Anesthetic and Perioperative Management of Adult Transplant Recipients in Nontransplant Surgery

Abstract

Each year, >16,000 patients receive whole organ transplants in the United States alone, and this number is expected to increase yearly (1). Because the 1-yr survival rate for most transplant recipients is approaching 80%–90% and continues to improve annually, an increasing number of patients who received a transplant present for either elective or emergency nontransplant surgery (2–4). Therefore, anesthesiologists and surgeons are often required to manage transplant recipients in hospitals that are not otherwise involved in transplantation procedures. The general considerations related to any transplant recipient are the physiological and pharmacological problems of allograft denervation, the side effects of immunosuppression, the risk of infection, and the potential for rejection. Pharmacological Considerations in Transplant Recipients Transplant recipients are always under various regimens of immunosuppression. The immunosuppressive drugs in common use are cyclosporine A, azathioprine, antilymphocyte globuline, monoclonal antibodies, and steroids. Newer drugs, such as tacrolimus (FK506), may replace cyclosporine A, and mycophenolate mofetil may replace azathioprine in some immunosuppression protocols (5). Because cyclosporine or tacrolimus levels must be kept within the indicated therapeutic range, the blood levels of patients receiving these drugs should be monitored daily during the perioperative period. Clinically, significant reductions of cyclosporine or tacrolimus blood levels can be caused by dilution with massive fluid infusion perioperatively (6) and cardiopulmonary bypass (7). Cyclosporine and tacrolimus are metabolized in the liver through the cytochrome P-450 system. Therefore, many drugs administered during anesthesia or perioperatively may affect cyclosporine or tacrolimus blood levels (Table 1). All immunosuppressive drugs now in use have significant side effects that may have a direct impact on anesthetic and perioperative management (8) (Table 2). Drugs that may cause renal dysfunction when administered with cyclosporine or tacrolimus are presented in Table 3 (8). Generalized major motor seizures are a serious complication of cyclosporine or tacrolimus therapy. Because the seizure threshold of patients treated with these drugs may be lowered, hyperventilation during mechanical ventilation should be avoided (9,10). Hyperkalemia and hypomagnesemia may be observed with cyclosporine or tacrolimus therapy (11–13). Table 1: Drugs That Affect Cyclosporine and Tacrolimus Blood LevelsTable 2: Side Effects of Immunosuppressives That Have a Direct Impact on Anesthetic and Perioperative ManagementTable 3: Drugs That May Cause Renal Dysfunction When Administered with Cyclosporine or TacrolimusAzathioprine’s major side effect is bone marrow suppression, and the drug dose may require adjustment for leucopenia or thrombocytopenia. Antithymocyte globuline (ATG) also may be responsible for thrombocytopenia. Drugs that may cause marrow toxicity when given to patients receiving azathioprine include allopurinol, angiotensin-converting enzyme inhibitors, sulfasalazine, and 5-amino salicilate acid (8). Steroids are used for the prevention of rejection and for the treatment of acute rejection episodes. Despite intense effort to eliminate or replace them, steroids are still a mainstay of the posttransplant immunosuppression protocol, and their long-term use may result in steroid-related side effects (8). Interactions Between Immunosuppressive and Anesthetic Drugs Immunosuppressive drugs may modify the pharmacological behavior of many drugs used in anesthesia. There are few data concerning the interactions of cyclosporine or tacrolimus with anesthetics used for either transplant or nontransplant surgery. Data on the effects of general anesthesia on IV cyclosporine or tacrolimus pharmacokinetics in humans are also limited. In patients who received their oral cyclosporine dose <4 h preoperatively, subtherapeutic blood levels have been reported (14). This may be due to a reduction in gastric emptying and absorption from the proximal small bowel, which can occur during isoflurane anesthesia in the rat (15,16). Steady-state blood levels of cyclosporine and cyclosporine clearance in rabbits are not altered by isoflurane/nitrous oxide anesthesia (17). Propofol infusion does not modify the cyclosporine blood levels in humans (18). Cyclosporine tends to enhance pentobarbital anesthesia and fentanyl analgesia in mice, but the mechanism is unclear (19,20). Cyclosporine enhances the effects of muscle relaxants. Prolonged neuromuscular block after vecuronium and pancuronium administration in patients receiving cyclosporine has been described (21–24). Cyclosporine and, to a lesser degree, its solvent, cremophor, enhance the neuromuscular block induced by vecuronium and atracurium (25,26). Therefore, patients receiving cyclosporine as immunosuppressive therapy may require a smaller dose of nondepolarizing muscle relaxant, and the recovery time may be prolonged (27,28). Clinically relevant doses of azathioprine do not antagonize neuromuscular blocking drugs in humans (9,24,29,30). Anesthesia and Perioperative Care Preoperative Assessment of Transplant Recipients The preoperative assessment of transplant recipients undergoing nontransplant surgery should focus on graft function, rejection, presence of infection, and function of other organs, particularly those that may be compromised due to either immunosuppressive therapy or dysfunction of the transplanted organ. Rejection results in a progressive deterioration in organ function tests, is the main cause of late mortality in the transplant recipients (5,31,32), and should be suspected if functional tests of the transplanted organ(s) are abnormal. The presence of rejection should always be ruled out preoperatively. There is some evidence that patients who undergo surgery during a period of rejection have higher morbidity (33). The presence of an infection should also always be ruled out preoperatively. Infection is a significant cause of morbidity and mortality after transplantation (5,8,31,32,34). Immunosuppressed patients are at risk of infections that may be bacterial, viral, fungal, or protozoan (5,31,32,34). Immunosuppression undoubtedly plays a role in the development of infections. However, reducing the dose of immunosuppressive drugs in the perioperative period may increase the risk of rejection. It is imperative to realize that the immunosuppressed patient does not present the typical signs and symptoms of intraabdominal sepsis—fever, leucocytosis, and physical signs of peritonitis are often absent. A very high index of suspicion is required in view of reports citing a 4%–26% incidence of abdominal complications requiring surgery (34,35). Renal function may be compromised because of immunosuppression therapy and should be assessed in all transplant recipients. In therapeutic doses, cyclosporine and tacrolimus, may cause a dose-related decrease in renal blood flow and glomerular filtration rate, due to renal vasoconstriction. Both increase thromboxane A2, and perhaps endothelin production, and are thus responsible for many of the renal hemodynamic effects (36,37). Upper gastrointestinal bleeding may be secondary to peptic ulcer disease, gastritis, or cytomegalovirus gastroenteritis (38). Hepatobiliary and pancreatic diseases are relatively common after transplantation (39–45). General Anesthetic Considerations A variety of anesthetic techniques (general, regional, neuroleptic) have been successfully used in patients with a transplant history. Standard premedication may be used, as in nontransplant patients. The choice of perioperative monitoring techniques is determined by the type of surgery, the anesthesia planned, and the equipment available. Perioperative invasive monitoring requires fully aseptic techniques and should be discussed in terms of the risk-benefit ratio (9,27,33,39). Oral endotracheal intubation is preferred over nasal intubation because of the potential of infection caused by nasal flora (46). The use of a laryngeal mask is acceptable (47). Appropriate perioperative antibiotic prophylaxis should be used, just as in nontransplant patients (39,48). When hepatic and renal function is normal, there is no contraindication to the use of any anesthetic (9,27,33,39). If an epidural or spinal technique is planned, clotting studies and platelet count should be normal. Patients taking azathioprine or antithymocyte globuline (ATG) may have thrombocytopenia, which increases the risks associated with central neural blockade (9,27,39). Azathioprine withdrawal in the perioperative period in patients taking warfarin may precipitate bleeding (49). Although the mechanism of this drug interaction is not established, it is possible that 6-mercaptopurine, the immediate metabolite of azthioprine, induces the hepatic microenzymes that metabolize warfarin. Bupivacaine is a commonly used local anesthetic. Although decreased renal function may result in the risk of increased toxic effects, this does not seem to be an issue in clinical doses (33,50). Epidural administration of bupivacaine is not associated with higher plasma bupivacaine concentrations in kidney transplant recipients compared with nonuremic patients undergoing kidney surgery (51). Some transplant recipients who have undergone repeated surgery do seem to develop tolerance to opioids. Regimens should be titrated according to the clinical effect and the potential of side effects. Although the excretion of morphine is not affected by renal impairment, the metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) can accumulate and may be responsible for prolonged sedation postoperatively (52,53). Nonsteroidal antiinflammatory drugs should be avoided because of the risk of adverse interactions (e.g., gastrointestinal hemorrhage, nephrotoxicity, hepatic dysfunction). They augment nephrotoxicity of cyclosporine, as both drugs affect the renal microcirculation, although the exact mechanism is unclear (54,55). Immunosuppressive therapy should be continued during the perioperative period, and daily monitoring of steady-state cyclosporine or tacrolimus blood levels is recommended. To maintain therapeutic blood levels, it is important to administer oral cyclosporine 4–7 h before surgery (14). The dose of other immunosuppressive drugs should not be altered perioperatively unless the route of administration needs to be changed from oral to IV. The oral dose of prednisone is equal to the IV methylprednisolone dose. Oral and IV doses of azathioprine are approximately equivalent (8,56). Supplemental “stress-coverage” steroids are probably not necessary, except in transplant recipients recently withdrawn from them (39,57,58). Although the effect of transplantation and, in particular, of cyclosporine on intravascular coagulation is controversial (59,60), special consideration should be given to deep venous thrombosis prophylaxis in transplant recipients, particularly if other risk factors are present (39). Severe perioperative airway obstruction may be caused by underlying posttransplant lymphoproliferative disease (61,62). Specific Anesthetic Considerations Kidney Transplant Recipients. The success of renal transplantation, especially in diabetic and elderly patients, is associated with an increase in the incidence and severity of cardiovascular disease in these populations (63,64). Recipients with adequately functioning kidney grafts may have creatinine levels within normal range. However, the glomerular filtration rate and effective renal plasma flow are likely to be significantly lower than those of healthy subjects, and the activity of drugs excreted from the kidney may be prolonged (9,64). Azotemia, proteinuria, and hypertension may indicate chronic rejection of the graft (65). Because variables of renal function are likely to be abnormal in kidney transplant recipients, it seems prudent to choose drugs that do not rely on the kidney for excretion (e.g., atracurium). Nephrotoxic drugs should be avoided. Diuretics should not be given without careful evaluation of the patient’s volume status. Renal hypoperfusion from inadequate intravascular volume should be prevented (9,27,66–68). Because of the high incidence of hypertension in this population, it is common for renal transplant recipients to receive oral antihypertensive therapy (68). Patients with renal graft dysfunction who have been recently hemodialyzed may have hypovolemia and/or hypokalemia. Hypovolemia leads to cardiovascular instability, and hypokalemia causes cardiac arrhythmia and increased susceptibility to muscle relaxants (69). Liver Transplant Recipients. After successful liver transplantation, tests of synthetic liver function are normal (31,66). In the immediate posttransplant period, there is a significant increase in all liver enzyme levels. However, the levels gradually decrease over the first 2 wk postoperatively as allograft function becomes normal. Recovery of drug metabolism capacity occurs immediately after reperfusion of the liver graft. Considerable metabolic capacity has been demonstrated by the liver grafts for morphine and midazolam (52,70). Renal dysfunction is common in liver transplant recipients, and renal excretion is an important pharmacological consideration for these patients (9,31,52). Liver transplantation results in reversal of the hyperdynamic state that characterizes patients with end-stage liver disease, and cardiac performance improves in the months after transplantation. Pulmonary dysfunction in patients with end-stage liver disease may result from (a) intrapulmonary shunting caused by intrapulmonary vascular dilatation; (b) ventilation/perfusion mismatch caused by pleural effusions, ascites, and diaphragm dysfunction and increased closing capacities; (c) diffusion abnormalities caused by interstitial pneumonitis and/or pulmonary hypertension; and (d) impaired hypoxic pulmonary vasoconstriction. Noncardiogenic pulmonary edema may be present in patients with fulminant hepatic failure. Very little is known about the biochemical relationship between hepatic dysfunction and subsequent pulmonary manifestations (71,72). After successful liver transplantation, oxygenation improves in most patients. Hypoxemia caused by ventilation/perfusion mismatch is reversed over the course of the first postoperative months. Patients with preexisting true shunts may require more time to achieve reversal of hypoxemia, or hypoxemia may not resolve at all (71,72). Normal physiological mechanisms that protect liver blood flow are blunted after liver transplantation (9). The liver is normally an important source of blood volume in shock states via a vasoconstrictive response, and this mechanism may be impaired after liver transplantation (73). In liver transplant recipients, there is no evidence of increased risk of developing hepatitis after the administration of inhaled anesthetics (27). Once vascular complications, such as hepatic artery thrombosis, occur, the mortality rate is high in this transplant population (74). Hepatic arterial thrombosis has been retrospectively associated with overtransfusion of blood products leading to hemoconcentration. Therefore, liver transplant recipients should have minimal blood viscosity (hematocrit approximately 28%) during the perioperative period (75). Heart Transplant Recipients. After successful heart transplantation, most recipients return to New York Heart Association (NYHA) class I functional capacity (76–85). The transplanted heart has no sympathetic, parasympathetic, or sensory enervation, and the loss of vagal influence results in a higher than normal resting heart rate (91–101 bpm). Unpredictable reenervation may occur after heart transplantation. There are two P waves on the electrocardiogram (ECG) after heart transplantation. The native pacemaker remains intact in cases in which a cuff of atria is left to permit surgical anastomosis to the grafted heart. Because the native P wave cannot traverse the suture line, it has no influence on the chronotropic activity of the transplanted heart. Intrinsic mechanisms and coronary autoregulation remain intact after heart transplantation. Carotid sinus massage and the Valsalva have no effect on the heart rate effects associated with heart include loss of cardiac and loss of to and intubation The heart may have a more blunted heart rate to inadequate anesthetic or analgesia (27). allograft rejection as coronary artery Therefore, heart transplant recipients may have significant without any clinical symptoms of Although rejection does not cardiac rejection can to significant and dysfunction The clinical of rejection heart on the and Because heart has important for the of many drugs often used in the perioperative period, the anesthetic and therapeutic must these In the the is from that in the normal heart because intact are required for the normal and metabolism of seems to be and the transplanted heart can to drugs (e.g., and have an effect in heart transplant recipients. In both to have a higher to or to by the of and, is a effective in the and effects and have effects in both and normal Therefore, are both effective in the heart. They increase more than drugs, such as have blunted on blood and heart rate in heart transplant recipients. Because drugs, such as are in increasing heart rate, other chronotropic drugs, and should be available. has no effect on heart rate in the heart. The use of most likely the risk to the patient with or without a transplanted heart (9). has no hemodynamic effects on the although it has normal effects (9). Heart transplant recipients may present with rejection with coronary or all of which must be before surgery. All preoperative drug therapy should be continued during the perioperative period. If a pacemaker is in its function should be venous monitoring or the of a pulmonary arterial is not indicated for surgical procedures. However, because heart transplant recipients are and may be to dysfunction and/or invasive hemodynamic monitoring is during surgery that volume There is a role for in or invasive hemodynamic monitoring in heart transplant recipients. General anesthesia is as there is a of impaired to after spinal or epidural anesthesia. A of anesthesia in this is the of significant and acute decrease of the Although inhaled general anesthetics have known are unless there is significant heart and Transplant Recipients. of the seems to have a effect on the of is the of the and patients with a anastomosis the and are more to of and to is normal in these patients If rejection and capacity may decrease and arterial blood may an increased to arterial is to be due to chronic rejection, and it occurs after the can an infection and include hypoxemia, and of or of the graft. Pulmonary function Because transplanted may have rejection that can affect pulmonary function, patients should undergo before surgery It is very to between chronic rejection and If allograft rejection or infection is suspected in these recipients of elective surgery should be and should be (27). Because transplant recipients a the anastomosis are to unless are In of an the potential and the increased risk of infection, it can be that a anesthesia technique be to a technique that requires intubation Because the of the in the transplanted may cause interstitial fluid particularly in the period, it has been that these patients be treated with and infusion In transplant recipients, fluid management can be a because the heart requires to maintain cardiac and the may have a lower threshold for developing pulmonary Therefore, invasive hemodynamic monitoring is more often required in these patients (9). Transplant Recipients. transplantation is effective in normal and transplant recipients do not require to for the to surgery Some patients with pancreatic grafts may from chronic because of the presence of in also significant of and loss in the may cause or metabolic levels are used for monitoring pancreatic graft function Because the long-term effect of transplantation on cardiovascular disease is not it is prudent to manage these patients with the that have coronary artery disease The effect of anesthesia on the to after transplantation has not been and there are no for the perioperative management of in transplant recipients with normal metabolism In patients with pancreatic perioperative management of levels and is the as that for any diabetic patient should be especially in these patients with of pancreatic Transplant Recipients. of transplantation can be on the cause and severity of and the presence of organ transplantation, transplantation of and liver or transplantation and dysfunction of the affect and absorption during the immediate period. If the is by rejection, or the and infections are often observed Because of the chronic use of venous is in transplant recipients. Some of these patients develop and in the period. should be monitored The number of invasive surgical in transplant recipients is can be successfully treated after kidney transplantation by under general anesthesia is as in the transplant population as in the general Despite a higher rate of to an in transplant recipients in the general the of a of oral immunosuppression, and return to preoperative are equivalent Transplant recipients should receive the as any dysfunction secondary to organ must be a few small of transplant recipients have been the of transplant recipients with significant retrospectively over months. The most common causes of and All patients and no transplanted organ or deep venous thrombosis, renal and Despite immunosuppression and preexisting renal in the patients Direct to the transplanted kidney may present immediately with massive or as graft dysfunction It is that immunosuppressed patients are more to the effects of and bone loss associated with or heart transplantation is a serious for most transplant recipients loss due to transplantation enhance the risk of which occur in the first after transplantation in transplantation present a organ transplant recipients are to is possible without allograft survival side effects of immunosuppression therapy include nephrotoxicity and All immunosuppressive drugs the during the first is not associated with an increased risk of during the and these drugs affect the and the result is a compromised and an increased risk of lower and other toxic effects of the and drugs are not to be and their use cannot be during in patients with renal can to a decrease in cyclosporine blood levels In or transplant recipients, the rate of complications, such as and risk of acute allograft rejection is higher than that in the nontransplant population with reports of immunosuppression in with liver transplants who receiving tacrolimus associated with a lower incidence of hypertension and but with a rate of and renal of the Renal dysfunction is the of adverse in liver transplant recipients A few by recipients of or transplants have been In these patients, a of can result in organ and increased risk of adverse of the in these patients on In transplant recipients have and pharmacological a of the of the transplanted the of the immunosuppressive drugs, and the underlying surgical is for these patients to undergo anesthesia and surgery. regional, or general anesthesia can be to transplant recipients, and a successful anesthetic and perioperative management can be of the perioperative problems in the transplant population have not been and there are no for their A for the perioperative problems of transplanted patients requiring other elective or emergency surgery is to management and