of venous thrombosis in patients on long-term hyperalimentation, all patients referred for intestinal transplantation should undergo preliminary mapping of their venous access by Doppler ultrasound, and patients with multiple thrombosed vessels should be considered for additional angiographic evaluation.

9. Small bowel transplantation is a long surgical procedure that can take up to 17 hours. It can be associated with large fluid shifts due to abdominal manipulation and significant intraoperative bleeding, dehydration, vascular clamping, long ischemia times, visceral exposure, and lymphatic interruption. Therefore, adequate vascular access is essential.

The kidneys were the first organs to be transplanted in humans. This led to the development of the field of immunobiology along with surgical and anesthesia advancement, allowing other organs to be transplanted. In this chapter we discuss the anesthesia care, perioperative considerations, and outcome in patients undergoing transplantation of the kidneys, pancreas, islet cells, hematopoietic stem cells, and small intestine.

History and Introduction

The first successful kidney transplant, performed in the mid 1950s, was between identical twins.1 Transplantation between identical twins resulted in excellent long-term graft and patient survival. However, the growth of kidney transplantation began in earnest with the development of improved immunosuppressive agents, particularly cyclosporine in 1983. In the United States alone, approximately 16 830 kidney transplants were performed in 2009.2

Organ Matching, Availability, and Allocation

Kidney transplantation is now the preferred treatment for end-stage renal disease (ESRD) of almost any origin. There is evidence that patients may benefit from earlier transplantation even if the donor organ is not optimal because the high mortality of long-term dialysis favors the risk:benefit ratio toward transplantation.3,4 The 5-year survival of patients on chronic hemo- or peritoneal dialysis is only 30%. In contrast, the 5-year survival following transplantation for ESRD is 70%. Therefore, except in rare instances, transplantation should be performed in all patients with renal failure where it is technically feasible.5

Several methods are used or being investigated to increase the number of kidneys available for transplantation (Table 59-1). Living kidney donation is becoming an important source of donor kidneys. Approximately 6388 patients received a transplant from a living donor in the Unites States in 2009.2 Recipients of living related kidney transplants generally suffer fewer episodes of acute and chronic rejection than those receiving cadaveric organs. Recipients also benefit because living related and unrelated transplantation is performed on an elective, nonemergent basis.6

Voluntary organ donation from living related and unrelated donors has led to the establishment of "the living donor exchange."7 Living donors may ask the anesthesia provider about the risks associated with kidney donation. A recent study8 reported that short-term (90-d) mortality was significantly increased when compared to a matched cohort that did not undergo donor nephrectomy, but the difference disappeared over time and the long-term mortality was actually less in those that underwent donor nephrectomy (Fig. 59-1). The early mortality was greater for men, black individuals, and those with a history of hypertension. Obesity and age did not have an impact. The long-term survival may reflect their better preexisting health status that led to them being selected as living donors.

Indications and Contraindications

The most common causes of end-stage renal failure in adults are diabetes mellitus, systemic hypertension, glomerulonephritis, and polycystic kidney disease. In children and adolescents, the most common causes of ESRD are congenital malformations of the kidneys and urinary tract and focal segmental glomerulosclerosis.5

Ideally, patients with progressive renal failure should receive a kidney transplant before they begin dialysis.5,9 Also, diabetic patients with marginal renal function who receive a pancreas transplant should receive a simultaneous kidney transplant because the immunosuppressive agents required for the pancreas transplant may cause further deterioration of renal function to the point of requiring dialysis.9

There are a decreasing number of absolute and relative contraindications to renal transplantation: Many conditions that were thought to be contraindications to transplantation previously, such as HIV, hepatitis C, age over 65, and advanced congestive heart failure, are now considered as acceptable.10-13 Highly sensitized patients, T-cell positive cross-match, and ABO blood group–incompatible patients are now considered potential renal transplant candidates, albeit with an increased morbidity and mortality.14

Although the indications for kidney transplantation have been expanded significantly, some individuals with ESRD are not good candidates for this procedure. Active infection, active drug abuse, complete thrombosis of the vena cava and iliac veins, and disseminated malignancies are among the contraindications to transplantation. Sensitization by previous failed transplants, blood transfusions, or pregnancy will require individual assessment because in some the graft survival would be too poor to transplant.15 Patients who have a history of noncompliance or mental retardation where it is unlikely that they will take their medications constitute relative contraindication to transplantation. However, patients with mental retardation can be transplanted successfully if they have a caregiver responsible for administering the medications.16

Surgical Procedure

The surgical procedure of kidney transplantation is straightforward. In adults and older children (>20 kg), the transplanted kidney is usually placed in the extraperitoneal iliac fossa via a curvilinear incision along the lateral margin of the rectus muscle approximately 8 to 10 in from just above the pubic bone to just above the umbilicus (Fig. 59-2). The common and external iliac arteries and veins are exposed retroperitoneally. The renal vein is anastomosed before the renal artery, and an end-to-side or end-to-end anastomosis may be performed depending on the anatomy of the vessels and depth of the renal pelvis. The renal artery is then anastomosed to the internal or external iliac artery. Occasionally, donors have multiple renal arteries, and several arterial anastomoses are required. Renal revascularization involves clamping of the iliac artery and vein. This can result in ischemia to the lower extremity for as long as 60 minutes. After the vascular anastomoses are completed the clamps are released in a staged fashion, resulting in perfusion of the kidney graft and lower extremities. The final stage of the operation involves reconstruction of the urinary drainage by anastomosing the donor ureter to the patient's bladder.

In infants and small children (<20 kg), a transperitoneal approach is used. An incision from the xiphoid process to the pubis is made (see Fig. 59-2). The bowel is mobilized and the aorta and vena cava are exposed. The donor artery and vein are then anastomosed to the aorta and vena cava end to side. Once the vascular anastomoses are complete, the clamps are released, resulting in reperfusion of both lower extremities and the donor kidney. The urinary drainage is then reconstructed.17

For living kidney donors, the laparoscopic and laparoscopy-assisted approach to nephrectomy is preferred due to a decreased need for pain medication, earlier discharge, and more rapid functional recovery.18 The left kidney is preferred due to implantation advantages associated with a longer renal vein. The patient is positioned in the left lateral position with elevated kidney rest. Positioning of the patient requires great care to prevent positioning-related injuries (see Chapter 27).

Pretransplant Evaluation

Patients undergoing kidney transplantation require a complete medical review and evaluation prior to surgery. (Preoperative evaluation of patients with renal disease is presented in Chapter 14; only brief comments that apply to transplantation will be provided here.) The evaluation is best done by the transplant surgery team prior to placing the patient on the transplant list. After the initial evaluation, cardiovascular surveillance is necessary. Frequency and type of surveillance, however, are a matter of discussion. In high-risk patients it may be prudent to do it annually or at least biannually.19

Comorbid Conditions

Table 59-2 lists medical conditions related to ESRD.

Cardiac Evaluation

Half of all deaths after renal transplantation are cardiac related, and cardiac disease is the leading cause of death in the first year posttransplant.20 Besides severe coronary artery disease, sudden cardiac death of arrhythmic origin is also important.21

Patients with diabetes, peripheral vascular disease, angina, or a longer duration of ESRD have a greater risk of mortality due to cardiovascular disease.20 However, what constitutes the optimal pretransplant evaluation is still debated. Exercise stress testing, myocardial perfusion studies such as dobutamine stress echocardiography and thallium scintigraphy, and cardiac computed tomography (CT) or cardiac magnetic resonance imaging (MRI) can be used. Coronary angiogram remains the gold standard with the ability to predict cardiac events.22 Data to strongly support preemptive myocardial revascularization in patients with stable coronary disease are lacking.

Special Considerations in Patients with ESRD

Diabetics

Due to a high incidence of cardiac disease, some centers recommend coronary angiography in patients with ESRD associated with diabetes if they are older than 45 years of age, have a smoking history, have a body mass index above 25, have had diabetes for more than 25 years, or have electrocardiographic signs of ischemia.23 Diabetic patients who have significant coronary disease with treatable lesions should have coronary artery surgery or an angioplasty prior to receiving a kidney transplant.23 Some diabetics have significant but diffuse coronary disease (identified by angiography) that cannot be treated surgically or by angioplasty. These patients may still benefit from combined kidney and pancreas transplantation instead of chronic dialysis, but they are at higher risk for perioperative cardiac events.24 Successful pancreas transplant in these patients slowed the progression of atherosclerotic lesions (mean segmental diameter loss 0.024 mm/y vs 0.044 mm/y) and caused regression of atherosclerotic lesions in 38% of patients with a functioning pancreas graft.

Furthermore, diabetic patients can suffer from a host of comorbidities that affect anesthetic care, including autonomic neuropathy, gastroparesis, peripheral neuropathy, and peripheral vascular disease. The time of insulin administration is important to note in diabetic patients because it can influence the plan for perioperative glucose management. Diabetic patients should also be asked about symptoms of gastroparesis, such as heartburn, bloating, and explosive diarrhea, because they may be at risk for aspiration of gastric contents upon induction of general anesthesia. These patients will benefit from a nonparticulate antacid, such as sodium citrate or related compounds, prior to induction of general anesthesia. (See Chapter 13 for a detailed review of the preoperative assessment of diabetics.)

Hypertension

Hypertension is another common cause of renal failure that affects multiple organ systems. Patient's usual blood pressure, years of hypertension, and the type and last dose of antihypertensive medications that the patient receives should be recorded. In general, patients should receive their usual blood pressure medications prior to surgery.25 However, angiotensin-system inhibitors administered immediately before operation have been associated with a greater incidence of hypotension upon induction of general anesthesia in hypertensive patients.26

β-Blocker therapy should be continued in those receiving treatment preoperatively, and started in those with a positive stress test, according to the most recent ACC/AHA guidelines. The evidence also favors perioperative β-blockers in high-risk patients (more than 3 risk factors: high-risk surgery, ischemic heart disease, congestive heart failure (CHF), cerebrovascular disease, insulin-dependent diabetes mellitus, renal failure—creatinine >2.0 mg/dL).27 The use of β-blockers in low- and intermediate-risk patients is not supported by current available data.

Sleep-Related Breathing Disorders

An increasing number of patients with ESRD are being recognized to have sleep-related breathing disorders (SRBDs).28 Lee et al examined patients before and after kidney transplantation. Kidney transplantation was effective in improving sleep patterns and also improving the apnea/hypopnea index (Fig. 59-3). (See Chapter 11 for a more detailed discussion of sleep-related breathing disorders.)

Physical Examination

Several components of the physical examination deserve special consideration in the preanesthetic evaluation of the renal transplant patient. The evaluation of the airway is particularly important for diabetics. Patients with long-standing diabetes often develop stiff joints due to glycosylation of the connective tissue that results from elevated blood sugars. The inability to oppose the palms of the hands is 1 sign in a diabetic patient that stiff connective tissue may be present. Patients with stiff joints may be difficult to intubate and may require an awake, fiberoptic intubation.29

The arms of patients on chronic hemodialysis should be examined for the presence of both functioning and nonfunctioning dialysis shunts and fistulas. Upper-extremity fistulas may clot during transplantation surgery from reduced blood flow during surgery or the perioperative elevation of clotting factors. Care must be taken in padding the upper extremity with a forearm fistula so that no restriction of blood flow in the fistula occurs. The blood flow through the fistula during surgery can be monitored by palpation or a Doppler device. The arm with a functioning fistula should not be used for blood pressure monitoring, venipuncture, or the placement of intravascular catheters because each such a maneuver may cause the fistula to thrombose.25 In the event of delayed graft function or even nonfunction following kidney transplantation, a functioning dialysis shunt is invaluable in the postoperative period.

Assessment of Fluid Balance

Fluid balance is often difficult to assess in patients on chronic dialysis. One method to help evaluate the volume status of a patient on chronic dialysis is to review the patient's body weight before and after dialysis. The weight of the patient at the completion of dialysis, the "dry" weight, can be determined and compared to the weight when the patient presents for surgery.17The type of dialysis, time of last dialysis, and frequency of dialysis are important to obtain as well.25 Depending on the type of dialysis and the interval since last dialysis, the patient is rarely euvolemic and usually arrives in the operating room either hyper- or hypovolemic. Significant hypotension upon induction of general anesthesia in recently hemodialyzed patients is therefore not uncommon.17 Anesthesia care providers must be prepared to rapidly replace the intravascular volume in these patients. Depending on the extent of hypovolemia, either intravenous normal saline or 5% albumin may be used to provide a more rapid and sustainable cardiovascular response.

Laboratory Tests

There are several laboratory tests that should be performed in all patients. Because electrolytes and blood glucose can change markedly over several days, particularly in patients on dialysis, most of these tests should be performed at or close to the time of operation. An electrocardiogram should be obtained in all patients at risk for cardiac disease, and the results compared to those of previous studies. The serum potassium may increase during surgery from the effects of drugs administered, blood transfusions, or from the infusion of hyperkalemic preservative solution from the new kidney. Therefore, surgery may have to be delayed and dialysis or other intervention performed if the patient is hyperkalemic (>6 mmol/L) preoperatively. Coagulation studies (international normalized ratio [INR], partial thromboplastin time [PTT], fibrinogen, platelet count) should be obtained if the patient has a prior history of bleeding or other evidence of a possible coagulopathy. Finally, the hemoglobin value should be determined and several units of blood made available preoperatively because patients with renal failure are often markedly anemic preoperatively.25 Fluid loading to increase central venous pressure in preparation for reperfusion and surgical blood loss may further decrease blood hemoglobin values and thus warrant intraoperative packed red cell transfusion.

Induction and Maintenance of General Anesthesia

The choice of induction agent depends on the overall health of the patient, the volume status of the patient, the presence of autonomic neuropathy, and the presence of cardiovascular or other disease. Relatively healthy renal transplant recipients tolerate induction of general anesthesia with propofol (2.0-3.0 mg/kg) or thiopental (2.5-3.0 mg/kg) without difficulty. However, etomidate (0.2 mg/kg) is better tolerated in hemodynamically compromised patients because it exerts minimal myocardial depression and preserves autonomic tone. This is particularly important in diabetic patients with autonomic neuropathy. Fentanyl (3-5 mcg/kg intravenously [IV]) can be administered during induction to blunt the hypertensive response to tracheal intubation. In patients who do not have a history of gastroparesis or acid reflux disease, intermediate-duration nondepolarizing muscle relaxants that do not depend on renal excretion for elimination, such as cis-atracurium (0.2 mg/kg), rocuronium (0.5 mg/kg), or vecuronium (0.1 mg/kg), can be administered to facilitate tracheal intubation.25

In patients with gastroparesis or acid reflux disease, a rapid sequence induction, including Sellick maneuver to prevent regurgitation of gastric contents, should be performed. The depolarizing agent succinylcholine (1.5 mg/kg IV) has classically been used in patients without renal failure to provide rapid skeletal muscle relaxation for immediate tracheal intubation. However, the serum potassium can increase 0.6 mmol/L with its administration, so it should be used with caution, if at all, in patients with renal failure who have an elevated preoperative potassium level (>5.5 mmol/L). Many anesthesia providers therefore prefer to use nondepolarizing agents even if a rapid sequence induction is required. Rocuronium is useful for this purpose because at high doses (1.2 mg/kg) it has an onset of action of 60 to 90 seconds and does not require renal function for elimination.25

The inhaled agents desflurane and isoflurane are both extremely useful for the maintenance of general anesthesia for kidney transplantation. Neither agent has nephrotoxic properties, and no deterioration of renal function has been noted with either agent in patients with or without renal disease.5 Nitrous oxide may be used along with the potent inhaled agent. It has minimal side effects, no renal toxicity, and rapid elimination. However, it is associated with increased nausea and vomiting in the postoperative period.30 As a result it may be used less frequently for these procedures in the future. Sevoflurane is rarely used for renal transplantation due to concerns of fluoride and compound A toxicity.31 Most human studies have not demonstrated deleterious effects of sevoflurane on the kidney.32 Many authors, however, feel that in the presence of other alternatives, there seems to be little reason to select sevoflurane for inhalation anesthesia in renal transplant patients. However, sevoflurane has been demonstrated to have anti-inflammatory and antinecrotic effects on renal tissue, which may be protective against ischemia-reperfusion injury.33 Overall, uncertainty remains regarding the use of sevoflurane in renal transplantation.

During anesthesia care, opioids such as fentanyl (50-100 mcg/h) are often administered throughout the transplant procedure to reduce the amount of inhaled agent required and decrease the likelihood of the patient awakening in severe pain. The pharmacokinetics and pharmacodynamics of fentanyl, sufentanil, alfentanil, and remifentanil are not significantly altered by kidney disease, and all have been successfully used during renal transplantation.34

Ongoing skeletal muscle relaxation can be provided with nondepolarizing muscle relaxants that do not depend on the kidney for elimination, such as cis-atracurium, rocuronium, or vecuronium. All 3 have been used successfully in patients with marginal or no renal function, and have minimal effects on the heart rate or blood pressure. Cis-atracurium is broken down in the plasma by Hoffman elimination, which does not depend on renal or hepatic function. Its duration of action is not prolonged in renal failure. Although the liver is the primary metabolic site for both rocuronium and vecuronium, the duration of blockade may be prolonged with these drugs if large doses are used, due to accumulation of metabolites that are excreted by the kidney.5,35 Pancuronium should not be used in kidney transplant recipients because it depends primarily on the kidney for elimination. If the new kidney does not function adequately initially, a prolonged neuromuscular block may result.5

Blood glucose determinations should be made every hour in renal transplant recipients who have insulin-dependent diabetes mellitus. Evidence suggests that the incidence of wound infections can be reduced in diabetic patients if the blood sugar is tightly controlled.36 The extent of glucose lowering, however, is questionable. The NICE (Normoglycemia in Intensive Care Evaluation) study demonstrated a 2.5% increase in mortality for patients on intensive insulin therapy where blood glucose was kept in the 80 to 110 mg/dL range.37 Middle-ground target glucose of between 140 and 180 mg/dL is suggested at this time.38 Whenever the intraoperative blood sugar is between 90 and 110 gm/dL, a low-dose dextrose solution (D51/2 normal saline at 25 mL/h) should be administered concurrently throughout the procedure to provide for intraoperative nutrition and prevent hypoglycemia.39

Emergence from General Anesthesia

Following the operation, most patients can be extubated in the operating or recovery room when they are alert, strong, and able to maintain adequate ventilation. Rarely is postoperative ventilation required.

Pain control can be achieved with neuraxial anesthesia, and the successful use of combined spinal-epidural anesthesia for both surgical anesthesia and postoperative pain relief has been described.40 However, although rare, there is a small risk of an epidural hematoma.

Because most graft recipients receive heparin intraoperatively, and some in the postoperative period, intravenous opioids such as fentanyl, morphine, or hydromorphone are usually used for postoperative analgesia. These drugs may also be used for patient-controlled analgesia following discharge from the recovery room.5

All opioids must be used cautiously in renal transplant recipients, particularly if the graft is not functioning properly. For example, a metabolite of morphine, morphine-6-B-glucuronide, has opioid agonist activity and is excreted by the kidneys. It can accumulate in renal failure and cause respiratory depression with long-term use. The metabolism of hydromorphone produces a neuroexcitatory compound that can accumulate in renal failure. However, hydromorphone has been used extensively in renal failure patients with no adverse effects. In contrast, a metabolite of meperidine (Demerol), normeperidine, can accumulate in significant amounts in patients with renal failure, and this compound can cause seizures. Therefore, meperidine should not be used for postoperative analgesia in renal transplant recipients.34

Monitoring

Patients undergoing renal transplantation usually benefit from central venous access. It provides convenient vascular access to obtain blood samples and for administration of the immunosuppressive drugs that must be administered centrally. Measurement of the central venous pressure (CVP) has been used in the past to determine if the volume status of the recipient is adequate at the time of reperfusion of the allograft. Alternative newer technologies based on pulse pressure variation and stroke volume variation are currently being validated as tools to determine volume responsiveness. Rarely is transesophageal echocardiography or pulmonary artery catheterization necessary except in those patients with severe cardiac disease (cardiomyopathy) or pulmonary hypertension. Direct arterial catheters are also used infrequently except in compromised patients where frequent blood gases must be determined25 or there is a need to monitor blood pressure more closely, as in those with cardiac disease or cardiomyopathy.

Immunosuppression

Immunosuppression has been the key to success of organ transplantation. The major thrust has been to improve long-term allograft survival. There is considerable variation of immunosuppressant protocols among institutions. To improve long-term allograft survival, researchers are trying to minimize exposure to drugs that are used to prevent acute cellular rejection.41 Commonly used agents for immunosuppression are calcineurin inhibitors (cyclosporine, tacrolimus), antiproliferative agents (mycophenolate mofetil), rapamycin (mTOR) inhibitors (sirolimus, everolimus), corticosteroids, and monoclonal and polyclonal antibodies. Occasionally, reactions to immunosuppressive drugs occur.42 For example, cyclosporine administration can result in hypomagnesemia, rhabdomyolysis, and other electrolyte disorders.43 Reactions to antibody OKT3 can be severe and result in hypotension and pulmonary edema. Treatment with diphenhydramine, vasopressors, steroids, diuresis, and postoperative ventilation may be required.25

Allograft Perfusion

Intraoperative volume expansion is widely used and is supported by studies that have shown increased renal blood flow and better immediate graft function with generous volume administration.44 Immediate graft function is associated with increased allograft and patient survival.5 One method to ensure adequate volume expansion in patients with good cardiac function is to raise the central venous pressure to 14 or 15 mm Hg with intravenous normal saline or 5% albumin prior to perfusion of the allograft. If the patient is relatively anemic (Hgb <10 g/dL), packed red blood cells may be used for this purpose as well. One needs to be aware that static measures of volume, such as CVP or pulmonary capillary wedge pressure, may not be reliable measures of volume responsiveness, especially in patients with decreased cardiac function. Dynamic measures such as pulse pressure variation, stroke volume variation, and changes in aortic flow velocity may be better but have not been extensively studied in this population.45 Furthermore, new studies suggest that overly aggressive fluid administration may not be necessary.46

In spite of adequate volume expansion, hypotension can still result from products of ischemia from the graft or lower extremity when the vascular clamps are released. The microvasculature of the graft and lower extremity are maximally vasodilated with reperfusion after a period of ischemia and can result in a low peripheral resistance. Therefore, it is helpful to intentionally raise the systolic blood pressure to 130 or 140 mm Hg by reducing the concentration of inhaled anesthetic agents administered prior to reperfusing the allograft. A vasopressor such as ephedrine (5-10 mg), phenylephrine (100-200 mcg), or an infusion of dopamine (3-5 mcg/kg/min) is occasionally required to treat hypotension during and after reperfusion. One advantage dopamine has over the other vasopressors is that it can increase diuresis in the allograft. However, graft survival has not been shown to increase despite this increased diuresis.5

Mannitol administration (0.25-1 g/kg) prior to perfusion of the allograft, when combined with volume expansion, has been shown to decrease the incidence of acute tubular necrosis in the transplanted kidney. The mechanism by which it does this may be related to decreasing tubular swelling by its osmotic effect, its action as a free-radical scavenger, or by flushing away sloughed renal tubule cells before they can cause injury by secondary obstruction.47 Other diuretics such as furosemide can be administered to enhance diuresis, but have not been shown to reduce the incidence of acute tubular necrosis or delayed graft function in the transplanted kidney.5

Monitoring Urine Output

After reperfusion of the allograft, the urine output, intravascular volume, and overall circulatory status should be followed carefully. Hypovolemia, hypotension, acute tubular necrosis, or acute rejection can result in diminished urine output. Evaluation of decreased urine output posttransplant usually begins with an assessment of the patient's volume status. A biopsy of the transplanted kidney may also be necessary to determine if the patient is suffering from acute tubular necrosis or graft rejection.25

Decreasing urine output may indicate a reversible surgical problem. Anuria may also be due to a mechanical factor. Vascular complications such as arterial thrombosis, arterial stenosis, or venous occlusion may result in oliguria. Distal obstruction of the ureter by a clot or kinking, or pressure on the kidney by a lymphocele or hematoma may compromise function of the new kidney as well. Fortunately, many of the mechanical causes of oliguria are correctible, if the diagnosis can be made in a timely fashion.25

Postoperative Considerations and Complications

Most patients do not require admission to the intensive care unit in the postoperative period provided the nursing unit is experienced in the care of transplant recipients. In addition to providing the standard postoperative care for a patient who has undergone major abdominal surgery, the function of the new kidney must be followed carefully in the transplant recipient. Rejection, viral infection, vascular thrombosis, and urinary obstruction are all complications that may occur in the perioperative period.25

However, the most common causes of death after transplantation are cardiovascular-related events, and studies estimate a 3-year cumulative incidence of myocardial infarction of 4.7% to 11%.48 Up to 6% of patients with coronary artery disease experience a cardiac complication within 30 days of transplantation.49 Providing perioperative β-blockade, normothermia, maintaining a hematocrit of greater than 30%, and ensuring that patients have optimum analgesia in the perioperative period are all measures that may help reduce the risk for patients with cardiac disease undergoing renal transplantation.5

Anesthetic Considerations for Patients with Prior Renal Transplantation

Even with a functioning graft, the renal excretion of drugs in transplant recipients is usually decreased when compared to those with normal functioning native kidneys. Further, recipients may still suffer from their other systemic disease, such as diabetes or hypertension that resulted in their renal insufficiency initially. Therefore, the anesthetic care of patients with a prior renal transplant is similar to the transplant itself. Muscle relaxants that depend on renal excretion for their elimination, such as pancuronium, should be used only with the recognition that there may be delayed excretion. Adequate hydration should be ensured in the perioperative period and hypotension avoided to ensure adequate perfusion to the allograft.50

Long-term immunosuppression can result in significant morbidity in kidney transplant recipients.51 The effect of immunosuppressive drugs should be considered when evaluating a kidney transplant recipient for nontransplant surgery. For example, cyclosporine use may cause hypertension and hyperlipidemia, and worsen atherosclerosis in kidney transplant recipients. Tacrolimus is associated with new-onset diabetes after transplant. Most patients have adrenal suppression to some degree because of long-term steroid use. Therefore, a stress dose of steroids may be necessary in renal transplant recipients who have received steroids for immunosuppression.50

Special Considerations in Pediatric Patients

The anesthetic care of older children and adolescents is similar to adults. Infants and small children less than 2 years of age are more challenging. Infants and small children usually receive an adult kidney rather than one from a donor similar in age because there is a high incidence of vascular thrombosis with allografts from infants and small children. However, an adult kidney is so large compared to an infant that it must be anastomosed to the infant's aorta and vena cava rather than the iliac vessels (see Fig. 59-2) as in older children or adults.52 Therefore, the aorta and vena cava both must be cross-clamped during performance of the vascular anastomoses. The adult kidney can sequester up to 300 mL of blood upon reperfusion. Reperfusion can also result in acidosis from the ischemic organ and lower extremities. Hyperkalemia may result from absorption of the standard hyperkalemic (University of Wisconsin) preservative solution. Hypothermia may result with reperfusion of the allograft. Ischemic vasodilatation upon reperfusion of the allograft can also result in a low peripheral vascular resistance and hypotension. In addition, the adult kidney can initially produce urine at a rate equal to the patient's blood volume every hour.53 All this dictates that caregivers pay close attention to circulatory hemodynamics in young infants receiving an adult kidney allograft.

Allograft Perfusion

The goals of the anesthetic management of kidney transplantation in infants and small children are the same as those for older children and adults. Adequate volume expansion must occur to prevent severe hypotension upon perfusion of the allograft. Often a permanent, large-bore (2-mm internal diameter) dialysis catheter is valuable for central vascular access and also provides a means for hemodialysis if the kidney does not function immediately. Direct arterial pressure monitoring is useful in infants and very small children because blood pressure changes can be rapid and profound. In contrast to older children and adults, in infants the central venous pressure must be increased to 16 to 20 mm Hg before reperfusion of the allograft. Colloids such as 5% albumin as well as blood products are generally used for this purpose. The amount of colloids and/or blood products administered can be profound. In 1 review of infants and small children receiving an adult kidney transplant, the amount of colloids and/or blood products administered averaged 90 ±41 mL/kg.53

Postoperative Admission to Intensive Care Unit

Postoperatively, pediatric patients are at an increased risk for pulmonary edema. Most pediatric patients tolerate the volume administration without morbidity. In 1 review of 24 infants receiving an adult kidney transplant, 17 (71%) were extubated in the recovery room, and most of the others in the intensive care unit the following day. Only 2 patients (8.3%) required mechanical ventilation beyond 24 hours to aid in fluid management. However, 7 of the 24 patients (29%) had radiographic evidence of pulmonary edema on the postoperative chest x-ray. Therefore, the pulmonary status of pediatric patients should be monitored in an intensive care unit setting following surgery, and some may require postoperative ventilatory support.53

Outcome

Approximately 25000 patients per year now receive a kidney transplant, either from a living or cadaver donor. The most recent 1-year graft survival is 92% from cadaveric nonextended criteria donors, 85% from extended criteria donors, and 96% from living related donors. At 5 years, the graft survival is 81% from living related donors, 72% from cadaveric nonextended criteria, and 57% from cadaveric extended criteria donors. The 5-year patient survival is 84% to 72% for recipients of cadaveric organs and 91% for recipients of living donors. In addition, comparison with earlier data shows improved survival of both patients and the allografts over time.54 Renal transplantation has become one of the great success stories in medicine.

The future may give us a new understanding of transplant failure. Recent genetic research has identified a gene variant in the CAV1 gene of kidney donors that carries a higher risk of graft failure following transplantation. This finding may allow us to identify biomarkers that predict graft survival ahead of time.55

Summary

Kidney transplantation offers both better survival and a better lifestyle to patients in renal failure. Patients with renal failure are a challenging group for the reasons discussed above. With careful anesthetic care, knowledge of the pathophysiology of renal failure and associated disease, and understanding of the physiology of perfusion of the renal allograft, satisfying outcomes can be obtained.

History and Introduction

In 1967 Kelly et al reported the first combined transplantation of the pancreas and duodenum along with a kidney in a human with diabetic nephropathy.56 Today this procedure is commonplace for the surgical treatment of Type 1 diabetes mellitus in patients with ESRD. Because renal failure often accompanies diabetes mellitus, and although pancreas transplantation can be done alone, it is most commonly done (as mentioned in the discussion on kidney transplantation) simultaneously with a kidney transplant procedure or following kidney transplantation.57 Thus transplantation of the pancreas or islet cells constitutes surgical treatment for patients with Type 1 diabetes mellitus and now increasingly for those with Type 2 diabetes mellitus (Fig. 59-4).58 Cadaveric donors provide whole pancreas grafts and islet cells, and living donors provide distal segments for transplantation. Autoislet transplantation is the method of choice to treat endocrine deficiency following total pancreatectomy.59 The most recent published data (2009) indicate that more than 30000 pancreas transplants from approximately 140 centers in the United States were reported to the International Pancreas Transplant Registry.60 Most (>22000) were performed in the United States. Most transplants done are simultaneous pancreas-kidney transplants (73%), then pancreas-after-kidney transplants (19%), followed by pancreas transplants alone (9%).60

Pathophysiology of Diabetes Mellitus

Diabetes mellitus is a multisystem disease characterized by hyperglycemia resulting from deficiency in insulin secretion or action. It is one of the leading causes of death and disability in the United States (see Chapter 13 for a detailed discussion of the pathophysiology of diabetes.)

Diabetes mellitus (DM) is classified based on the pathogenic process leading to hyperglycemia.61 Type 1 diabetes occurs when there is an absolute insulin deficiency that is immune mediated or of idiopathic origin. This is usually the result of the synergistic effects of genetic, environmental, and immunologic factors leading to pancreatic beta-cell destruction. Approximately 5% to 15% of diagnosed cases of diabetes are Type 1 and affect individuals during childhood and adolescence.62 The nonsurgical treatment of Type 1 diabetes involves life-long administration of exogenous insulin. The Diabetes Control and Complications study demonstrated that tight glucose control delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy.63,64 These studies have concluded that the risk of the 3-fold increase in severe hypoglycemia outweighs the benefits of delay in progression of diabetic end-organ damage. The surgical option of pancreas or islet cell transplantation offers patients with insulin-dependent diabetes mellitus (IDDM) an endogenous source of insulin. Even though sicker recipients are being transplanted, long-term insulin independence is achieved in 77% to 85% of pancreas transplant recipients.57,65

Insulin resistance with a relative insulin deficiency is classified as Type 2 diabetes.61 It is the more common type of diabetes that is managed by diet, oral hypoglycemic agents, and/or exogenous insulin administration.58 It is usually seen in adults over age 40 years, but the incidence of adolescent onset is increasing rapidly as is metabolic syndrome, which consists of obesity, hypertension, and diabetes mellitus.66 In patients with metabolic syndrome, high amounts of visceral fat are influential in the development of diabetes-related complications, such as cardiovascular disease.

Patients with Type 1 DM develop progressive changes in almost every organ system due to microangiopathy. Chronically increased blood glucose concentration leads to glycosylation of proteins. Acute complications of diabetes include diabetic ketoacidosis, hyperglycemic hyperosmolar nonketotic coma, lactic acidosis, and hypoglycemia.67 Chronic complications of Type 1 DM include coronary artery disease, peripheral vascular disease, cerebrovascular disease, nephropathy, autonomic and peripheral neuropathy, and retinopathy.58,63,64,68 The cumulative prevalence and relative risk of these complications is 21% for myocardial infarction and 22% for renal failure, followed by blindness, amputation, and stroke of approximately 10% in patients with insulin-dependent diabetes mellitus.69

Rationale for Pancreas Transplantation

The goal of pancreas and islet cell transplantation is to restore normoglycemia and the glucagon response to hypoglycemia, allowing patients to be insulin-free and eat a regular diet.58,70 Carbohydrate metabolism after pancreas transplant may stabilize and even improve macro- and microvascular disease.71 A secondary benefit is the improved quality of life reported by patients.72 Although most patients are insulin-free, some may still develop retinopathy and show progression of macrovascular disease despite successful kidney and/or pancreas transplantation.73

The current recommendations for pancreas transplantation are summarized in Fig. 59-4. The American Diabetes Association's position statement74 on pancreas and islet transplant recommends pancreas transplant as an acceptable therapeutic alternative to insulin therapy in diabetic patients with imminent or established end-stage renal disease who will have a renal transplant. Survival is better if a pancreas transplant is also done in patients requiring a kidney transplant.75 Diabetic patients with a history of frequent, acute, and severe metabolic complications; incapacitating clinical and emotional problems with exogenous insulin therapy; and consistent failure of insulin-based management to prevent complications should be considered for pancreas transplant in the absence of indications for kidney transplant. Islet cell transplantation is projected to be the method of choice for the future care of patients with Type 1 diabetes. Many centers are conducting research with both human cadaveric islets as well as pig-encapsulated islets. However, these technologies are still in an infancy stage and thus should be performed only in a controlled setting where facilities for doing this procedure are available.

Surgical Options

Several surgical techniques have been described but all require vascularization of the pancreas and a method to drain the pancreatic duct.76 Exocrine secretions can be managed by either enteric or bladder drainage (Fig. 59-5). From 1987 to 1995 over 90% of pancreas transplants were done using bladder drainage (Fig. 59-5B), which allows serial measurements of urinary amylase to monitor for rejection.57,77,78 Chronic loss of pancreatic secretions into the bladder can result in dehydration, electrolyte abnormalities, local bladder irritation, hematuria, urethritis, and allograft pancreatitis.79 With improvement in surgical technique, enteric drainage (Fig. 59-5A) has now become the surgical procedure of choice.77 Initially, it was associated with a high morbidity rate due to leakage and need for frequent reoperations. However, enteric drainage avoids the complications associated with bladder drainage77.

Vascular management includes arterial anastomosis and venous drainage either systemically or into the portal venous system. Portal venous drainage has remained constant for patients undergoing simultaneous pancreas and kidney transplantation, but has been decreasing since 2002 for the other transplant categories.57 Both portal and systemic drainage are associated with excellent glycemic control, but fasting serum insulin levels are significantly lower in portal drainage without an effect on graft survival rates at 1 year for simultaneous pancreas-kidney or pancreas-after-kidney transplantation.80 Currently, vascular management strategies have little impact on graft survival rate.57

Because of technical problems, pancreas grafts are associated with the highest surgical complication rate of all routinely transplanted solid organs. Causes for technical failure of cadaveric primary pancreas transplants include pancreatitis, anastomotic leak, bleeding, and rejection.81 Significant risk factors for graft loss include older donor age, donor obesity, retransplantation, relaparotomy for infection, leak, or bleeding, and the immunosuppression protocol.82 The quality of a cadaveric donor graft can directly affect graft performance.82 Table 59-3 lists the inclusion criteria for a cadaveric pancreas donor.58 As experience with pancreas transplant increases, the incidence of relaparotomy has decreased.83 Risk factors for recipient death include older recipient, retransplantation, and relaparotomy for thrombosis, infection, leak, or bleeding.57,58

Preoperative Evaluation

Cadaveric pancreas procurement is usually part of a multiple organ harvest, and for successful graft function, preservation time should preferably be limited to less than 24 hours. This requires that the anesthesia provider be able to perform a thorough evaluation of the recipient in an efficient manner. As emphasized in the discussion on kidney transplantation, for patient care efficiency it is imperative that pancreas transplant centers exercise a stringent policy with regard to evaluation and selection.77 An advance evaluation should include coronary artery disease,84 renal status, autonomic nervous system, systemic neuropathy, metabolic status, presence of gastroparesis, and the possibility of difficult intubation.58 Table 59-4 outlines areas that should be included during the preoperative assessment.

Coronary artery disease is responsible for most perioperative mortality in pancreas recipients.23,85 Noninvasive screening tests or coronary angiography done preoperatively help plan intra- and postoperative care to decrease complications.23,85,86 Pretransplantation coronary revascularization reduces the risk of subsequent cardiac events.86 Because simultaneous pancreas-kidney transplants account for 78% of pancreas transplants, and pancreas-after-kidney account for 16% of transplants,57 it is important to evaluate renal function, including determination of acid-base status, glucose levels, electrolyte concentrations, and time of last hemodialysis. ESRD is often associated with anemia, which can have a significant impact on morbidity and graft success.58

Autonomic nervous system dysfunction predisposes patients to severe hypotension during anesthesia. There also are reports of sudden death in patients not continuously monitored during the immediate postoperative period, possibly from an altered response to hypoxia.87,88

When gastroparesis is present, aspiration prophylaxis with nonparticulate antacids, H2-antagonists, and metoclopramide are suitable options. Rapid sequence induction with cricoid pressure should be considered in patients with gastroparesis.

Careful evaluation of the airway is necessary in pancreas transplant recipients. As discussed earlier, patients with long-standing Type 1 diabetes have an increased incidence of intubation difficulty. The inability to oppose palms due to stiffness of the interphalangeal joints is predictive of difficult tracheal intubation.29,89

Intraoperative Care

General anesthesia is induced with agents appropriate for the patient's baseline medical condition followed by orotracheal intubation. A combination of anesthetic drugs is used to maintain general anesthesia. In patients with renal dysfunction, isoflurane and desflurane appear to be virtually devoid of nephrotoxicity. As described earlier in the discussion on kidney transplantation, one may choose among the opioids fentanyl, sufentanil, alfentanil, and remifentanil if renal disease is present. Morphine and meperidine are best avoided for the reasons enumerated earlier. At our institution, fentanyl is the opioid of choice; it is also associated with minimal hemodynamic alterations. The choice of muscle relaxant should take into account the degree of renal impairment. Thus patients who are on dialysis should not receive pancuronium (see discussion on kidney transplantation); vecuronium and rocuronium are eliminated by both the hepatic and renal routes and may be used in those with chronic renal disease if neuromuscular junction monitoring (eg, train-of-four response) is used to guide repeat dosing after an initial bolus dose has been administered. At our institution, cis-atracurium is used most commonly because it is cleared by Hoffmann elimination rather than hepatic or renal function. In addition to standard anesthetic monitors, patients receiving a pancreas transplant need central venous access, which is useful in the assessment of intravascular volume status, to provide access for possible pressor support, immunosuppressive drugs, and as a means for frequent intraoperative blood sampling. In patients with significant cardiovascular disease, direct arterial pressure monitoring, and right heart monitoring with a pulmonary artery catheter and/or transesophageal echocardiography are available monitoring options to assist during surgery.90

Blood glucose levels must be checked at least hourly or more frequently during general anesthesia with the goal of keeping serum glucose levels between 100 and 150 mg/dL.90 Animal studies have shown hyperglycemia to cause islet cell dysfunction.91 Maintaining serum glucose levels in an acceptable range is accomplished by continuous infusion of regular insulin at a rate of 1 to 5 U/h with concurrent dextrose infusion when blood glucose levels are below 150 mg/dL (Table 59-5). The addition of dextrose ensures uninterrupted intracellular nutrition to avoid intraoperative ketosis.

Pancreatic beta cells can start releasing insulin as early as 5 minutes after reperfusion.92 Delayed graft function may be treated postoperatively with an insulin infusion titrated to keep blood glucose levels less than 150 mg/dL.93 Somatostatin may be administered to decrease pancreatic enzyme secretion.94

To ensure adequate perfusion and prevent hypotension upon allograft reperfusion, the patient's hemodynamic status must be optimal prior to release of the vascular clamps. Administration of intravenous fluids, either crystalloid or colloid, to achieve a CVP in the 12 to 14 mm Hg range and a systolic blood pressure of at least 140 mm Hg is recommended in patients without significant heart disease.58 Alternatively, in those with a pulmonary artery catheter, careful titration of volume versus filling pressures and cardiac output can be used to optimize intravascular fluid status prior to vascular unclamping. In preparation for unclamping, potent inhalational agents may need to be reduced. Hypotension at unclamping may require administration of fluids, the use of pressors, and blood products as appropriate. It is important to maintain perfusion pressure and blood flow to the new allograft. Hetastarch is often preferred as a colloid in those who have functioning kidneys, as it not only improves preload but also improves graft vessel flow. This prevents graft vessel thrombosis, the most common cause of technical pancreatic graft failure.57 The goals of successful intraoperative care are cardiovascular stability, maintaining graft perfusion pressure with mean arterial pressure (MAP) of greater than 70 mm Hg, metabolic control, normothermia, and electrolyte homeostasis.

Most patients can be extubated in the operating room after surgery provided they meet extubation criteria, that is, they are alert, normothermic, have recovered from neuromuscular blockade, and are hemodynamically stable. When the patient arrives in the postanesthesia care unit, blood glucose, hemoglobin, electrolytes, and troponin levels should be checked. Dehydration, electrolyte, and acid-base disorders, and hypoglycemia or hyperglycemia can develop quickly in the postoperative period. Patients with a bladder anastomosis may get dehydrated and develop frequent infections and often require supplemental sodium bicarbonate to treat the metabolic acidosis caused by the loss of pancreatic secretions into the bladder.77,79,81,93,94 In our institution all diabetic patients undergoing solid-organ transplant are assessed for myocardial infarction (MI) with serial troponins and electrocardiogram (ECG) due to the incidence of silent MI in this patient population. Postoperatively, patients receive 5% dextrose in 0.45 N saline as maintenance fluid. Nasogastric and urine output losses are replaced in equivalent amounts with 0.45 N saline.

Immunosuppression

Pancreas transplant recipients have a higher incidence of acute rejection and immunologic graft loss than transplant recipients of any other solid organ. There were 4 main agents of initial maintenance immunosuppression from 1996 to 2002 for US cadaveric primary pancreas transplants: azathioprine, cyclosporine, mycophenolate mofetil, and tacrolimus. Sirolimus was also used.57,95 In recent years in the United States, the most common induction protocol uses antithymocyte globulin, alemtuzumab, or interleukin-2 receptor antibody followed by tacrolimus, mycophenolate mofetil, and steroids.54

Pancreas transplant recipients are at risk of developing infection for numerous reasons, including immunosuppression, contamination from the duodenal segment of the graft, and blood glucose irregularity due to diabetes.93 Infection prophylaxis with broad-spectrum antibiotics for community-prevalent bacterial infections, antivirals for CMV, and antifungals is routine in many centers.77,83,94 Prophylaxis against vascular thrombosis consists of either low-dose intravenous heparin (300-500 U/h) or subcutaneous heparin followed by aspirin.77,83

Islet Cell Transplantation

The transplantation of pancreatic islet cells is a developing alternative treatment of diabetes mellitus. In 2000 Shapiro et al reported 7 patients who were rendered insulin independent after islet cell transplantation.96 Recent reports suggest that 72% of recipients become insulin independent.97 Further, an increasing number of recipients can become insulin independent with cells from a single donor.98 Major drawbacks of islet cell transplantation are related to logistical problems of setting up an infrastructure to perform islet isolation on a large scale.99,100 Advances in immunosuppression and isolation techniques have been shown to improve outcomes with islet cell transplantation.101 Similarly, it has been found that recipients with a low body mass index (BMI) have a higher success rate with islet cell transplantation when the islets are obtained from a donor with a high BMI because of a higher yield of islets.102 In spite of numerous advancements, islet cell transplantation is still hampered with lack of durability, and approximately 50% of patients require insulin treatment within 2 years.103

Islet isolation requires special processing of pancreas tissue to yield a maximum number of islets available for transplantation.104 Pancreatic islet cell preparations with greater than 5000 islet equivalents and a volume of less than 5 to 10 mL are generally acceptable for transplant after proper dilution in Connaugh Medical Research Laboratories (CMRL) media supplemented with albumin or Hetastarch and heparin.105,106 These harvested islet cells can be transplanted in diabetic recipients using local anesthesia and sedation.107 At our institution we commonly use a mixture of propofol plus ketamine (1 mg of ketamine per 10 mg of propofol) and titrate to a level that provides sedation plus analgesia with spontaneous breathing and supplemental oxygen by nasal cannula. If required, one may also consider adding a low-dose infusion of dexmedetomidine (0.2-0.5 mcg/kg/h). For the surgical procedure, a cannula is placed either percutaneously directly into the portal vein via the liver or via a mini-laparotomy into a mesenteric vein draining into the portal vein. After final catheter position is confirmed (by ultrasound and fluoroscopy when the percutaneous approach is used), the portal vein pressure is measured and the islets are infused by gravity over 20 to 60 minutes.108 Portal pressures are measured every 15 minutes to monitor for acute portal hypertension that commonly occurs if the islets are transfused rapidly. After the islets are transplanted, before removal of the percutaneously placed portal vein infusion catheter, heparin is administered directly into the portal vein.106,107 As the infusion catheter is removed, thrombin-soaked gelfoam is embolized into the peripheral hepatic parenchymal catheter tract.107,109

Complications of islet cell transplant include posttransplant hemorrhage (requiring transfusion), intraparenchymal hemorrhage, subcapsular hemorrhage, portal vein thrombosis, hemothorax, pneumothorax, hemobilia, and inadvertent puncture of the neighboring structures.107 Some patients require more than 1 islet transplant to achieve insulin independence.109

Due to a limited supply of islet cells, research has explored other possible sources of beta cells. Progress has been made with stem-cell biology, transdifferentiation, and xenotransplants, and there is evidence that beta-cell regeneration within the pancreas is possible.110

Outcome Following Transplantation

Analysis of the results reported in the International Pancreas Transplant Registry (IPTR) indicates that following transplantation, long-term insulin independence has improved over time.57 The patient survival rates for all 3 categories (simultaneous pancreas-kidney, pancreas-after-kidney, pancreas transplant only) are over 90% at 3 years posttransplant.57 Most deaths occur as a result of cardiovascular disease. Pancreas graft survival rates are better with simultaneous pancreas-kidney (85% vs 79% for pancreas-after-kidney, vs 77% for pancreas transplant only) transplantation. Chronic rejection continues to be a major challenge.111

Conclusions

Pancreas transplantation is now an established procedure for the surgical treatment of diabetes mellitus. It is most commonly done simultaneously during kidney transplantation because the patients will already be receiving immunosuppression, and individual graft survival is improved when both organs are transplanted. Islet cell transplantation will no doubt be the procedure of choice once it becomes a more routine procedure because of the minimal surgery involved. The perioperative care of patients for pancreas transplantation involves understanding the goals of the procedure and the pathophysiology of diabetes mellitus and renal failure.

Introduction

Anesthesia providers may encounter patients who have an illness requiring hematopoietic stem cell transplantation (HSCT), who are being prepared for HSCT, or who have undergone prior HSCT and are encountered because of a complication. The success of HSCT was recognized as early as 1968112 when a 2-year-old boy with severe Wiskott-Aldrich syndrome was successfully treated with bone-marrow cells provided from his histocompatible, healthy sister, and he has been followed up for 15 years.113 HSCT has since become quite popular for patients with severe combined immunodeficiency114 and also many other diseases. Autologous HSCT as rescue therapy for the bone marrow is usually done following chemotherapy to treat malignancy (Table 59-6).115 Hematopoietic stem cells (HSCs) may be used for autologous, syngeneic, and allogenic transplantation. Autologous HSCT involves stem cell transplant with the patient's own HSCs, whereas allogenic transplantation involves HSCs from another human; transplantation between genetically identical members of the same species is referred to as syngeneic transplantation (eg, identical twins). The most common source of HSCs is bone marrow harvest, and another is the peripheral blood compartment; mobilization protocols are often used to increase the efficiency of this source. Umbilical cord blood is another source of HSCs and has become a popular marrow source for both adults and pediatric patients.116 There is minimal risk of viral exposure with cord blood, and the donor is not placed at risk. In addition, the incidence of graft versus host disease is markedly lower than that for standard bone marrow or peripheral stem cell transplants.117 Although the death rate from graft failure, infection, and graft versus host disease is still high (approximately 40%), the success rate has improved over time with advances in immunosuppression, chemotherapy, antibiotics, and supportive care.118 The number of children receiving HSCTs for various disorders is increasing approximately 10% to 15% per year119 and has reached a steady number of between 4000 and 4500 per year.120

Indications for HSC Transplantation

In a recent review, Gratwohl et al reported that 50 417 first HSCTs were performed globally (Fig. 59-6) in 2006 with the most frequent malignant disease being acute myeloid leukemia and the most frequent nonmalignant disease being bone marrow failure syndrome. A plasma cell disorder was the most frequent indication for an autologous HSCT.120 HSC transplantation is also done to treat a variety of hematologic, metabolic, genetic, and oncologic disorders in adult and pediatric patients.121-123 Table 59-6 is a summary of the annual report by the Center for International Blood and Marrow Transplant Research (CIBMTR; http://www.cibmtr.org/) that lists the diseases for which HSCT was performed. Most HSCTs are done for either acute or chronic myeloid leukemia, followed by acute lymphoblastic leukemia, myelodysplastic leukemia, and non-Hodgkin lymphoma. HSCT is also done for a variety of metabolic disorders and inborn errors of metabolism. Most recently, HSCT has also had initial success as definitive treatment for children with epidermolysis bullosa dystrophica.

Preconditioning, Associated Risks, and Complications

Adults and children who receive HSCT are at risk for complications.124 Thus they may develop respiratory failure or acute graft versus host disease.124,125 Acute graft versus host disease is the most important complication that significantly influences clinical outcome.

Almost all patients who receive HSCT undergo total body irradiation and/or myeloablative preconditioning to eradicate malignant disease if present, to suppress the recipients' immune system (to decrease the chance for graft rejection), and to create space in the bone marrow microenvironment to allow donor stem cell engraftment.126 This predisposes them to hemorrhagic and infection risks as noted by Bacigalupo and others (Fig. 59-7 and Fig. 59-8).125 Infection risks occur from the secondary immunodeficiency and neutropenia. Because neutropenia ensues as a result of the preparatory regimen prior to HSCT and lasts until full engraftment of transplanted stem cells occurs, patients are at risk for infection. This is another cause of morbidity and mortality for several weeks. T- and B-cell function may also be depressed for several months following bone marrow transplantation and cause recipients to be susceptible to viral and fungal infections.118,127 Some patients may also require help from the anesthesia pain service due to calcineurin-inhibitor (tacrolimus)–induced pain syndrome after bone marrow transplantation.128,129

Total body irradiation as part of the HSCT preparation protocol may cause pneumonitis, restrictive cardiomyopathy, pulmonary fibrosis, and oral mucositis. Oral mucositis can be extremely painful and in addition to opioids may require special oral swishes including the use of ketamine as a mouthwash to control mucositis pain.130 The authors used a solution of ketamine (20 mg/5 mL) for oral mouthwash swishes every 4 hours with significant oral mucositis pain relief. Chemotherapeutic agents such as adriamycin can result in cardiomyopathy or other toxicities. In addition, veno-occlusive disease of the liver may develop following intensive chemo- and irradiation therapy. This complication, which is most often fatal, occurs approximately 2 weeks posttransplant when the small hepatic venules become fibrotic and develop pericentral hepatocyte necrosis and congestion.131

Another condition called graft versus host disease (GVHD) can significantly influence the outcome of HSCT recipients (Fig. 59-9). GVHD starts off as an acute disorder but sometimes manifests as chronic GVHD. Acute GVHD may be mild or life threatening (Table 59-7).132 In GVHD, immunologically competent donor T cells transplanted in the recipient react against host tissue cells that are recognized as host-foreign antigens. This results in the secretion of cytokines including interleukin-1, interleukin-2, and tumor necrosis factor that are responsible for the signs and symptoms of acute GVHD.132

Chronic GVHD develops more than 100 days after HSCT and is characterized by multiorgan involvement.132 Patients present with features resembling naturally occurring autoimmune disease due to chronic cytokine effect, thymic atrophy, and lymphocyte depletion. Thus they may present with scleroderma, oral mucositis, interstitial pneumonitis, and polymyositis.118,133-135

During preanesthesia assessment for HSCT, recipients must be investigated for multiorgan involvement.136 Noninfectious pulmonary and other complications typically occur before the first 100 days following HSCT (see Fig. 59-8).137 Thus HSCT recipients are at risk for airway complications during the first 2 months of transplantation.

Anesthesia Considerations

Before receiving a bone marrow transplant, pediatric (and some adult) patients often require anesthesia for permanent central venous catheterization, biopsies, and total body irradiation. Following transplantation these same individuals often need anesthesia for (1) biopsies to evaluate the status of the bone marrow transplant and determine if GVHD has developed and (2) treatment of the surgical complications that may follow this procedure. Most patients undergoing HSCT tolerate anesthesia for these procedures without difficulty. However, complications can occur, particularly in those recipients less than 2 years of age. In these individuals, anesthesia providers must keep in mind the unique medical problems associated with children undergoing bone marrow transplantation.118,127 Children with inborn errors of metabolism may also require anesthesia for several procedures related to HSCT and may be anesthetic challenges because of their primary disease.138 Thus some patients with metabolic disease may be difficult to intubate. In addition, mucositis and upper airway edema can complicate anesthesia care. When endotracheal intubation is required either for complications related to HSCT or for anesthesia needs, the airway care must be provided in an environment equipped to handle a patient with a difficult airway. Clinical judgment also needs to be exercised to determine whether an otolaryngologist skilled in pediatric and adult upper airway care needs to be present during anesthesia induction and/or sedation and intubation, and for extubation in some instances.

Radiation and/or chemotherapy and GVHD can result in nausea and vomiting. Tracheal intubation and airway protection may therefore be required in some patients.

Anesthetic Management

There are a variety of anesthetic techniques that can safely be used to anesthetize children and adults receiving care for HSCT. No drug, agent, or technique is absolutely contraindicated.118,135 Nitrous oxide suppresses methionine synthetase, and other anesthetics are myelosuppressive but are not contraindicated during anesthesia care.139-141

The concern that is unique to bone marrow recipients is the high incidence and potential morbidity from mucositis that occurs when patients are neutropenic. Pediatric anesthesia care providers must minimize airway manipulation if possible, and thus intravenous propofol has proved useful for sedation for total body irradiation using spontaneous ventilation without airway instrumentation. It is the preferred drug because of its rapid recovery and antiemetic profile. This allows earlier feeding and better nutrition in infants undergoing radiation therapy than other intravenous agents such as ketamine or thiopental.118 Even in children with Hurler syndrome, proper neck and head positioning can allow safe propofol sedation, but in some instances the laryngeal mask airway has been used. Because of potential injury it must be used with caution in cases of mucositis.142 When tracheal intubation is required for airway care, the preoperative airway examination may be difficult due to severe pain.143 For the same reason, awake intubation may be impossible as well. Movement and struggling during the procedure may cause bleeding and edema, and obscure the laryngeal inlet. Therefore, one may have to resort to a rapid sequence induction technique to minimize the time with an unprotected airway while providing as optimal conditions as possible for rapid endotracheal intubation. However, when stridor or other signs of airway obstruction are evident, an inhaled induction of general anesthesia with sevoflurane and oxygen similar to that used in a child with epiglottitis may be required. In such patients, anesthesia providers must be prepared with adequate suction and several tracheal tube sizes because the laryngeal inlet may be narrowed due to edema and inflammation.118

Care must be taken with extubation as well. Most patients with mucositis can be extubated when fully awake. Often these patients develop croup in the postoperative period and may require treatment with dexamethasone (0.5-1 mg/kg) and 1 or more courses of racemic epinephrine. However, patients with mucositis and severe edema of the laryngeal inlet may require prolonged intubation until the edema resolves.118

Children may also require procedural sedation for follow-up after HSCT. In a recent study the authors found that a combination of propofol/ketamine was better than propofol/alfentanil to provide deep procedural sedation for lumbar puncture in children with acute lymphoblastic leukemia.144 The use of ketamine instead of alfentanil prevented the need for respiratory assistance because respiratory depression was noted with alfentanil when used with propofol.

Conclusions

For the successful care of patients requiring HSCT, the anesthesia practitioner must be aware of the unique problems that accompany the process of patient preparation and those related to myeloablative therapy. Most acute problems occur in the first 100 days following transplantation. Children may require HSCT for metabolic diseases including some inborn errors of metabolism. The primary disease can be challenging for anesthesia providers. The outcome of HSCT depends on the indication and also the severity of the disease prior to HSCT.

History and Introduction

Lillehei et al performed the first transplant of a small bowel in humans at the University of Minnesota when they performed a graft of the stomach, small bowel, and pancreas in a patient with a mesenteric venous thrombosis.145 Further attempts were made over the years, but all were unsuccessful due to a very high mortality from uncontrolled graft rejection and patient sepsis. Grant et al reported the first long-term survivor from combined small bowel-liver graft using cyclosporine-based immunosuppression in 1990.146 It was not until the introduction of tacrolimus for immunosuppression in 1991 that outcomes improved.147

The number of patients undergoing intestinal transplantation is still rather modest. For example, in 2009 only 180 patients underwent intestinal transplantation.2 Graft survival rates by the end of 2008 were 86% at 1 year and 61% at 5 years.2 These outcomes are markedly improved from earlier reports, and single centers have reported survival rates of 92% at 1 year and 70% at 5 years when antilymphoid pretreatment immunosuppressive strategies were used.148 Living related bowel transplantation is also being developed.149 The progress in the field of intestinal transplant is especially important due to the high mortality of patients on transplant lists (20%).150

Indications

The primary reason for intestinal transplant is intestinal failure, which is defined by the inability to maintain nutrition, fluid and electrolyte balance, or normal growth and development of the body. Conditions that lead to intestinal failure differ between children and adults (Table 59-8). In children gastroschisis, necrotizing enterocolitis, intestinal atresia, midgut volvulus, aganglionosis, and pseudoobstruction are most frequent. In adults ischemia, inflammatory bowel disease, volvulus, tumors, and trauma are most prevalent.151 The Center for Medicare and Medicaid accepts the following indications for intestinal transplant when liver failure/injury due to parenteral nutrition has occurred: thrombosis of 2 or more central veins, 2 or more episodes of catheter-related sepsis or 1 episode of fungemia, septic shock, or ARDS, and dehydration despite adequate fluid supplementation.

Surgical Procedure

Isolated Intestinal Transplantation

Isolated intestinal transplantation is recommended for patients with irreversible intestinal failure without liver failure.152 Fig. 59-10 demonstrates the isolated bowel transplant. Vascular continuity is established between the superior mesenteric artery bowel graft and the aorta, and superior mesenteric vein of the graft and the recipient vena cava.

Combined Liver and Small Bowel Transplant

The presence of cirrhosis or advanced bridging fibrosis of liver is a well-known complication of total parenteral nutrition. For patients with irreversible intestinal failure and end-stage liver disease, a combined small bowel–liver transplant is the recommended treatment.152 In a combined liver-bowel transplant, the liver and bowel can each be transplanted separately. This is the method used if a living related combined liver-bowel transplant is performed. In certain circumstances en bloc combined liver-bowel transplants may be performed (Fig. 59-11).

Multivisceral Transplantation

At the 2007 International Small Bowel Transplantation Symposium, a more descriptive anatomic nomenclature was proposed for multivisceral transplant. The procedure is performed in patients with debilitating trauma, massive resections, multiple surgeries with short-gut syndrome, dysmotility disorder, extensive mesenteric vascular thrombosis, multiple enterocutaneous fistulas, and irresectable tumor.151 Complete evisceration of the native foregut and midgut followed by en bloc transplant of the stomach, pancreaticoduodenal complex, liver, and small bowel or different modifications of surgery are possible (Fig. 59-12).

Living related intestinal transplantation is an option entertained especially in countries where the availability of cadaveric organs is limited. It has so far been successfully performed in a limited number of patients.153

Preoperative Considerations

Patients being considered for small bowel transplantation require a thorough evaluation of each organ system. If the patient is over 40 years of age or has a history of cardiac disease, tests such as an echocardiogram, dobutamine stress test, or assessment of the coronaries by angiography may be required. The patient's liver function must be evaluated because most patients have been on chronic intravenous hyperalimentation, which is hepatotoxic. Electrolyte and acid-base imbalance is common due to diarrhea and/or dehydration and should be checked preoperatively. Some patients with short gut syndrome have lost their intestines from vascular thrombosis. Therefore, a thorough investigation of the coagulation status of patients undergoing small bowel transplantation is required.154

Evaluation of Patency of Central Vessels

Due to the high incidence of venous thrombosis in patients on long-term hyperalimentation, it is recommended that all patients referred for intestinal transplantation undergo preliminary mapping of their venous access by Doppler ultrasound, and patients with multiple thrombosed vessels should be considered for additional angiographic evaluation.155

Anesthetic Management

Induction and Maintenance of Anesthesia

Often patients presenting for bowel transplantation have delayed gastric emptying. Therefore, a rapid sequence induction of general anesthesia is indicated. In many instances, this may require intravenous induction of general anesthesia with attention to hemodynamic stability. Maintenance of general anesthesia is similar to that for liver or renal transplantation. Balanced anesthesia using desflurane or isoflurane for the potent inhaled agent along with opioids (fentanyl, sufentanil) and muscle relaxants (vecuronium, cis-atracurium, rocuronium) is commonly used.154 Because many of these patients have impaired renal function, muscle relaxants such as pancuronium that are dependent on renal elimination are not utilized. Similarly, sevoflurane is generally not utilized because its safety in patients with impaired renal function has not been established.25

Small bowel transplantation is a long surgical procedure that can take up to 17 hours.152 It can be associated with large fluid shifts due to abdominal manipulation and significant intraoperative bleeding, dehydration, vascular clamping, long ischemia times, visceral exposure, and lymphatic interruption.156 Therefore, adequate vascular access must be established. A rapid infusion device is often beneficial and should be available, and blood-salvaging devices should be used. Frequent (hourly) determinations of laboratory values such as arterial blood gases, electrolytes, lactate levels, hemoglobin and platelet levels, and clotting studies are often necessary.157 These patients can also be hypothermic due to the long, extensive dissection in the abdomen and exposure of the bowel to ambient temperature. Forced air surface warming and application of other newer technologies to preserve core temperature are extremely valuable to prevent significant hypothermia in patients undergoing extensive abdominal operations such as bowel transplantation.158

When bowel transplant surgery is completed it is rare that the patient can be extubated in the recovery room. Often patients require positive pressure ventilation for a period equivalent to the duration of surgery or longer because the edematous graft placed in the small abdominal cavity limits the descent of the diaphragm. Positive pressure ventilation may be needed until the edema resolves and the abdominal cavity stretches to accommodate the new bowel.159 The peripheral edema also resolves after several days postoperatively.156

Monitoring

All patients need a large-bore central venous catheter placed prior to beginning transplantation for rapid volume administration and measurement of the central venous pressure. Because the venous drainage of the small bowel allograft is into the vena cava, elevated central venous pressure can reduce perfusion of the allograft and increase small bowel edema. Measurement of pulmonary artery pressures and cardiac output may be beneficial in patients where it is technically feasible.154 Monitoring of cardiac output may help in the handling of the hypotension often seen with reperfusion of the small bowel allograft.154 Direct arterial pressures should also be monitored, preferably from a catheter in an upper extremity artery because the aorta is partially or completely cross-clamped for some of the procedure.159 Transesophageal echocardiography may also be helpful, particularly in patients with chronic occlusions of the central venous system that preclude access for pulmonary artery catheterization.154

Allograft Perfusion and Fluid Management

In most cases of isolated small bowel transplantation, both the aorta and vena cava must be cross-clamped while the venous and arterial anastomoses are made. In some cases, the vascular anastomoses can be made with side-biting or partially occluding vascular clamps for either the aortic or venous anastomoses. With partial occlusion, the hemodynamic effects of cross-clamp release are usually diminished. Also in some cases, if technically feasible, the venous drainage of the intestinal allograft is made into the portal system of the recipient. The portal vein rather than the vena cava is completely or partially occluded.154 This may result in less hemodynamic compromise because venous drainage from the lower extremities is maintained. Finally, in combined small bowel–liver transplants or multivisceral transplants, separate anastomoses for the small bowel may not be made. Instead, the small bowel is reperfused as the liver and other organs are reperfused. The hemodynamic changes with reperfusion are likely to be profound in these operations.160,161 With the aid of a rapid infusion device one can ensure rapid fluid replacement during reperfusion. This diminishes the likelihood of hypovolemia-related hypotension and hypoperfusion of the newly anastomosed allografts.

Regardless of the type of anastomoses or operation, the small bowel prior to reperfusion is cold and filled with University of Wisconsin solution for preservation. University of Wisconsin solution is very high in potassium. Particularly if the venous drainage of the bowel is to the inferior vena cava, flushing of the cold preservative solution into the venous system with release of the aortic cross-clamp can result in hypotension and myocardial depression. With portal drainage, buffering by the liver occurs and the direct effect of the preservative solution on the heart is less profound.159

Prior to reperfusion of the allograft, the anesthesia provider should be sure that the patient has been adequately hydrated with blood products and/or colloid solution as guided by the central venous pressure and hemogram assessments. Excessive crystalloid solution beyond the maintenance rate should not be administered to minimize peripheral edema. If the urine output decreases below 1 mL/kg/min despite a central venous pressure of 10 mm Hg, mannitol, furosemide, or dopamine (2-3 mcg/kg/min) should be administered.159

Ten to 15 minutes prior to release of the vascular clamps, the volatile agent can be reduced to raise the systemic pressure to counter the fall commonly seen with reperfusion. The anesthesia provider must be prepared to administer calcium chloride (10 mg/kg) to counteract the hyperkalemia occasionally seen with wash out of the preservative solution, as well as vasopressors such as phenylepherine (50-100 mcg). Inotropes such as dopamine and/or epinephrine may also be required if the hypotension persists.

Reperfusion changes can occur several minutes after cross-clamp release as well. A recent review of 30 adults undergoing small bowel transplantation showed that reperfusion was associated with an increase in cardiac filling pressures, an increase in the cardiac output, a decrease in the mean arterial pressure to less than 60 mm Hg in 47% of the patients, and a decrease in the systemic vascular resistance, which persisted 5 minutes after release of the vascular clamps. Approximately one-half of the patients required inotropic support. However, the changes resolved by the end of surgery.160

Immunosuppression

Intestinal transplant has been a challenge for scientists due to its immune and functional complexity. Immunosuppression developed through 3 phases.152,162 Initially, high-dose tacrolimus in combination with steroids was used. In the second phase, induction therapy with cyclophosphamide was followed by multiple maintenance drugs with numerous side effects causing morbidity and mortality. Current immunosuppressive protocols use induction therapy with lymphoid ablating agents such as thymoglobulin or alemtuzumab and maintenance therapy with decreasing doses of tacrolimus. Some centers are attempting a steroid-free maintenance regimen to decrease the side effects of immunosuppressive therapy. Furthermore, immune modulation with single-dose bone marrow cell infusion and ex vivo allograft irradiation has been attempted.152

Postoperative Considerations and Complications

All patients undergoing small bowel transplantation require care in the intensive care unit in the immediate postoperative period. Many patients require postoperative positive pressure ventilation. Intravenous infusions of vasopressors may still be required. Close observation for early complications such as arterial or venous thrombosis, which require immediate action to correct, is needed.159 Following the immediate postoperative period most patients still require a prolonged period of hospitalization. Small bowel function is impaired in the immediate postoperative period from denervation, dysmotility, and interruption of the lymphatics. High ileostomy output is also common in the perioperative period and may result in dehydration.159

Other complications are also serious and may result in mortality and graft loss.163 Rejection is still a common cause of graft loss and mortality, although less so than during earlier time periods. Innate immunity plays a role in the development of graft rejection as suggested by a higher rate of rejection in patients with Crohn disease with nucleotide oligomerization domain 2 polymorphism.164 Graft versus host disease where the lymphoid cells transplanted from the intestinal graft reacts against the host can occur after intestinal transplants in up to 5% of recipients.159 It manifests itself with skin and gastrointestinal changes (rash, blisters, ulceration of oral mucosa, diarrhea), pancytopenia, pneumonitis, altered mental status, and native liver dysfunction. Unfortunately, bacterial, fungal, and viral infections still result in graft loss and/or mortality. The barrier to bacterial translocation is altered following ischemic injury to the bowel. Immunosuppression can further alter the bowel flora as well as the patient's ability to fight infection if bacterial translocation occurs.165 Posttransplant lymphoproliferative disease also may develop in bowel transplant recipients and is more prevalent in children, after splenectomy, and was high prior to the use of tacrolimus. It still occurs, but less often, with tacrolimus as the immunosuppressive agent.159

Anesthetic Considerations for Patients with Prior Intestinal Transplants

A high level of multidisciplinary support is required for prior recipients of intestinal and multivisceral transplants. The nutritional status of the bowel transplant patient needs to be assessed prior to surgery. If the transplant is functioning poorly, the patient may be malnourished. Dehydration from diarrhea may also be a problem. These patients will benefit by consultation from those who specialize in the management of bowel transplantation whenever possible.50

Patients with prior intestinal or multivisceral transplants are also prone to infection for multiple reasons, including the chronic need for immunosuppressive medications to prevent rejection, altered intestinal permeability and absorption, and intestinal denervation and lymphatic dysfunction. Strict aseptic technique is mandatory. Stress-dose steroids may be necessary in the perioperative period if the patient is taking prednisone as part of the immunosuppression regimen.50

If the patient requires abdominal surgery, difficult dissection with the potential for massive bleeding and need for large-volume fluid resuscitation should be anticipated as these patients have usually undergone multiple previous laparotomies and adhesions can be extensive. Early on, patients may still have a long-term venous access device such as a Hickman catheter, which can be utilized. However, if the patient presents years later he or she may no longer have a venous access device. Venous access may be extremely challenging; previous studies should be reviewed and ultrasound guidance or assistance requested by interventional radiology.50

Results and Outcome from Intestinal Transplantation

As noted earlier, the initial results for small-bowel transplantation were disappointing and resulted in few organs being transplanted. The results have improved since the late 1990s. Recently, a patient survival rate of 89% for intestine transplant was reported.166 Eighty percent of the survivors had stopped total parenteral nutrition and resumed normal daily activities. Over 60% of grafts transplanted since 1998 are functioning 5 years or more. The longest survivor was on an oral diet 14 years following an intestinal transplant for volvulus.167

Summary

Intestine transplantation has improved significantly over the past few years. As immunosuppression improves, it is likely that it will be used more often to prevent the complications from long-term hyperalimentation. The medical care of these patients can be challenging for the anesthesia provider. However, it can also be rewarding because many patients can benefit from this procedure who earlier could not be treated.

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