Anesthesia for Abdominal Organ Transplantation C. Spencer Yost, Claus U. Niemann Key Points Solid Organ Transplantation 1.

Solid organ transplantation is an accepted treatment of end-stage organ disease. 2. The discrepancy between the number of organ donors and organ recipients is increasing. 3. To increase the donor pool, living organ donors and extended criteria donors are being used. 4. Preoperative evaluation of organ systems should consider interval changes. Kidney Transplantation 1. Patients with end-stage renal disease are subject to accelerated atherosclerosis and should be considered to have a significant perioperative cardiac risk. 2. Maintenance of adequate perfusion pressure to the newly transplanted kidney is crucial for initial graft function. 3. Anesthetic drugs that are dependent on renal excretion, especially muscle relaxants or their metabolites, should be used with caution.

Pancreas Transplantation 1. Patients may undergo pancreas transplantation alone, in combination with kidney transplantation, or after kidney transplantation. 2. Close glucose monitoring is required throughout the procedure. 3. Administration of colloids is preferred intraoperatively. 4. The immunosuppressive drug OKT3 can cause significant hemodynamic instability and noncardiogenic pulmonary edema. Liver Transplantation 1. The model of end-stage liver disease calculates the severity of liver disease. 2. Preparation for massive transfusion and significant hemodynamic instability is essential. 3. Extubation in the operating room can be safely performed in selected patients.

Improvement in the success of solid organ transplantation over the past decades is remarkable and well documented. Refinement of perioperative care and improved post-transplant patient management over recent years have resulted in dramatic improvements in 1-year and 5-year graft survivals. These changes have led to a significant increase in the number of medical centers

performing solid organ transplantation and increased public awareness. In addition, the indications for solid organ transplantation have been broadened. Some perceived contraindications, such as concomitant human immunodeficiency virus (HIV) infection and advanced age, are being overlooked in selected cases. [1] [2] Similarly, patients receiving methadone maintenance therapy are considered for transplantation. [3] [4] As of the end of 2004, 153,245 people were living with a functioning organ transplant in the United States. The number of patients wait-listed for solid organ transplantation is steadily increasing and is currently around 90,000. The organs most frequently transplanted are the kidney and liver, which together accounted for more than 70% of all transplanted organs. Only 54% of all donated organs from deceased donors were actually recovered in 2001. This fact, in conjunction with public perception about organ donation and brain death and limited awareness of health care professionals, has contributed to a severe shortage of cadaver donor organs. Different strategies have been adopted to increase the donor pool, including extension of donor criteria and the use of living related and unrelated donors, particularly for kidney and liver transplantation. These attempts alone are unlikely, however, to ameliorate the donor organ shortage in the long run. To help address the issue of maximizing the number of organs available for transplant, the Health Resources and Services Administration launched the Organ Donation Breakthrough Collaborative in 2005. As outlined in the

mission statement, the collaborative intends to identify and promote the best practices in organ donation for adoption by hospitals and organ procurement organizations, ultimately with the goal to increase transplantable organs from deceased donors. One recognized need is the identification of beneficial interventions in donors after determination of neurologic death. The success of organ transplantation is based on a highly specialized team approach, including the cooperation of procurement organizations, transplant coordinators, and nurses, and physicians from many specialties. Except for kidney transplantation, most solid organ transplantations are performed at tertiary medical centers, which can provide all the needed medical, logistic, and technical expertise necessary to support a successful transplant program. Increasingly, medical subspecialties are providing physicians dedicated to the field of transplantation. In addition to transplant surgeons, most major centers rely on dedicated transplant hepatologists and nephrologists. Anesthesia for kidney and pancreas transplantation is performed by most anesthesiologists, whereas most major centers have a dedicated liver transplant anesthesia team. Smaller centers may not have enough transplant volume or personnel, however, to staff a separate liver transplant anesthesia team. As a result, anesthesiologists who have experience in major hepatic surgery or cardiothoracic surgery are frequently called on to provide anesthesia for these complex and challenging

cases. New guidelines regarding perioperative anesthesia coverage are currently being considered by the American Society of Anesthesiologists and United Network for Organ Sharing (UNOS). This chapter reviews anesthetic considerations for kidney, liver, pancreas, and intestinal transplantation in adult recipients. Solid organ transplantation in pediatric patients is not addressed in this chapter (see Chapter 82 ). Care of Organ Donors after Neurologic Determination of Death Most potential deceased donors are previously healthy or relatively healthy individuals who have experienced brain death and do not have an extracranial malignancy or untreatable infection. Less than 5% of deaths satisfy these criteria, and only 10% to 20% of these eligible subjects actually become organ donors. In addition, a significant proportion of potential organ donors are lost because of medical exclusion (e.g., sepsis, malignancy, incurable infection) or inability to obtain consent for donation. [6] [7] Historically, organs from older donors (>60 years old) have inferior survival rates than grafts from younger donors, but if proper selection criteria are applied, long-term graft survival reaches those of younger donors.[8]

In an attempt to fulfill the need for more organs, organs are being transplanted from extended criteria donors donors who are considered not ideal because of underlying demographics or medical conditions (e.g., age, hypertension) or subsequent prolonged ischemia times. Outcomes data for all solid organs are not consistent with studies performed in kidney transplantation, reporting either similar or inferior post-transplant graft quality. Nonetheless, significant ethical conflicts surrounding the definition of brain death in different social and cultural settings have been an obstacle in transplantation.[9] In the United States and Western Europe, a consensus has been reached among the scientific community with regard to the definition of brain death. There is, and will continue to be, considerable discussion, however, about concepts and definitions of death and the legal definition of death.[10] These issues are colored by the effects of cultural differences; concepts and definitions of death are not equally accepted from one culture to another. Many Western cultures have committed to deceased organ donation, and the emphasis of discussion is quite different from that in Japan or Taiwan, for example. Determination and Declaration of Brain (Neurologic) Death There is uniform agreement on the neurologic examination of adult brain-dead subjects, also called donors after determination of neurologic death, with the exception of the apnea test (see Chapter 98 ).

Standardization of the procedures for diagnosing brain death is quite different among countries, however.[11] Criteria promulgated by the American Academy of Neurology in 1995 are generally applied in North, Central, and South America. [11] [12] These standards grew out of the landmark Harvard Criteria published in 1968.[12] In Europe, criteria for the clinical evaluation of brain death also are fairly uniform, with the principal difference being the number of physicians needed to confirm the diagnosis. Several requirements need to be met to declare brain death. At the time of examination, the patient must be comatose with neither spontaneous movement nor response to painful stimuli. A lack of brainstem activity should be confirmed by assessment of brainstem reflexes ( Table 67-1 ) and the apnea test. Possible causes of reversible cerebral dysfunction should be excluded (e.g., hypothermia, residual drug effects). For the apnea test, the patient breathes 100% oxygen for 10 minutes, during which time the Pco2 is confirmed to be in the normal range (35 to 45 mm Hg). Subsequently, mechanical ventilation is terminated, and blow-by oxygen is administered with a T-piece. After 7 to 10 minutes, an analysis of arterial blood gases is performed. A Pco2 value greater than 60 mm Hg confirms lack of brainstem control of ventilation and represents a positive apnea test. No signs of spontaneous respiratory effort should be observed during this procedure. Confirmatory tests, such as transcranial Doppler, electroencephalography, and auditory evoked potentials, also may be used.

Table 67-1 -- Brainstem Reflexes That Should Be Absent in Brain Death Pupillary response to light Corneal reflex Oculocephalic reflex (doll's eye response) Oculovestibular reflex (caloric response) Gag and cough reflex Facial motor response

Intraoperative Management Organ retrieval is not performed solely at major medical centers. Most organ retrievals are performed at community hospitals without academic affiliation. Any anesthesiologist may be confronted with a brain-dead patient and the attendant pathophysiologic perturbations. The logistics of harvesting organs, the social circumstances (i.e., interaction with relatives of the potential organ donor), and the unusual sequence of intraoperative events may seem intimidating to the anesthesiologist.

Cessation of cerebral function invariably results in a sequence of pathophysiologic changes leading to death of the potential organ donor within a few days, unless appropriate intervention is undertaken. At the same time, it may take several days for identification of a possible organ donor, declaration of brain death, consent, and eventual organ recovery. Perioperative hemodynamic stabilization is crucial for prevention of donor organ damage or loss. After an initial hyperdynamic response consisting of hypertension with or without tachycardia, brain-dead patients brought to the operating room for organ recovery experience hypotension, reduced cardiac output, myocardial dysfunction,[14] and vasodilation (decreased systemic vascular resistance). In addition, diminished oxygenation as a result of neurogenic pulmonary edema and diabetes insipidus secondary to decreased circulating levels of antidiuretic hormone may be observed. The latter also may lead to hypernatremia and hypokalemia. Hyperglycemia, coagulopathy, and hypothermia may be encountered and must be corrected when severe. The aggressiveness of treatment is determined by which organs are being recovered because the quality of resuscitation may have an impact on organ viability. Certain guidelines[15] can be summarized as follows: Systolic blood pressure greater than 100 mm Hg (mean 70 to 110 mm Hg)

Po2 greater than 100 mm Hg Urine output greater than 100 mL/hr (1 to 1.5 mL/kg/hr) Hemoglobin concentration greater than 100 g/L Central venous pressure (CVP) 5 to 10 mm Hg Fio2 less than 40% (if tolerated) for lung retrieval Glucose concentrations less than 200 mg/dL (or even <150 mg/dL)

To achieve these goals, the anesthesiologist should use standard monitors, measure urine output, and use invasive measurements of arterial pressure and CVP (frequently with a pulmonary artery catheter). Hypotension should be treated initially by intravenous administration of fluids. A mixture of crystalloid and colloid solutions, and occasional administration of blood, most rapidly corrects hypovolemia with the goal of increasing urine output. For lung and pancreas transplant retrieval, colloids are preferred over crystalloids. Frequent communication with the surgical team regarding intravascular volume replacement is essential. Excessive fluid administration may result in swelling and even loss of the organ. To decontaminate the intestines for retrieval of the pancreas, a mixture of povidone-iodine (Betadine), amphotericin, and normal saline is administered through an orogastric/nasogastric tube. If pharmacologic support of the circulation is necessary, the

inotrope of choice is usually dopamine; however, other cardiovascular drugs, such as norepinephrine, epinephrine, vasopressin, and dobutamine, may be added to maintain hemodynamic stability during the later stages of organ dissection and harvest. Surgical techniques may vary depending on whether the procedure is for recovery of a single organ or multiple organs.[13] Generally, wide exposure of the surgical field is established, cannulas are placed for in situ perfusion, and the organs to be removed are isolated with preservation of their central vascular structures. Heparin is administered (approximately 20,000 to 30,000 IU) when requested by the recovery team. If recovery of the heart or lung is anticipated, pulmonary artery catheters or central venous catheters need to be withdrawn before cross-clamping. If lung recovery is anticipated, the lungs are ventilated well beyond cross-clamping and initiation of organ recovery other than the lung. Removal of the organs is performed under cold protection by applying ice to the surgical field. Organs are removed according to their susceptibility to ischemia, with the heart first and the kidney last in a multiorgan donor. Excellent communication between the often different surgical teams (e.g., abdominal organ team versus thoracic organ team) and the anesthesiologist is crucial to ensure optimal organ quality.[13] In the United States, several donor management initiatives critically review current standard-of-care practices and develop new and uniform management algorithms. In several Western European countries, uniform treatment algorithms are already successfully used.

Vasodilators such as phentolamine or alprostadil (lung recovery) may be administered during cross-clamping with the goal of decreasing systemic vascular resistance and allowing even distribution of the preservation solution. Long-acting nondepolarizing muscle relaxants should be used for optimal intra-abdominal and intrathoracic exposure. Clinically significant bradycardia in brain-dead patients does not respond to atropine, so a direct-acting chronotrope such as isoproterenol must be readily available. Patients declared brain-dead do not have pain perception, so analgesia is not required. Volatile anesthetics or narcotics may facilitate hemodynamic stability, however. The changes in heart rate and arterial blood pressure that may occur with surgical stimulation are the result of intact spinal reflexes. Although these hemodynamic changes can often be easily controlled with vasoactive agents alone, the anesthesiologist probably would be most comfortable responding to these changes by increasing the amount of volatile anesthetics. Finally, the anesthesiologist may be asked to draw blood for several pretransplant tests. The volume may vary in different organ procurement organizations, but is generally 60 to 200 mL in adults. Donation after Cardiac Death A more recent development to increase the organ supply is the use of donation after cardiac death, formerly known as nonheart-beating organ donors. Originally introduced

in the 1960s, it was subsequently abandoned and has been reintroduced only more recently. Medical centers reexplored this source of potential donors for abdominal organs (mainly kidneys).[16] In the United States, the use of organs from donations after cardiac death has steadily increased over the past decade, and these donors now represent about 7% of kidney transplants.[17] In 1993, the number of nonheart-beating organ donors in the United States was 42; it increased to 167 by 2001 and increased further to 561 by 2005.[18] Policies were developed by organ procurement officials and hospitals to allow organ donation as an option to be considered for relatives of patients who potentially qualify as donors after cardiac death. In contrast to deceased donors, whose heart function, circulation, and tissue oxygenation are preserved until the organs are retrieved, organs from donors after cardiac death can be removed only after cardiac arrest. The difference invariably introduces a longer warm ischemia time that can potentially result in suboptimal donor organs. Donation after cardiac death can be categorized as controlled or uncontrolled, and these categories determine the extent of warm ischemia experienced by the organ donors. Controlled donations after cardiac death are from patients for whom the transplant team is awaiting the cardiac arrest, and all necessary preparations for rapid organ recovery are in place. In contrast, uncontrolled donations after cardiac death are from patients who have experienced unanticipated cardiac arrest; resuscitation has been unsuccessful, and consideration is being given to possible organ donation.

In addition to a prolonged warm ischemia time, legal, ethical, and logistic concerns prevent many centers from adopting this form of organ donation.[19] More recent studies from Switzerland and the United States have shown favorable long-term results, however, with regard to graft function in recipients of organs donated after cardiac death. [20] [21] [22] It remains to be seen whether this form of organ procurement from donation after cardiac death will achieve wider acceptance in the transplant community and provide a means to augment the donor organ pool significantly. Organ Preservation Solid organ harvesting and transplantation invariably cause injury to the donor organ. Three main distinct periods have been identified that contribute to injury: (1) storage of recovered organs ex vivo during transport (generally under hypothermic conditions) from the donor to the recipient, (2) the implantation phase (rewarming phase) without reperfusion, and (3) the initial reperfusion phase with the reintroduction of oxygen. Each period contributes to deterioration of the organ through a different pathway. Ex vivo storage involves immediate cooling and flushing of the organ after recovery with several available preservation solutions. Currently, most organs are stored at 4C without continuous perfusion after initial flushing. At some centers and organ procurement organizations, organs are continuously perfused, in some cases with normothermic preservation.

Various cold storage solutions used worldwide include Collins, Euro-Collins (Fresenius, Germany), Bretschneider/Histidin-Tryptophan-Ketogluterat (HTK) (Franz Koehler Chemie, Germany), Celsior (Sangstat Medical Corporation, United States), Perfadex (Vitrolife, Sweden), and University of Wisconsin (UW) (Du Pont, United States). [23] [24] Although the UW solution is probably the most frequently used solution, especially for intra-abdominal organs, the significantly cheaper HTK solution has been increasingly used with good results.[25] Most solutions are modified with additives (e.g., oxygen radical scavengers) that are believed to improve organ storage conditions. The content of the various organ preservation solutions varies widely, as does the amount used. UW solution contains 120 mmol/L of potassium versus only 10 mmol/L in the HTK solution. These differences may have clinical implications, such as a greater potential for hyperkalemia after reperfusion of organs (mainly liver) preserved in UW solution. Hyperkalemia is seen mainly, however, in cases in which the preservation solution is not adequately flushed with colloids before implantation. Organ-specific flush solution is commonly used with Euro-Collins solution, and more recently, Perfadex solution especially for lung storage. The heart is frequently stored in Celsior preservation solution, but medical centers occasionally may have center-specific cardioplegia solutions. Sometimes perfluorocarbons are used as a component of the twolayer method for preservation of the pancreas.[26] Organ preservation solutions are under constant review and undergo frequent modifications.

The maximum cold preservation time varies among organs and solutions used. Typically, kidneys can be stored in cold preservation solution for up to 24 to 30 hours before transplantation, although the ischemia time does have an impact on outcome. In contrast, hearts must be transplanted within hours of retrieval. Continuous machine perfusion (as opposed to cold storage) of the organ has attracted some attention.[27] This method is not widely adopted currently, however, and large randomized trials are necessary to show its feasibility.[28] Care of Living Organ Donors The first living donor transplantation was performed in 1954, when a kidney was transplanted from one man to his twin brother.[29] The lack of effective immunosuppressive treatment at that time prohibited the use of deceased organs. With the introduction of immunosuppressive drugs, improved long-term graft survival was achieved, and the use of deceased donors rapidly accelerated in most Western countries. In Japan, transplantation from deceased donors has not been well accepted, mainly because of cultural and ethical norms. In 1997, legislation was passed in Japan that allowed organ donation from selected brain-dead donors.[30] Organ transplantation from living donors has become an important, well-developed alternative for patients with end-stage organ disease in Japan and other Asian countries.[31] The benefits to donor and recipient must outweigh the risk associated with the recovering of a living donor organ.[32]

Living donors generally are very healthy and almost exclusively classified as American Society of Anesthesiologists grade I or II patients. In the past, donors were usually relatives of the prospective recipient. More recently, candidates unrelated to the recipient are increasingly being accepted as donors. By the time that they are determined to be eligible for donation, donors have undergone an extensive medical, psychological, and social evaluation. [33] [34] Many living donor and recipient pairs are turned down during the screening process for medical and nonmedical reasons (e.g., social or psychological concerns) that may affect the donor or recipient. A major concern surrounding living organ donation is the potential for great harm to be inflicted on entirely healthy individuals who undergo major surgery for purely altruistic reasons. The ethical and psychological aspects (e.g., coercion of the donor) of living organ donation, particularly liver donation, continue to be widely examined and discussed. [32] [35] [36] [37] [38] [39] In addition, the quality of life after organ donation and the financial impact on the donor are of great concern. [40] [41] Organ donation from living donors has significant advantages over deceased organ donation. In contrast to deceased donors, living donors are always hemodynamically stable, and the procedure can be planned on an elective basis. In addition, the cold ischemia time of the organ can be minimized compared with that associated with deceased donors. Perhaps the most important advantage of living donor transplantation

is the significant reduction in time spent on the waiting list to receive an organ from a deceased donor. Living Kidney Donor Renal transplantation with organs from living donors has rapidly been increasing in recent years. In the past, donor nephrectomy was done by the traditional approach through a subcostal lateral incision, by minimal incision nephrectomy, or by the laparoscopic approach. Laparoscopic live donor nephrectomy now has almost completely replaced the traditional open approach via subcostal lateral flank incision. Melcher and colleagues[42] reported 500 consecutive laparoscopic donor nephrectomies without the need to open or reoperate for technical difficulties. The laparoscopic approach has been shown to be advantageous with regard to decreased postoperative pain, time of hospitalization, recovery, and improved cosmetic results. [43] [44] Morbidity after living kidney donation is low, and the type of complication (e.g., reoperation, ileus, readmission to the hospital) depends on the surgical technique. Matas and coworkers[45] reported two donor deaths and one donor who has remained in a persistent vegetative state in a series of 10,828 living kidney donations between 1999 and 2001. Shokeir[46] performed a meta-analysis of 69 studies comparing open versus laparoscopic donor nephrectomy and discovered eight perioperative deaths after laparoscopic nephrectomy. More recent studies

confirmed that laparoscopic donation results in a safer procedure, a more rapid convalescence, and a lower opioid consumption compared with open donation. Placement of an epidural catheter is not indicated. [46] [47] [48] Nevertheless, Ellison and colleagues[49] caution that the long-term risks may not yet be apparent, and that long-term follow-up data are needed. Either kidney can be used for donation; however, the left kidney is usually preferred because of easier surgical exposure and a longer vascular supply. The patient is placed in either a right or a left lateral position with the table flexed and the kidney rest elevated. Invasive monitoring is not required, and one or two large peripheral intravenous lines suffice. Some centers have 2 U of blood (frequently autologous) available in the operating room in case of injury to major vascular structures, which would require emergency exploratory laparotomy. To maintain good diuresis and to optimize graft function, fluid administration is generous (10 to 20 mL/kg/hr), even though blood loss is minimal in most cases. The preferred type of fluid in this setting is unknown because no human trial has yet addressed this issue. In the absence of scientific data, most centers use isotonic crystalloids. The anesthetic technique in these healthy patients is not different from that used for other laparoscopic procedures. Nitrous oxide is contraindicated because it causes bowel distention and worsens surgical exposure.[50] Similarly, the potential complications seen during any laparoscopic procedure (e.g., pneumothorax, subcutaneous emphysema) can be encountered during this procedure.

The first phase of the procedure consists of mobilization of the colon followed by the upper portion of the kidney, with subsequent identification and dissection of the ureter, renal vein, and artery. Division of the adrenal vein also is performed.[51] The surgeon may request administration of furosemide or mannitol (or both) during the operation to maintain adequate urine output. Shortly before the renal vessels are clamped, intravenous heparin (3000 to 5000 IU) is administered. Protocols may vary among institutions, and close communication with the transplant surgeon is essential. After complete mobilization of the kidney and clamping of the vascular structures, the kidney is retrieved by either a handassisted or nonhand-assisted[52] technique through a small periumbilical or infraumbilical incision under direct laparoscopic vision. If heparin has been given, protamine may be administered to normalize coagulation. After the kidney is removed, the surgical field is inspected again for bleeding. Closure, as in all laparoscopic cases, is rapid, and care should be taken to maintain reversibility of neuromuscular blocking agents at the conclusion of the procedure. Postoperative pain is usually mild to moderate and can be managed easily in most cases with supplemental intravenous opioids in the immediate postoperative period. Living Liver Donor Living donor liver transplantation began in the early 1990s and quickly became a widely accepted technique in children. [37] [53] The regenerative capability of the liver has long been recognized and exploited, and

complete recovery of liver function in the donor and the recipient can be expected after donation of a portion of the liver. The primary presurgical consideration is determination of the mass of transplanted liver that is needed to support a given patient and to leave enough liver mass with the donor. Several formulas, including the graft-recipient body weight ratio and graft weight as percentage of standard liver mass, are used to ensure adequate liver mass in the donor and recipient. [33] [54] Pediatric living donor liver transplantations generally require resection of only the left lateral segment (segments II and III) or a total left hepatic lobectomy (segments II, III, and IV) to provide sufficient liver mass. These types of grafts are expected to grow along with the patients as they mature. From a surgical point of view, a left hepatectomy is less complex, and the duration of surgery is shorter. [55] [56] This technique has been extended to adult patients as well. The number of living donor liver transplantations performed annually in the United States grew slowly through most of the 1990s (representing about 1% of liver transplants), but increased dramatically beginning in 1998 (from 56 in 1996 to 515 in 2001). The number has now plateaued between 200 and 300. This rapid increase is primarily due to increased numbers of right hepatic lobectomy for adult-to-adult living donor liver transplantation. The surgical technique for right hepatectomy involves separation of the right hepatic lobes (segments V, VI, VII, and VIII) from the left ( Fig. 671 ). This technique results in a graft weighing 500 to 1000

g, which leaves the donor with about one third of the original liver mass. In select cases, the left lobe of a large donor may suffice for a small recipient, either with or without a portal shunt.

Figure 67-1 A, Segmental liver anatomy. Each segment is supplied by a portal pedicle consisting of the hepatic artery, portal vein branch, and bile duct. B, Segments V to VIII are frequently used for adult-to-adult living donor transplantation. (Redrawn from Renz JF, Yersiz H, Farmer DG, et al: Changing faces of liver transplantation: Partialliver grafts for adults. J Hepatobil Pancreat Surg 10:31-44, 2003.)

Volumetric studies have shown that the donor's liver regains its original size in a short time, often within weeks to months. [57] [58] Functional recovery may take much longer, however. [59] [60]

Most living donor liver transplantations are done in patients with chronic liver failure and are done on an elective basis. Although it is controversial, living donor transplantation may be performed in rare cases in patients with very advanced disease or decompensated end-stage liver disease. [61] [62] In contrast, in children with subacute or acute liver failure, living donation, mostly from parents, is commonly accepted. The ethical issues, such as coercion of the donor, involved in these cases are even more pronounced. [63] [64] In addition, relative inexperience with the procedure may lead to an unacceptably high complication rate. Worldwide, several donor deaths related to the surgical procedure have occurred. The overall complication rate is variable[35] and ranges from 0% to 67%, with a crude morbidity rate of 31%. This large variation can be attributed to differing definitions of morbidity and study design.[66] Editorials have raised significant concern about donor safety, the lack of adequate outcome data, and the need for regulation and oversight. [39] [67] [68] The intraoperative care of patients undergoing right hepatectomy for liver donation is similar to care of other patients having hepatic surgery. Preoperative placement of a thoracic epidural catheter is done in some transplant centers; however, other centers use only patientcontrolled analgesia for postoperative pain control. The choice of postoperative pain control seems to depend partly on the postoperative monitoring capabilities and the familiarity of the nursing staff on the floor with each technique. Avoidance of epidural catheter placement based on concerns of postoperative coagulopathy from extensive hepatectomy does not seem to be justified. The

prothrombin time usually peaks on postoperative day 2 to 3 and returns to baseline by day 5. Several studies have failed to show any adverse effect of epidural catheters in this patient population. [60] [69] The largest study was reported from Japan and involved 755 donors who received an epidural catheter for postoperative pain management.[70] No complications associated with the epidural catheter were reported. A study from South Korea including 242 living liver donors also showed that epidural analgesia seems to be a safe option when used carefully.[71] Because of the very low incidence of epidural hematomas overall, however, these studies lack the power to assess the risk of epidural hematoma developing in this patient population. General anesthesia is standard and may consist of a balanced technique or be combined with intraoperative supplementation of epidural analgesia. Intraoperatively, the patient is placed in a supine position, frequently with one arm tucked (right or left) at the side and the other abducted. An orogastric/nasogastric tube is placed for decompression of the stomach and improved surgical exposure, particularly when a left hepatectomy is performed. Two large-bore intravenous catheters and invasive arterial blood pressure monitoring are used in most centers. [60] [70] Continuous monitoring of CVP has been advocated by some authors to ensure a low CVP because an elevated CVP is considered to be a prime determinant of bleeding from liver parenchyma during transection.[72] Fluid is administered sparingly until the donor liver lobes are removed. In a retrospective study, CVP monitoring did not seem to reduce blood loss compared with patients

without CVP monitoring. In centers with extensive experience, CVP monitoring may be unnecessary.[73] As an alternative to conventional CVP measurements, Choi and colleagues[74] suggested peripheral venous pressure measurements in the arm. An autotransfusion system is used at most centers, and patients frequently donate 1 to 2 U of whole blood preoperatively. At centers where this procedure is done on a routine basis, blood loss is generally less than 1 L. [60] [75] Because of the nature of the procedure, however, preparation and vigilance for sudden extensive blood loss are always warranted. Frequently and especially for right lobe donation, an Lshaped (hockey stick) or standard bilateral subcostal incision with a midline extension is used. The procedure can be divided into three stages: (1) mobilization of the liver and identification of vascular structures, (2) transection of the liver, and (3) hemostasis and closure. During the first stage of the operation, manipulation of the liver occasionally can result in decreased venous return to the heart with consequent brief episodes of hypotension. It is important to be aware of this possibility before initiating any therapy. The parenchymal division is completed with several different devices, such as the CUSA ultrasonic surgical aspirator (Valley Lab, Boulder, CO) or the Harmonic Scalpel (Ethicon Endo-Surgery, Somerville, NJ). [59] [60] After the vasculature of the donor lobe is clamped and divided, the graft is removed, and the vasculature and bile duct are oversewn. Subsequently, hemostasis is achieved, and the abdomen is closed.

In uncomplicated cases, the patient can be extubated in the operating room and transferred to the postoperative care unit. Admission to the intensive care unit (ICU) is generally unnecessary. Nevertheless, standard practice in some institutions has been to manage living liver donors in the ICU in the early postoperative period. Contraindications to Solid Organ Transplantation For all transplant candidates, the number of absolute and relative contraindications has diminished in recent years. Overall, candidates for kidney transplantation are increasingly older and have more complex medical problems. Active infection is an absolute contraindication until it has been treated, and the infection has resolved. Evidence of malignancy is not a contraindication per se. Hepatocellular carcinoma with underlying cirrhosis is considered an indication for liver transplantation as long as the tumor burden does not exceed established guidelines, such as the Milan[76] or the University of California San Francisco criteria.[77] Similarly, select patients are reconsidered for renal transplantation after successful treatment of malignancy and no evidence of recurrence. Relative contraindications, such as noncompliance or a history of drug abuse, exist, but vary among centers. Contraindications to specific transplant procedures are outlined as necessary in each section. Kidney Transplantation

The first description of anesthesia for kidney transplantation appeared in the early 1960s. It detailed the pioneering efforts in Boston with living donor kidney transplantation between identical twins.[78] The only monitors used then were a blood pressure cuff and electrocardiogram (ECG), and the recipient received spinal anesthesia. Much has changed in the anesthetic management of these cases. What was previously seen as heroic and exceptional is now commonplace. These patients are challenging to anesthetize because endstage renal disease (ESRD) often causes dysfunction of other organ systems, which may produce less predictable responses to anesthetic drugs and techniques. In addition, these patients are at high risk for cardiac and other perioperative complications because of their underlying disease. Kidney transplantation is indicated for patients with ESRD caused by glomerular disease, diabetes mellitus, hypertensive kidney disease, polycystic kidney disease, other familial or congenital diseases, and tubulointerstitial disease. Kidney transplantations are the most commonly performed transplantations in each of three major regions of the worldthe United States, Europe, and Asia.[79] This number represents a steady increase throughout the 1990s. Considerable variation in the proportion of organs that come from deceased versus living donors occurs worldwide, with some countries relying almost entirely on deceased donors (e.g., China) and some relying largely on living donors (e.g., Japan, Taiwan). In the United States, transplantation of kidneys from deceased donors were 8849, down from 10,659 in

2006, whereas the number of living donors also decreased from 6432 in 2006 to 5094 in 2007. In early 2008, approximately 78,700 patients were awaiting kidney transplantation in the United States, with an average waiting time of longer than 3 years.[5] This fact implies that recipients as a group are older and sicker than previously. Nonetheless, kidney transplantation is one of the most important, costeffective methods of treating ESRD; it confers a 40% to 60% decrease in the death rate compared with patients remaining on dialysis. The overall graft survival rate among cadaver kidney transplant recipients at 3 years is greater than 88%, and it is approximately 93% in recipients who receive a kidney from a living donor.[80] Organ Matching and Allocation Initial testing is done to determine major blood group (ABO) compatibility. A second test determines the HLA profile of the recipient. Finally, a crossmatch is done by mixing recipient blood with donor blood cells to determine the presence of preformed reactive antibodies against donor antigens.[81] Pathophysiology of End-Stage Renal Disease The kidneys are essential for adjusting body fluid volumes, electrolyte composition, acid-base balance, and

hemoglobin concentration. The kidneys receive about 25% of cardiac output and function as filters for toxins and drugs in the circulation. When kidney function declines, these functions are impaired. Chronic renal failure results in a steady decline in glomerular filtration and urine production, which has deleterious effects on multiple organ systems throughout the body. Patients with glomerular filtration rates less than 30 mL/min/1.72 m2 (normal 120 mL/min) show an increase in blood nitrogenous wastes, mainly urea, and begin to retain fluid and electrolytes. When urine production declines to less than 400 mL/day, the patient becomes oliguric and is unable to excrete dietary fluid and electrolyte loads. Abnormalities in Na+, K+, Ca++, Mg++, and phosphate levels can develop, with the most life-threatening being hyperkalemia. Cardiovascular disease is the predominant cause of death in patients with ESRD, and even after renal transplantation it is a major cause of death.[82] Acute myocardial infarction, cardiac arrest of unknown etiology, cardiac arrhythmia, and cardiomyopathy account for greater than 50% of deaths in patients maintained on dialysis.[83] The death rate from cardiac causes in dialysis patients increases with age; it is approximately twofold higher for patients 45 to 64 years old and four times higher in patients older than 65 compared with patients 20 to 44 years old. When echocardiography is done as a screening tool, a high incidence of abnormalities is found. Furtermore, left ventricular or right ventricular hypertrophy or pericarditis was detected in 60% of autopsies performed on dialysis patients.[84]

Dilated cardiomyopathy and concentric hypertrophy can develop in response to increases in intravascular volume and afterload. Fluid overload and congestive heart failure occur when the kidneys cannot excrete the daily fluid intake, and hypervolemia ensues. The accumulation of uremic toxins and metabolic acids contributes to poor myocardial performance. Cho and coworkers[85] documented that some patients with a low ejection fraction secondary to uremic cardiomyopathy completely normalized their cardiac function after successful renal transplantation. ESRD with significantly depressed ventricular function is not a contraindication to renal transplantation, but it may complicate the anesthetic management. Hypertension produced by renal disease is the result of (1) deranged renal handling of Na+ and fluids leading to volume expansion and (2) alterations in levels of vasoactive substances resulting in systemic and local changes in arterial tone. Hyperreninemia may lead to increased systemic vascular resistance and elevated systemic blood pressure, but it is not always present. If untreated, the elevated systemic pressure within the kidney causes damaging sclerotic changes in the renal vasculature. A vicious cycle ensues in which hypertension damages the kidney and creates the conditions for escalating hypertension. Hypertension also can be a manifestation of fluid overload when oliguria has developed, causing increased myocardial afterload and wall stress, which, in conjunction with uremia, produce changes in the heart consistent with cardiomyopathy. Chronically elevated systemic pressure lead to left

ventricular hypertrophy and increased myocardial oxygen requirements. Renal failure also accelerates the progression of atherosclerosis, especially in the coronary circulation. Uremia causes changes in lipid metabolism, leading to increased concentrations of serum triglycerides and reduced levels of protective high-density lipoproteins. Other cardiac conditions, such as pericardial disease and arrhythmia, may be encountered in patients with ESRD. Pericarditis, which may coexist with hemorrhagic pericardial effusion, is reversible with dialysis. Generally, patients who are adequately dialyzed have resolution of their pericardial effusion. The occurrence of arrhythmias may be the consequence of electrolyte abnormalities, or may represent episodes of myocardial ischemia. Diabetes mellitus is the cause of ESRD in nearly 30% to 40% of cases, and these patients represent more than 30% of individuals on the waiting list for a kidney transplant. Nephropathy develops in nearly 60% of insulin-dependent diabetics. Patients with ESRD and diabetes mellitus have higher cardiovascular risk than patients with uremia alone because of the associated acceleration of small-vessel atherosclerosis. Chronic uremia also causes delayed gastric emptying. The mechanism for this is unknown, but gastric dysrhythmia with discoordinated myoelectric activity has

been found in uremic patients on maintenance hemodialysis.[86] There seems to be no difference in delayed gastric emptying whether patients are undergoing peritoneal dialysis or hemodialysis. All patients presenting for kidney transplantation should be considered to have full stomachs, regardless of the period of preoperative fasting. Rapid-sequence induction should be considered, especially in patients with diabetes. This recommendation is underscored by the finding that gastric volumes greater than 0.4 mL/kg were found in 50% of diabetic uremic patients, but in only 4 of 24 nondiabetic uremic patients. Patients in renal failure generally have normochromic, normocytic anemia because of decreased erythropoiesis and retained toxins secondary to kidney failure. Treatment with recombinant erythropoietin frequently can increase hemoglobin levels to 10 to 14 g/dL, which reduces symptoms of fatigue and improves cerebral and cardiac function. [87] [88] [89] In some patients, preexisting hypertension can worsen with erythropoietin therapy.[87] An association between renal failure and bleeding tendency has long been recognized. A qualitative defect in platelet function produced by uremia itself seems to be central. The defect results from accumulation of the compound guanidinosuccinic acid in uremic blood, which inhibits adenosine diphosphateinduced platelet aggregation.

Although a qualitative platelet defect can be identified in uremic patients, more recent studies have pointed out that a prothrombotic state also may coexist with uremia. A thromboelastographic study of whole-blood clotting found increased coagulability and decreased fibrinolysis in uremic patients versus controls.[90] Platelet-derived microparticles (small vesicles with procoagulant activity that are released from activated platelets) may be involved in clinical thrombogenesis.[91] Uremia may cause central nervous system disturbances ranging from drowsiness, memory loss, and decreased concentration to myoclonus, seizure, stupor, and coma. Signs of peripheral or autonomic neuropathy are considered strong indications for dialysis. Surgical Procedure Donor kidneys, whether from a living or a deceased source, are usually implanted in the iliac fossa. Either side of the abdomen can be used. An incision approximately 8 to 10 inches (20 to 25 cm) provides sufficient exposure. Usually, the incision extends from the midline of the pubic symphysis to a point 2 to 3 cm superomedial to the anterior superior iliac spine. Anatomic variations are common and often require repair or reconstruction of vessels or the ureter. Two or more renal arteries can supply the donor kidney, with both originating from the aorta. Although vascular anastomoses can be done with different recipient vessels, the external iliac artery and vein are frequently used for

the vascular anastomoses ( Fig. 67-2 ). Distal and proximal clamps are placed on the external iliac artery and vein, and the donor renal artery (occasionally two) and vein are connected by end-to-side anastomosis. The period of warm ischemia generally lasts 15 to 30 minutes.

Figure 67-2 A, Renal artery anastomosis performed end-to-side to the external iliac artery. B, Renal vein anastomosis performed end-to-side to the external vein. C, Ureteral anastomosis to the bladder mucosa. (From Hardy JD: Hardy's Textbook of Surgery, 2nd ed. Philadelphia, JB Lippincott, 1988.)

After completion of the anastomoses, the clamps are released in staged fashion. The bladder is subsequently filled through a Foley catheter to facilitate implantation of the ureter directly into the bladder. The wound is closed in layers with special attention paid to urine output to identify vascular or ureteral compromise during closure.

Preoperative Considerations Fifty percent of patients with ESRD have one or more of the comorbid conditions described previously. The presence of these comorbidities greatly influences the approach to anesthesia chosen for these patients. Although transplants involving deceased donor organs are often scheduled as urgent or emergency cases, prolonged cold preservation of the kidney is well tolerated and should provide enough time to allow transplant candidates to be reasonably well prepared for surgery. If possible, recipients should be dialyzed to correct electrolyte imbalances and volume status before surgery. Patients not maintained on dialysis generally produce sufficient urine volume to prevent fluid overload. Electrolyte concentrations, particularly K+ and HCO3-, still may be grossly abnormal, however, and suggest a worsened homeostatic condition. One method to estimate volume status is to compare patients weight with their dry weight, which hemodialysis patients usually know. Occasionally, continuous ambulatory peritoneal dialysis is used as an alternative to hemodialysis. Patients undergoing hemodialysis may have fluid removed just before surgery to facilitate perioperative fluid management. Such removal of fluid may render patients hypovolemic and put them at risk for significant hypotension on induction of anesthesia. Potassium levels should be reviewed immediately before surgery, especially in patients who may have missed a regular dialysis appointment. Although unlikely after immediate preoperative

completion of dialysis, potassium levels greater than 6 mEq/L may require a delay in surgery and correction of potassium levels. Preoperative evaluation of cardiac function is of central importance and is dictated by the underlying renal disease, its duration, and attendant comorbidities. A preoperative ECG and stress test may be sufficient for a patient who is young with newly diagnosed ESRD unrelated to diabetes, whereas a stress echocardiogram or a cardiac catheter may be indicated for symptomatic patients or patients with long-standing ESRD associated with diabetes. Many older and diabetic patients are unable to undergo exercise ECG testing and may have silent cardiac ischemia.[92] There is not absolute consensus at this point on the optimal cardiac workup for ESRD patients coming for kidney transplant. Several noninvasive screening tests have been studied to determine their ability to identify coronary artery disease (CAD) in this patient population. In a prospective study, Herzog and coworkers[93] performed dobutamine stress echocardiography before quantitative coronary angiography in a mixed population of ESRD patients who were candidates for transplantation. More than 50% of patients had some degree of CAD (coronary stenosis >50%). Dobutamine stress echocardiography displayed a sensitivity of only 52% to 75% and a specificity of 74% to 76%, however, in identifying patients with CAD. These patients were monitored for 2 years. During this time, 20% of patients with negative dobutamine stress echocardiography experienced cardiac death or

myocardial infarction or underwent coronary revascularization. Herzog and coworkers[93] concluded that dobutamine stress echocardiography was a useful, but imperfect tool for identifying patients needing further workup. Dobutamine stress echocardiography detects functionally significant stenosis; however, most sudden cardiac deaths occur in functionally insignificant lesions (e.g., acute thrombosis in patients with coronary stenosis of 20% to 30%). Other noninvasive tests also have been found to have limited usefulness in identifying ESRD patients with CAD. In one study, dipyridamole thallium scintigraphy showed adequate sensitivity (80%), but poor specificity (37%). Other studies suggest that determination of cardiac risk should begin with the analysis of easily obtainable clinical variables, rather than widely pursuing expensive tests with limited sensitivity and specificity.[94] A history of chest pain is a helpful starting point in detecting CAD in these patients because it has a sensitivity and specificity of 65% for CAD.[92] A more comprehensive system, such as the revised cardiac risk index, was originally derived from retrospective data and shown in a prospective population to be a good predictor of the cardiac risk for patients without renal failure undergoing noncardiac surgery. It focuses on the presence or absence of six variables: high-risk surgical procedure, history of ischemic heart disease (excluding previous coronary revascularization), history of heart failure, history of stroke or transient ischemic attacks, preoperative insulin therapy, and preoperative creatinine levels greater than 2 mg/dL (>152.5 mol/L).

These risk factors appear with high frequency in patients presenting for kidney transplantation. With zero or one risk factor, the rate of a major perioperative cardiac event is quite low; however, the rate increases rapidly to 6.6% and 11% when two and three or more of these risk factors are present. In addition, it is now widely understood that patients awaiting kidney transplantation require repeated cardiovascular surveillance. In the case of an initial negative cardiovascular evaluation, patients are risk-stratified (e.g., diabetic ESRD, nondiabetic risk factors) and assessed annually, biannually, or less frequently. Patients with a positive initial cardiovascular workup (with or without a previous medical intervention) are mostly evaluated annually.[65] Patients can be initially stratified into basic risk groups (low, medium, or high) based on history, symptoms, and basic examination (see Chapter 34 ). Low-risk patients may proceed to transplantation without additional workup, and high-risk patients should probably undergo invasive studies (e.g., cardiac catheterization). For intermediate-risk patients, it may be useful to perform a screening stress test, such as dobutamine stress echocardiography or radionuclide scintigraphy. The use of perioperative -blockade is suggested as a means of decreasing perioperative risk in these high-risk patients undergoing kidney transplantation. Several studies throughout the late 1990s established that perioperative -blockade provides significant risk protection from major cardiac events in high-risk, nontransplant patients, although the POISE trial has

questioned this contention. No prospective, randomized trials have been conducted with perioperative -blockade in kidney transplant patients. It is unknown at present whether such treatment can be applied safely to these patients, especially patients with diabetes mellitus (see Chapter 35 ). Diabetic patients have a higher incidence of autonomic neuropathy, which can be manifested as a higher heart rate and blood pressure than in nondiabetic ESRD patients.[95] Type 2 diabetics often have a combination of visceral obesity, atherogenic dyslipidemia (low levels of high-density lipoprotein and elevated levels of triglycerides), hypertension, and insulin resistance. This combination leads to a heightened risk of CAD and cardiovascular disease. It should be determined when antiglycemic agents were last taken. Oral agents should not be taken the day of surgery because of the potential for unrecognized hypoglycemia under anesthesia. Insulin-dependent patients who are extremely brittle and have declining insulin levels are at risk for the development of ketosis and intraoperative acidemia. Coagulation status, as reflected by prothrombin time, international normalized ratio, partial thromboplastin time, fibrinogen, and platelet count, is routinely assessed before surgery. Although ESRD patients may be consuming protein-restricted diets, it is rare for such diets to cause a significant clotting factor deficiency. A helpful

preoperative screen to predict bleeding is a carefully conducted history that includes family, dental, obstetric, surgical, transfusion, and drug histories; the bleeding time is not a useful screening test to predict intraoperative bleeding.[96] Intraoperative Management Although spinal anesthesia was used exclusively for the first reported anesthetics,[78] and other centers have more recently reported successful use of regional anesthesia for these cases,[97] most centers now use general endotracheal anesthesia to provide stable hemodynamics, excellent muscle relaxation, and predictable depth of anesthesia. A balanced technique combining volatile anesthetics with opioids has been compared with total intravenous anesthesia using opioids and propofol, with no differences found.[98] Standard American Society of Anesthesiologists monitors may be all that are needed for these cases. Patients with more advanced stages of comorbid conditions may require more extensive monitoring, such as continuous arterial pressure or CVP monitoring, or both. Major swings in blood pressure may occur, with hypotension (49.6%) being more likely than hypertension (26.8%) in one large series. Patients with the most severe comorbid conditions, such as symptomatic CAD or a history of congestive heart failure, should be monitored for the development of ischemia or severe hemodynamic impairment intraoperatively with a pulmonary artery catheter or transesophageal echocardiography (TEE). The status of hemodialysis shunts or fistulas should be

monitored during positioning and intraoperatively to confirm the presence of a thrill and to document patency. With CVP monitoring, the goal is to keep CVP 10 to 15 mm Hg to optimize cardiac output and renal blood flow. Immediate graft function has been associated with a blood volume greater than 70 mL/kg and a plasma volume greater than 45 mL/kg.[99] Another study showed that pulmonary arterial pressure correlated with graft function. Higher filling pressure (pulmonary arterial pressure >20 mm Hg/diastolic pulmonary arterial pressure >15 mm Hg) resulted in better graft function than lower filling pressure. Recently, there has been some discussion of whether a particular crystalloid is better than others in terms of postoperative renal function. A national survey of fluid choice at 49 hospitals in the United States found that greater than 90% of patients receive normal saline or normal salinebased solutions during their transplant.[100] However, a single prospective randomized, double-blind study comparing normal saline with lactated Ringer solution for intraoperative intravenous fluid therapy for kidney transplantation showed significantly higher rates of severe hyperkalemia and metabolic acidosis in the normal saline group.[101] Although the recipient's blood should be typed and screened, transfusion is unlikely to be necessary because blood loss is usually minimal. Patients with uremia and other comorbid conditions (e.g., diabetes) should be considered at risk for aspiration during induction of anesthesia. Pretreatment with a clear, nonparticulate antacid, such as 30 mL of sodium citrate,

increases gastric pH. To prevent reflux and aspiration, rapid-sequence induction while maintaining cricoid pressure should be considered. Several studies have shown that the induction dose of propofol needed to achieve clinical hypnosis and reduction of the bispectral index to 50 was 40% to 60% higher than needed for normal patients. [102] [103] In the study of Goyal and colleagues,[103] 0.2 mg/kg of propofol was titrated every 15 seconds to predefined end points. The authors found a negative correlation between the propofol dose and preoperative hemoglobin levels. The exact mechanism is not understood, and administering an increased bolus induction dose based on these findings is strongly discouraged. Patients with preexisting hypertension are at risk for large fluctuations in arterial blood pressure and heart rate during induction of anesthesia and endotracheal intubation. Because these patients have a high prevalence of CAD and myocardial ischemia, goals at induction should include careful control of the heart rate and blood pressure to minimize the possibility of myocardial ischemia. Several methods have been used to achieve adequate heart rate and blood pressure control during induction. Moderate to large doses of opioids such as fentanyl can blunt the response to laryngoscopy; however, blood pressure frequently may be more difficult to maintain without the use of vasoconstrictors after induction. In recent years, the short-acting opioid remifentanil, metabolism of which occurs in plasma, has been an effective drug for good heart rate control. The

rate of remifentanil administration can be titrated to allow for rapid adjustment of anesthetic depth. The shortacting -adrenergic blocker esmolol (0.5 to 1 mg/kg) is used to blunt the hemodynamic response to intubation and is ideally suited in this patient population with adequate ventricular function. The use of succinylcholine is not absolutely contraindicated in patients with ESRD (see Chapter 29 ). [104] Plasma cholinesterase activity is less than normal in more than 20% of ESRD patients regardless of whether they were receiving any form of dialysis. Whether receiving peritoneal dialysis, hemodialysis, or no dialysis, the patients did not experience prolonged paralysis after an intubating dose of succinylcholine, unless they also had an atypical form of serum cholinesterase. The increase in serum potassium after an intubating dose of succinylcholine is the same, approximately 0.6 mEq/L, for patients with and without ESRD. This increase can be tolerated without significant cardiac risk even with an initial serum K+ concentration greater than 5 mEq/L. Long-acting muscle relaxants (e.g., pancuronium) depend on the kidney for elimination and have a prolonged duration of action in patients with ESRD. Atracurium and cisatracurium are metabolized by spontaneous Hofmann degradation and plasma cholinesterase, which makes their duration of action independent of either liver or kidney function. Patients with ESRD have an increased sensitivity to vecuronium with a prolonged duration of action.[105] Rocuronium at a bolus dose of 0.6 mg/kg also has a prolonged duration of action (25% T1 recovery:

49 minutes versus 32 minutes with normal renal function).[106] Inhaled anesthetic include desflurane, isoflurane, and sevoflurane. The metabolism of sevoflurane has been implicated in renal toxicity, but no controlled studies are available to indicate clearly either safety concerns or danger when using sevoflurane in the setting of a newly transplanted kidney. There are two concerns with regard to toxicity: (1) production of fluoride ion from the metabolism of sevoflurane and (2) generation of compound A by the breakdown of sevoflurane by sodium or barium hydroxide lime. However, sevoflurane seems to have a very good safety record. It has been administered to tens of millions of patients worldwide with no conclusive evidence of renal toxicity. Two volunteer studies have found biochemical evidence of renal injury during sevoflurane anesthesia, whereas five other volunteer studies have not. [107] [108] [109] [110] Kidney transplantation represents a situation of increased renal risk, however, as defined more recently by Artru. [111] Two studies have shown that sevoflurane, at fresh gas flow rates greater than 4 L/min, did not change renal function indices or biochemical markers in patients with mildly impaired renal function (baseline creatinine >1.5 mg/dL).[112] In addition, no significant effect on renal function parameters such as serum creatinine or creatine clearance were found in patients with baseline renal insufficiency (creatinine >1.5 mg/dL) after exposure to low-flow sevoflurane or low-flow isoflurane.[113]

With regard to perioperative pain control, drugs such as morphine, meperidine (Demerol), or oxycodone should be used with caution in patients with renal failure because these agents or their active metabolites depend on renal excretion and may accumulate. [114] [115] [116] Fentanyl, sufentanil, alfentanil, and remifentanil are safe alternatives. The pharmacokinetic parameters of sufentanil are very similar in patients with ESRD and healthy control patients. [114] [117] The duration of action of remifentanil is short, even in patients with ESRD.[118] The principal metabolite of remifentanil, GR90291, is eliminated primarily by the kidneys. The fact that it is only as potent as the parent compound makes remifentanil safe to use in these patients.[119] Hypotension may occur after unclamping the iliac vessels and reperfusion of the graft. Because renal graft function depends on adequate perfusion, every effort should be made to avoid episodes of marked hypotension. It is generally thought that vasoconstrictors with strong aadrenergic effects, such as phenylephrine, should be drugs of last resort. Several animal models have shown that vessels in the transplanted organ seem to be more sensitive to sympathomimetics, which are thus more likely to compromise renal blood flow to the transplanted kidney. [120] [121] Immediate urine production is seen in more than 90% of living donor kidney transplants and 40% to 70% of deceased transplants. During the latter stages of closure of the surgical wound, a decrease in urine output strongly suggests mechanical impingement of the graft, vessel, or

ureter. The Foley catheter should be irrigated to ensure that clot or tissue has not affected its patency. If intraoperative ultrasound is immediately available, it can be used to examine flow in the arterial and venous anastomoses. In addition to maintaining adequate intraoperative perfusion pressure, urine production is frequently enhanced intraoperatively by mannitol, loop diuretics, and occasionally dopamine, albeit the evidence is controversial. Mannitol is freely filtered and not reabsorbed by the nephron, which causes osmotic expansion of urine volume. It also may have a protective effect on the cells lining the renal tubule. Mannitol is usually administered to donors before recovery and to recipients just before unclamping the arterial blood flow. In this way, mannitol may protect from ischemic injury and induce osmotic diuresis in the newly transplanted kidney. In most centers, low doses of mannitol are administered, 0.25 to 0.5 mg/kg, and reports of large changes in electrolyte concentrations are unwarranted. Delayed graft function of deceased kidneys can be prevented by the intraoperative administration of mannitol.[122] Loop diuretics work by blocking the action of Na+/K+ pumps present in the thin ascending limb of Henle, preventing reabsorption of electrolytes in this segment of the nephron. The high-osmolar fluid that is carried along to the distal tubule prevents the reabsorption of water, and causes the excretion of large volumes of urine with high electrolyte content. Although the main effect of loop

diuretics is increased urine output, the ability to prevent oliguria (<400 mL/day) can be a significant achievement. Renal-dose or low-dose dopamine (2 to 3 g/kg/min) is commonly used to stimulate DA1 dopaminergic receptors in the kidney vasculature to induce vasodilation and increased urine output. Some small trials have shown improved urine output and creatinine clearance[123] with low-dose dopamine during kidney transplantation, whereas other larger studies have shown no significant improvement. [124] [125] The utility of this approach has been questioned because a newly transplanted, denervated kidney may not respond to low-dose dopamine the way normal kidneys do. Doppler ultrasound examination of newly transplanted kidneys found no significant change in blood flow at dopamine infusion rates of 1 to 5 g/kg/min.[126] Another dopamine agonist, fenoldopam, maintains renal blood flow during cardiopulmonary bypass and during surgery involving aortic cross-clamping and in critically ill patients. The effects of fenoldopam on the function of newly transplanted kidneys have not been systematically studied. Postoperative Care All renal transplant patients should have muscle relaxants fully reversed, be extubated if possible, and be taken to the postoperative recovery area. Renal transplant

patients generally have a low incidence of postoperative ICU admissionaround 1% in one large series. If ICU admission is required, it is usually for sepsis or fluid overload.[127] Urine output is closely monitored, and any significant decline should raise suspicion of a possibly correctable mechanical problem with the newly transplanted kidney. Re-exploration of the wound should not be delayed if kinking of the vascular attachments or obstruction of the ureter along its course or at the site of bladder reimplantation is suspected. Postoperative pain is usually mild to moderate after kidney transplantation. One study showed that the choice of intraoperative anesthetic influenced postoperative pain controlpatients who received propofol as a component of anesthesia had better recovery of psychomotor function and used patient-controlled analgesia more effectively than patients receiving halothane or isoflurane.[128] Placement of intercostal nerve blocks did not change the use of patient-controlled analgesia or pain scores after surgery.[129] Anesthesia for Patients after Kidney Transplantation Patients with good graft function as determined by laboratory values (e.g., blood urea nitrogen, creatinine) and with sufficient urine volume should be considered to have adequate renal function. The average glomerular

filtration rate 6 months after deceased renal transplantation is almost 50 mL/min.[130] About 50% of patients show a slow decline in glomerular filtration rate over the course of years, but 30% have a stable glomerular filtration rate. Given the improvement in patient survival after renal transplantation, it is likely that the rapid progression of cardiovascular disease is slowed, but not halted. These patients are still at higher cardiac risk than individuals who did not have ESRD; this is mainly due to persistent risk factors, such as hypertension, diabetes, dyslipidemia, and secondary hyperparathyroidism. Considerable progression of coronary artery calcification was found in renal transplant patients at least 1 year after surgery. Findings were related to ethnicity of patients, blood pressure, body mass index, renal function, and baseline coronary artery calcification.[131] Patients who do require cardiac surgery after successful kidney transplantation showed no difference in the 30-day complication rate, however, compared with a nontransplant control population, except for a significantly increased likelihood of postoperative renal dysfunction and need for hemodialysis.[132] Aside from cardiac risk, graft rejection, viral infection, anemia, [83] [133] and treatment with immunosuppressive drugs such as cyclosporine may cause significant cardiovascular morbidity (e.g., hypertension), but newer immunosuppressants seem to be better tolerated.[134] Congestive heart failure (e.g., cardiomyopathy), left ventricular hypertrophy, and ischemic heart disease remain important complications in renal transplant recipients.[83]

Pancreas and Kidney-Pancreas Transplantation Pancreas transplantation is a primary cure for diabetes mellitus because it provides nearly physiologic insulin replacement. Nephropathy develops in about 50% to 60% of insulin-dependent diabetic patients, so it is common also to transplant a kidney at the time of pancreas transplantation. The appearance of new immunosuppressants, such as tacrolimus and mycophenolate mofetil, has dramatically increased pancreas graft survival.[135] The best results in terms of graft survival are obtained with simultaneous pancreaskidney transplantation (SPK), but good results also are achieved with a pancreas transplant alone (PTA) or a pancreas transplant after successful kidney transplantation (PAK). Diabetic patients who undergo SPK have greater long-term survival than diabetics who receive a deceased kidney alone.[136] In 2005, 540 pancreas transplants and more than 900 SPKs were performed in the United States. More than 23,000 pancreas transplants have been performed worldwide according to the International Pancreas Transplant Registry through 2004. The 3-year graft survival rate is around 65%. In early 2008, approximately 1600 patients were waiting for a pancreas transplantation and 2350 patients were waiting for a kidney and pancreas transplantation.

Organ Matching and Allocation Solid organ pancreas transplantation is indicated for the treatment and cure of patients with type 1 diabetes mellitus and select patients with type 2 diabetes mellitus (<5%). Pancreas transplantation also can be considered in patients with diabetes mellitus secondary to chronic pancreatitis or cystic fibrosis. The initial testing determines the major blood group (ABO) compatibility and HLA profile of the recipient. These data are used for the initial matching of donor to recipient. A final check is made at crossmatch when recipient blood is mixed with donor blood cells to determine whether the recipient has preformed reactive antibodies against donor antigens. Pathophysiology of Pancreatic Insufficiency The primary defect in diabetes mellitus is a relative deficiency of insulin for regulation of blood and tissue glucose levels. Two forms of the disease are recognized. Type 1 diabetes mellitus is characterized by a significant deficiency in insulin production by the islet cells of the pancreas, possibly from autoimmune destruction. In type 2 diabetes mellitus, insulin levels may be normal, but patients have a relative resistance to the action of the hormone. Patients with type 1 diabetes mellitus are more likely to require daily administration of exogenous insulin, to be prone to ketosis, and to have wide fluctuations in

blood glucose levels. The symptoms can be completely relieved by successful pancreas transplantation, but it is still uncertain whether the progression of comorbidities in all organ systems is abated. Diabetes mellitus severely affects the cardiovascular system by accelerating atherosclerotic vascular disease. Accelerated atherosclerosis and autonomic nervous system dysfunction are the major cardiovascular changes present in diabetic patients. If ESRD also is present, the cardiovascular risk increases dramatically. Diabetic patients with severe CAD may not recognize anginal symptoms due to impairment of the autonomic nervous system. Autonomic dysfunction also can limit control of the cardiovascular reflexes and result in increased lability of blood pressure and heart rate. One index of autonomic dysfunction that has been studied is a decrease in heart rate variability, which reflects a defect in the autonomic nervous system. These defects may give rise to dysrhythmias and put patients at increased risk for sudden death during pancreas transplantation.[137] Patients with ESRD superimposed on diabetes mellitus are subject to the same hemodynamic, fluid, volume, and electrolyte problems as patients with ESRD alone. They probably are maintained on some form of dialysis to manage fluid overload and accumulation of electrolytes. They may also have significant systemic hypertension for the reasons discussed in the section on kidney transplant. Finally, they may have the same problems of chronic anemia and uremic coagulopathy as patients with renal failure alone.

After successful SPK, pathologic cardiac changes, such as diastolic dysfunction and left ventricular hypertrophy, can improve or stabilize.[138] It has not been proved whether other manifestations of diabetes mellitus, such as accelerated atherosclerosis, neuropathy, or vascular insufficiency, improve or stabilize. Surgical Procedure The usual exposure for pancreatic transplantation requires a generous midline incision extending from the epigastrium to the symphysis pubis ( Fig. 67-3 ). The pancreas is placed in the abdomen with an arterial blood supply from the aorta via a vessel graft. Several options are available for venous drainage and implantation of the exocrine duct. Venous outflow from the pancreas, which is the source of insulin, may go into the inferior vena cava directly into the systemic circulation, or it may be directed in a more physiologically correct manner into the portal vein draining the splanchnic circulation. The exocrine pancreatic flow may be connected to the small bowel or, less often, through a cuff of donor intestine into the bladder. The latter method allows for monitoring of urine amylase as a marker of rejection or injury to the transplanted pancreas. Enteric drainage is preferred for SPK because it is more physiologic and avoids bladder complications. Bladder drainage may be a better option for PTA and PAK, however, because of the greater likelihood of rejection with these types of transplantation. Surveillance of urine amylase allows for early detection of rejection.

Figure 67-3 Transplantation of the pancreas with drainage of the bladder through a pancreaticoduodenocystostomy. A renal transplant also is shown with the common iliac vessels used for vascular anastomoses. (Modified from Moody FG [ed]: Surgical Treatment of Digestive Disease, 2nd ed. St Louis, MosbyYear Book, 1990.)

Preoperative Considerations Diabetic patients have a more frequent incidence of autonomic neuropathy, which can be manifested as a higher heart rate and higher blood pressure than in nondiabetic ESRD patients (see Chapter 35 ).[95] Patients with type 2 diabetes often have metabolic syndrome, a combination of visceral obesity, atherogenic dyslipidemia (low levels of high-density lipoprotein and elevated levels of triglycerides), hypertension, and insulin resistance. This combination leads to a heightened risk for CAD and cardiovascular disease. Orally administered drugs should

not be taken the day of surgery to avoid the potential for unrecognized hypoglycemia under anesthesia. Insulindependent patients who are extremely brittle and have declining insulin levels are at risk for ketosis and intraoperative acidemia. Historically, the principal candidates for pancreas transplantation have been younger than individuals receiving kidney transplants, with most being in the age range of 18 to 35 years. Younger patients tended to have fewer of the long-term manifestations of diabetes mellitus, such as atherosclerotic vascular disease and severe autonomic dysfunction. More recently, increasing numbers of older diabetic patients are being considered for pancreas transplantation. These patients are at higher risk for a major cardiovascular event perioperatively. An extensive cardiac workup is indicated before surgery to rule out severe CAD. Preoperative evaluation by history and physical examination, ECG, treadmill testing, echocardiography with or without dobutamine stress, radionuclide scintigraphy, and cardiac angiography represents the full spectrum of workup that may be applicable. It was suggested in the early 1990s that tracheal intubation should be considered more difficult in diabetic patients as a group because of changes in their upper airway tissues from exposure to high serum glucose levels. One study found a 31% incidence of difficult intubation conditions in this patient population. Subsequently, a large study by the Mayo Clinic reviewed the anesthetic records of 150 patients with diabetes who

underwent general anesthesia and tracheal intubation, and found only a slightly increased incidence of more difficulty visualizing airway structures.[139] Halpern and associates[140] reported only one difficult intubation in a series of 130 patients presenting for pancreas transplantation. It seems that long-standing diabetes mellitus alone does not predispose to airway difficulties, but may be considered a contributing factor in a patient with other potentially problematic airway features. Intraoperative Management Because pancreas transplantation procedures can be long and surgically tedious, and involve extensive abdominal exposure, general endotracheal anesthesia with muscle relaxation is the best choice. Patients may have significant postoperative pain from the extensive abdominal dissection, so placement of an epidural catheter for postoperative pain control may be warranted. Splanchnic perfusion to the transplanted organs is a major concern, however, and some centers opt to defer placement of an epidural catheter. Because the pancreas seems to be a highly immunogenic organ, intensive immunosuppression is needed to prevent graft loss. The anesthesia team administers the initial dose of immunosuppressant, so it is essential that the desired drugs be present and administered correctly in the operating room.

Standard monitors (e.g., five-lead ECG, noninvasive blood pressure measurement, pulse oximetry, end-tidal gas concentrations) plus arterial and central venous lines are usually required. The arterial line enables careful tracking of blood pressure and the ability to draw samples for blood gas, glucose, and electrolyte determinations. Insertion of a central venous catheter permits monitoring of cardiac filling pressure and central administration of drugs. Diabetic patients, by virtue of their high incidence of autonomic dysfunction, are likely to have gastroparesis and large residual gastric volumes. This risk is even greater if the patient has ESRD and uremia. Administration of a nonparticulate antacid along with maintenance of cricoid pressure during rapid-sequence induction should be considered. Patients with autonomic neuropathy apparently are not at greater risk for severe cardiovascular depression during induction of anesthesia. A study of uremic patients undergoing kidney transplantation found, that diabetic patients with known preexisting autonomic neuropathy had hemodynamic responses to induction that were similar to the responses of nondiabetic uremic patients. [141] Hemodynamic stability for long periods is probably best achieved by using a balanced anesthetic technique. As with kidney transplantation alone, adequate arterial blood pressure is desired to provide good perfusion pressure for a newly anastomosed pancreas.

One of the most challenging aspects of these cases is determining the amount and type of fluids to administer. If fluid is given, it is probably best from a surgical standpoint to use colloid-based fluid, rather than a large volume of crystalloid solutions alone. Although no controlled studies have been conducted, swelling of the pancreas graft seems to be less with colloids than with crystalloids. Abdominal muscle relaxation is essential for these procedures. The same issues outlined previously for patients undergoing kidney transplantation apply to the choice of muscle relaxant to be used in patients undergoing SPK. Because of the duration of these cases, a continuous infusion of cisatracurium allows for titration of the level of block with reliable reversibility. Alternatively, the intermittent administration of vecuronium, if titrated by train-of-four monitoring,[105] can produce excellent relaxation conditions. For patients who are undergoing PTA or PAK and have adequate renal function, the use of any intermediate-acting nondepolarizing muscle relaxant should not cause problems. Control of blood glucose intraoperatively is important to prevent the development of ketoacidosis in patients with unopposed counter-regulatory hormone secretion and to allow assessment of the function of the transplanted pancreas. Before unclamping the pancreas, glucose should be checked hourly. Hyperglycemia may cause depressed immune function and decreased wound healing and put patients at an increased risk for

worsened neurologic injury if brain ischemia occurs.[142] After the pancreas is unclamped, glucose should be monitored every 30 minutes. Typically, glucose concentrations decrease approximately 50 mg/dL/hr after unclamping the pancreas. A randomized trial of insulin administration to patients with insulin-dependent type 2 diabetes compared a continuous glucose-insulin infusion with intermittent intravenous insulin injection in major and minor surgery. Very little difference was found in the ability to control intraoperative and postoperative glucose levels and metabolism.[143] The manner of reducing glucose does not seem to be as important as the glucose level itself. Postoperative Care Successful transplantation usually results in rapidly declining insulin requirements. Blood glucose levels should be monitored closely in the recovery room or ICU to avoid hypoglycemia (see Chapter 92 ). If simultaneous kidney transplantation is performed, close monitoring of urine output to detect reversible graft impingement is necessary. Anesthesia for Patients after Pancreas Transplantation Surgical complications after these complex operations are frequent and often require one or more re-explorations

during the perioperative period. If pancreas graft function is good, blood glucose levels are corrected within days of transplantation. During the perioperative period, the same cardiac concerns that were present before transplantation apply. Liver Transplantation In 2007, the number of liver transplantations performed in the United States decreased slightly to 6494 from 6650 in 2006. In 2007, 1559 liver transplantations were reported by Eurotransplant, which covers seven central European states. * As of early 2008, approximately 17,200 patients were on the waiting list for liver transplantation in the United States; approximately 1600 to 1800 patients die each year while awaiting liver transplantation. Nationwide, the 3-year patient survival rate after transplantation is greater than 75%.[144] This rate underscores the fact that liver transplantation should not be considered experimental and is the treatment of choice for eligible patients with end-stage liver disease.

The growing discrepancy between organ supply and recipients on the waiting list has made finding alternatives to deceased liver transplantation of paramount importance. This discrepancy may become greater in view of the fact that cirrhosis is likely to develop in 25% to 30% of the more than 4 million Americans with hepatitis C. [145] [146] Recurrent

disease, especially with hepatitis C, necessitates retransplantation in future years, which aggravates the acute organ shortage problem further.[147] Based on UNOS data, there has been no improvement in long-term liver transplant graft survival in the last decade. This finding could be explained by an increase in patients with hepatitis C virus and an increase in patients with hepatitis C virus antibody.[148] The challenge of meeting organ shortages may be overcome if donor liver allocation is optimized, and the donor pool can be increased with new approaches, such as the use of living liver donors or extended criteria donors. Combined liver-kidney transplantation is done infrequently and constitutes only a very small fraction of abdominal transplant volume. Renal disease in the setting of cirrhosis can be due to primary renal disease, hepatorenal syndrome, and acute tubular necrosis.[149] Considerable controversy exists with regard to patient selection for this procedure because of the organ shortage and the possibility of inferior patient and graft survival compared with single-organ transplantation. It is advocated that patients be highly selected, and that hemodynamically stable patients with primary disease in both organs be preferred.[149] * Austria, Belgium, Croatia, Germany, Luxembourg, the Netherlands, Slovenia. Organ Matching and Allocation

The ABO blood group system is the primary immunologic barrier to transplantation,[150] and this classification system is the most important for liver transplantation. The four ABO groups are not proportionally distributed among cadaver donors and possible recipient candidates. The matching strategy between donor and possible recipient is crucial in liver allocation. Donor and recipient ABO blood type matching can be classified as follows: identical (e.g., A to A), compatible (e.g., O to A), and incompatible (e.g., A to O).[151] Identical matching generally is preferred because patient and graft survival is superior with compatible organs. In select cases, such as acute hepatic failure or acute deterioration of chronic liver disease, incompatible organs are transplanted. Graft survival is poorer in patients receiving incompatible organs compared with patients receiving identical matching. Acceptable patient survival may be achieved by retransplantation, however. The organ allocation policy varies among countries. In the United States, deceased donor livers are allocated to patients who are registered with a national registry. In contrast, several European countries allocate donor livers primarily to transplant centers. These centers subsequently identify a suitable recipient candidate. Regardless of the respective organ allocation policy, recipient candidates have to be well screened regarding their eligibility for liver transplantation. The number of diseases amenable to treatment with liver transplantation has steadily increased in recent years.

Although there is regional variation, the most important cause of end-stage liver disease is chronic hepatitis C, which is responsible for almost 40% of all liver transplantations, especially in the United States. Causes of chronic disease in adults can be classified as follows: (1) noncholestatic (e.g., alcohol, hepatitis A, hepatitis B, hepatitis C), (2) cholestatic (e.g., primary biliary cirrhosis, primary sclerosing cholangitis), (3) metabolic disease (e.g., Wilson's disease), and (4) selected cases of hepatocellular carcinoma often associated with hepatitis B or C. Fulminant hepatic failure can be drug induced (e.g., acetaminophen overdose, idiosyncratic), caused by the ingestion of poisonous mushrooms or herbs, and secondary to acute viral hepatitis. [152] [153] Reasons to deny transplantation may vary among centers. Liver transplantation is an extremely stressful procedure for patients. Significant CAD, cardiac dysfunction, and moderate to severe pulmonary hypertension are considered contraindications to liver transplantation. Uncontrolled infection or sepsis also excludes a patient from transplantation. A positive HIV test, without evidence of acquired immunodeficiency syndrome, is no longer a contraindication. Recent case series have reported good results in HIV-infected patients undergoing liver or kidney transplantation.[1] Advanced malignant hepatic disease or metastatic disease generally is considered to be a contraindication, as is uncontrolled and markedly documented elevated intracerebral pressure in the setting of fulminant hepatic failure. Psychosocial factors, such as active alcohol abuse or the lack of a good social support system, may prevent a patient from being a candidate for transplantation.

Advanced age per se is not a reason to deny liver transplantation. Patients older than 65 years are increasingly undergoing transplantation. In the past, the Child-Turcotte-Pugh (CTP) classification had been used widely as an index of disease severity for patients with end-stage liver disease. This classification, in conjunction with UNOS status, was the determining factor for organ allocation in the United States until early 2002. Because of shortcomings of CTP scores and subsequent limitations in organ allocation, the model for end-stage liver disease (MELD) has been introduced for adults in the United States. [154] [155] This model resulted from a growing realization that the previous UNOS scoring system, which was based on the CTP score of liver disease severity plus the amount of time on a waiting list, did not always ensure that organs were allocated to the sickest patients with the greatest risk of mortality. The MELD risk score is a mathematical formula based on the following factors: 1. Creatinine (for adult patients undergoing dialysis twice a week within the last week, the creatinine value would be automatically set to 4 mg/dL) 2. 3. Bilirubin (mg/dL) International normalized ratio

MELD calculates a single numerical value from a formula that gives each value particular weighting. Most patients on the liver transplant waiting list have a MELD score between 11 and 20.[144] The MELD system was originally devised as a means for predicting the risk of death in patients with liver failure after transjugular intrahepatic portosystemic shunting (TIPS).[156] TIPS patients with scores greater than 18 had a median survival of 3 months or less after a TIPS procedure. MELD scoring proved superior to the CTP score in predicting survival.[156] Several adjustments in the new system have been introduced to make it as equitable as possible. Hepatocellular carcinoma confined to the liver can progress to inoperable lesions before manifesting changes in MELD criteria. UNOS has adopted the rule that patients with hepatocellular carcinoma be assigned a MELD score equivalent to the risk of death based on rapid disease progression. [157] [158] Some studies have suggested that sodium should be added to MELD to improve accuracy of survival prediction. Finally, a peer review mechanism has been instituted, and the current classification is under constant review and adjustment. Nevertheless, reports indicate that use of the MELD criteria has been shown to be better associated with 1year patient survival in liver transplant recipients than the former UNOS status.[159] Pathophysiology of End-Stage Liver Disease

Although the reasons for end-stage liver disease may vary significantly, similar organ pathophysiology tends to develop in patients with advanced liver disease. Virtually all organ systems can be affected by end-stage liver disease. Consequently, a global assessment that includes consideration of all organ systems is of great importance. A significant number of the complications in patients with end-stage liver disease are the result of portal hypertension, which can be defined as portal venous pressure greater than 10 to 12 mm Hg.[160] The pathogenesis of portal hypertension is increased hepatic resistance to flow as a result of cirrhotic changes in the liver and a hyperdynamic circulatory state secondary to systemic vasodilation and presumably volume expansion. [161] There is some controversy whether patients with endstage liver disease have an excessively large or depleted intravascular volume. In advanced disease, abnormalities in fluid, such as altered extracellular fluid regulation and electrolyte balance, are frequently manifested as ascites, pleural effusion, and edema.[162] Subsequent changes in the splanchnic and renal circulation may lead to sodium and water retention. Abnormalities in sodium electrolyte levels are frequently observed and are often related to volume status and sodium retention; these abnormalities can result in either hyponatremia or hypernatremia.[163] Similarly, renal dysfunction and diuretic use can cause either hyperkalemia or hypokalemia along with hypomagnesemia.

Central nervous system changes in chronic liver disease are often manifested as hepatic encephalopathy, but the degree of encephalopathy may vary significantly among patients. [164] [165] Ammonia levels are frequently monitored, but do not seem to correlate well with the degree of hepatic encephalopathy. Increased intracranial pressure (ICP) may develop in patients with acute hepatic failure, primarily because of cerebral edema. Accurate assessment of the severity of ICP and remaining neurologic function is of paramount importance because intractable elevated ICP is a significant reason to exclude a patient from transplantation. There is considerable controversy, however, whether the potential benefits of invasive monitoring for elevated ICP (e.g., bolt placements) outweigh the potential risk of devastating bleeding during placement.[166] The U.S. Acute Liver Failure Study Group recommends (beyond generally accepted supportive measures for elevated ICP) a stepwise approach to management of elevated ICP. When ICP is greater than 25 mm Hg, osmotic therapy should be started, and sodium should be kept within normal limits. Hypertonic saline may be considered as an alternative to mannitol. Additional treatment that may be considered is moderate hypothermia, broad-spectrum antibiotics, and barbiturate coma. Supporting scientific evidence for these interventions is insufficient, however.[167] In addition to the standard treatment of elevated ICP, early studies have shown that the molecular adsorbents recirculating system (MARS) may be able to decrease ICP and improve cerebral perfusion pressure.[168] Designed as a liver support device for patients in fulminant hepatic failure or the acute decompensation of chronic failure,

[169] MARS has been able to improve systemic vascular resistance and mean arterial blood pressure.[170] Presumably, these improvements in organ function may account for a reduction in mortality. [171] [172] A clear survival benefit for patients treated with MARS has not been shown, however. MARS is based on dialysis across an albumin-impregnated membrane that removes plasma albumin-bound toxins. The dialysate is subsequently cleaned by activated charcoal and anion exchange resin. [173] The cardiovascular system undergoes profound changes in patients with advanced liver disease that result in a hyperdynamic state. Generally, systemic vascular resistance is low, the heart rate is elevated, and arterial blood pressure is normal or slightly decreased.[174] These hemodynamic changes result in supranormal cardiac output in patients with end-stage liver disease, unless the patient is taking a -blocker for the prevention of upper gastrointestinal bleeding. Occasionally, relatively depressed cardiac function can be associated with cirrhotic cardiomyopathy, alcoholic cardiomyopathy, or infiltrative cardiac involvement in unrecognized hemochromatosis, and these conditions should be kept in mind. [175] [176] Left ventricular diastolic dysfunction seems to be more common than previously assumed. A more recent study in transplant candidates showed a high prevalence of atherosclerotic risk factors and a 26% prevalence of moderate to severe coronary artery disease. Severe CAD was found in older men with risk factors such as hypertension and diabetes.[177] The results mirror current practice of accepting older candidates with comorbidities for liver transplantation.

Overall, more patients with cardiac disease and a history of interventions such as coronary artery stent placement are expected to be undergoing liver transplantation. In select cases, liver transplantation is combined with simultaneous cardiac surgery. The pulmonary system in patients with end-stage liver disease can undergo changes, and two distinct pathophysiologic syndromes that can be recognized are hepatopulmonary syndrome and portopulmonary syndrome. The principal finding in hepatopulmonary syndrome is decreased oxygenation (Pao2 <70 mm Hg or a Pao2 - Pao2 gradient >20 mm Hg on room air) associated with intrapulmonary vascular dilation. A hallmark of this syndrome is intrapulmonary shunting. [178] [179] Patients with hepatopulmonary syndrome may show changes in oxygen saturation when changing from the supine to erect positions. The presence of orthodeoxia is a significant clue for the examining physician that the patient has hepatopulmonary syndrome. The hepatopulmonary syndrome is an independent risk factor for mortality and an indication for liver transplantation. Frequently, but not always, hepatopulmonary syndrome resolves spontaneously months after liver transplantation.[180] After transplantation, long-term survival of patients with hepatopulmonary syndrome is favorable, albeit a small study suggested that postoperative mortality may be higher.[181]

Such resolution is not the case with portopulmonary hypertension, a fairly uncommon complication of portal hypertension,[182] which may worsen after liver transplantation. Patients with liver disease experience an increased prevalence of pulmonary vascular diseases compared with the normal population.[183] Although cirrhosis was thought to be the etiology, portal hypertension seems to be the only consistent factor predisposing patients to the development of pulmonary hypertension. Patients are considered to have portopulmonary hypertension if they meet the following three criteria: (1) mean pulmonary arterial pressure greater than 25 mm Hg, (2) pulmonary vascular resistance greater than 240 sec cm-5, and (3) pulmonary capillary wedge pressure less than 15 mm Hg in the setting of portal hypertension.[184] Although these criteria are reasonable, diagnostic caution should be exercised because interpretation of measured hemodynamic values may be obscured by the hyperdynamic circulation that occurs in patients with liver disease.[178] Portopulmonary hypertension may progress rapidly and carries high perioperative morbidity and mortality when significant. Therapeutic agents used to treat primary pulmonary hypertension not associated with liver disease also have been administered to patients with this condition, with mixed results. [185] [186] [187] [188] Renal dysfunction also develops in many patients with end-stage liver disease. Calculated glomerular filtration rate tends to overestimate actual glomerular filtration rate in patients with end-stage liver disease. Renal dysfunction is usually the result of primary renal disease,

acute tubular necrosis, or hepatorenal syndrome. Hepatorenal syndrome develops in the setting of severe liver disease and in the absence of other causes, such as hypovolemia, drug toxicity, or underlying intrinsic renal disease. There are two types of hepatorenal syndrome. Type I develops rapidly over weeks and is progressive and associated with high mortality. [189] [190] Renal function may recover spontaneously when liver function improves, or the patient receives a liver transplant. It is most frequently seen in patients with acute liver failure, alcoholic hepatitis, or acute decompensation of chronic liver disease. Type II follows a less acute course and is seen mainly in patients who become resistant to diuretic therapy. Patients who experience spontaneous bacterial peritonitis are at risk to develop renal failure. Spontaneous bacterial peritonitis is considered the most frequent cause of renal failure in patients with cirrhosis.[190] The mechanism of hepatorenal syndrome is thought to be a combination of reversible renal vasoconstriction in structurally normal kidneys and changes in vasoconstrictor and vasodilator factors.[190] The degree of preoperative renal dysfunction correlates with increased patient mortality postoperatively. [149] [191] This correlation is mainly observed in patients undergoing only liver transplantation from a deceased donor, but not in patients undergoing combined kidney and liver transplantation.[192] Various hemostatic abnormalities are found in patients with end-stage liver disease who present for liver transplantation. These changes can be caused by

preoperative coagulation disorders or may be related to the procedure itself. Levels of procoagulant factors (II, V, VII, IX, X) and anticoagulant factors (protein C and S, antithrombin III) are frequently decreased in patients with end-stage liver disease. [193] [194] [195] Thrombocytopenia as a result of hypersplenism, qualitative platelet dysfunction, and disorders of the fibrinolytic system (reduced levels of plasminogen, a2antiplasmin, and factor XIII, and increased plasma tissuetype plasminogen activator levels) are often encountered during the perioperative period.[196] Although end-stage liver disease often increases the risk of bleeding, thrombotic complications such as portal vein thrombosis also are seen in this patient population. Several case reports and case series have shown intraoperative thrombus formation in the cardiopulmonary system. [197] [198] [199] [200] [201] Frequently, thrombus formation was associated with the coadministration of antifibrinolytics, such as aprotinin or aminocaproic acid. A conclusive statement with regard to antifibrinolytics and thrombus formation cannot be made because of the lack of sufficient data and the absence of large controlled studies. Surgical Procedure Liver transplantation generally can be divided into three stages: (1) the dissection phase, which includes lysis of adhesion and mobilization of the liver; (2) the anhepatic phase, which consists of removal of the native liver and implantation of the donor liver; and (3) the reperfusion (neohepatic) phase, which involves the completion of

several anastomoses, hemostasis, and closure. Each phase is described in more detail. Preoperative Considerations Patients who are candidates for liver transplantation will have undergone a rigorous preoperative evaluation by multiple medical specialists (see Chapters 34 and 35 [Chapter 34] [Chapter 35] ). Patient evaluation is usually conducted in different phases and may take weeks to months to complete. Pathophysiologic changes as described previously should be identified and addressed. An increasing proportion of patients are now admitted for liver transplantation from home, which often results in a significant interval between the last evaluation or diagnostic test and admission for liver transplantation. All cases should be considered emergency cases (with the exception of living donor recipients). It is important to perform a detailed medical and physical examination with a strong emphasis on changes that have occurred since the last evaluation. Of great importance is the time span between performance of the diagnostic test and the anticipated liver transplantation. Patients may wait several years for liver transplantation, and tests performed early in the evaluation process may not reflect the progression or new onset of organ-specific disease. Simultaneously, all diagnostic tests (i.e., echocardiogram, cardiac catheterization, pulmonary function tests, renal function tests) performed during the workup for liver transplantation and any recent notes

from the primary team should be evaluated. In the case of pulmonary hypertension, two-dimensional echocardiography has been shown to be a sensitive tool for detecting portopulmonary hypertension. Because echocardiography has a poor positive predictive value, however, catheterization of the right side of the heart is recommended to confirm portopulmonary hypertension. [202] Most tests are likely to show that either the patient is fit for surgery without any further medical therapy, or medical management is needed before liver transplantation (e.g., treatment of moderate pulmonary hypertension before transplantation). Knowledge and documentation of preoperative testing are essential because the results of such testing dictate the perioperative management of the patient. Evidence of moderate pulmonary hypertension on echocardiography in a patient without cardiac catheterization may warrant perioperative placement of a pulmonary artery catheter with pressure measurements before incision. Ideally, placement of the pulmonary artery catheter should be done in the ICU before taking the patient to the operating room. Conversely, immediate preoperative right cardiac catheterization with no evidence of pulmonary hypertension may render placement of a perioperative pulmonary artery catheter for monitoring purposes unnecessary. Preoperative renal dysfunction has been shown to be an independent risk factor for postoperative morbidity and mortality in patients undergoing liver transplantation.

[191] Longitudinal assessment is crucial because previously diagnosed borderline renal function may have progressed to renal failure requiring intraoperative interventions such as continuous venovenous hemofiltration or dialysis,[203] or even a combined liverkidney transplant. Screening for any new infections on the day of surgery also is crucial because new-onset or uncontrolled ongoing infections may require postponement of surgery.[204] Intraoperative Management The intensity of intraoperative resource and personnel usage varies widely among liver transplant centers and is influenced by institutional practice, caseload, and personal experience. Standardization of clinical practice has not been fully established for liver transplantation as it has for other procedures. Hemodynamic monitoring may include a pulmonary artery catheter, TEE, or simple CVP monitoring. The type of high-volume infusion equipment differs among transplant centers, as does the use of venovenous bypass (VVBP) during the anhepatic phase. In a survey of 62 transplant centers in the United States done by Schumann, a pulmonary artery catheter was used in approximately 30%, TEE was in 11.3%, and VVBP was used in roughly half of adult transplants. A tendency toward decreased use of pulmonary artery catheters and VVBP was shown with increasing case volume.[205] Binding recommendations with regard to resource use are difficult to make and depend on various factors. More recently, TEE has been increasingly used for management of fluid therapy, monitoring of cardiac

function, and identification of intraoperative complications (e.g., pulmonary embolus). Close communication with the blood bank before surgery is crucial. Standard protocols should be instituted with a recommended setup for blood products. Blood products may include 10 U of red blood cells and 10 U of fresh frozen plasma to be brought to the operating room, with 4 U of single-donor platelets available on request. Because of the magnitude of fluids that may be administered, separate laboratory and fluid flow sheets can facilitate more accurate record keeping and aid in identification of trends. The frequency of blood sampling for laboratory analysis is dictated by the medical condition of the patient, progress of the procedure, and experience of the transplant team. Most patients already have intravenous access on arrival at the operating room that can be used during induction. The use of epidural catheters is discouraged in this procedure because a significantly prolonged perioperative coagulopathy can persist. Placement of an arterial line to monitor blood pressure or a central line/pulmonary artery catheter before induction is not essential. Many patients presenting for liver transplantation may receive nonspecific -blockade for secondary prophylaxis of upper gastrointestinal bleeding (e.g., esophageal varices). These patients tend to be stable during the induction.

Most patients have well-preserved cardiac function and no significant arterial or pulmonary hypertension. Induction can be achieved with an intravenous anesthetic, such as propofol, thiopental, or etomidate, with or without opioids and short-acting or intermediateacting neuromuscular blocking agents. End-stage liver disease results in changes in hepatic blood flow, decreased ability to biotransform certain drugs, hypoalbuminemia, and altered volume of distribution.[174] Several studies in patients with endstage liver disease have shown changes in the pharmacokinetics and pharmacodynamics of drugs commonly used in anesthesia, including nondepolarizing muscle relaxants and benzodiazepines. Extrapolation of this information to intraoperative management is difficult, however, in view of the dynamic nature of the procedure (i.e., anhepatic phase, major blood loss, hypothermia). Most importantly, a functioning liver is implanted at a given point, which makes longitudinal pharmacokinetics and pharmacodynamics studies very difficult to interpret. Most studies have focused on one particular aspect of liver transplantation, such as the impact of the anhepatic phase or hypothermic preservation on drug metabolism. Such studies have suggested that drugs such as sufentanil and propofol exhibit some degree of extrahepatic metabolism.[206] Based on existing knowledge, it is reasonable to choose cisatracurium or atracurium over vecuronium as the muscle relaxant of choice for liver transplantation. The pharmacokinetics and pharmacodynamics of vecuronium

have been shown to be substantially altered by liver disease, whereas cisatracurium and atracurium are cleared independently of liver function.[207] Muscle relaxants have been used as a probe to evaluate the function of the newly implanted liver. [208] [209] [210] [211] Nonetheless, all nondepolarizing agents have been used successfully in liver transplantation as long as appropriate neuromuscular monitoring is performed. Similarly, different opioids, such as fentanyl, sufentanil, alfentanil, and remifentanil, have been used during liver transplantation. A rapid-sequence or modified rapidsequence induction is often warranted because patients frequently have significant ascites or experience delayed gastric emptying. Postinduction hypotension may occur as a result of the very low systemic vascular resistance and relative hypovolemia of these patients. It usually can be treated with small amounts of vasoconstrictors (e.g., phenylephrine). With the exception of halothane, all volatile anesthetics are suitable for liver transplantation. Isoflurane and desflurane are the most frequently used. Correction of severe coagulopathy before line placement may be considered, and the use of ultrasound may facilitate central venous cannulation, but there are no generally accepted guidelines. Line placement should include a radial arterial line for invasive blood pressure monitoring and two to three large-bore intravenous catheters, ideally including a rapid-infusion catheter. The choice of hemodynamic monitoring is determined by institutional practice. When pulmonary hypertension is suspected or known, a pulmonary artery catheter should

be placed, and pulmonary arterial pressure should be determined before induction or incision. Newly diagnosed moderate to severe pulmonary hypertension should be considered a reason to abort the procedure. These patients can be relisted for transplantation after successful medical therapy has been initiated. The diagnosis alone does not imply that the patient is denied a necessary transplant. An orogastric/nasogastric tube is placed to decompress the stomach and improve surgical exposure. This is important during the dissection phase, and even more so during the anhepatic phase when the vascular anastomoses are performed. Patients are frequently severely coagulopathic, and the placement of a nasogastric tube may result in significant bleeding. Rarely, patients undergoing liver transplantation experience uncontrolled upper gastrointestinal bleeding during surgery that may require placement of a Minnesota or Sengstaken-Blakemore tube. Before the incision is made, appropriate antibiotic and immunosuppressive (e.g., steroid administration) coverage should be ensured. Immunosuppressive protocols vary among medical centers, and clear communication is crucial. The patient should be kept normothermic throughout the operation. A large surgical field combined with prolonged exposure, major fluid shifts, and the implantation of a cold organ renders the patient susceptible to significant

hypothermia, which may worsen coagulopathy and drug metabolism. It also may prevent extubation of the patient at the end of the procedure. All administered fluids should be delivered through a fluid warmer, and forcedair heating blankets should be applied to all patients. No optimal anesthetic technique has been established for maintenance of anesthesia. A balanced technique using volatile anesthetics in an oxygen/air mixture and opioids results in stable intraoperative hemodynamics. A combination of opioids and benzodiazepines and total intravenous anesthesia with propofol also have been used for liver transplantation. Nitrous oxide should not be used to avoid intestinal distention, and because in selected cases (not always predictable) a Roux-en-Y choledochojejunostomy is done at the end of the procedure. Significant coagulopathy, blood loss, and electrolyte and metabolic derangements require frequent intraoperative laboratory tests. Measurement of arterial blood gases, blood glucose, electrolytes (sodium, potassium, and ionized calcium), and hematocrit is routine in most transplant centers. Monitoring of arterial blood gases allows one to assess oxygenation and base deficits and possibly lactate levels. Correction of the base deficit and reduction in lactate levels may be indirect indicators that the donor liver is functioning adequately. The glucose-insulin pathway is frequently impaired in patients with end-stage liver disease. In contrast to

patients with acute liver failure who may have hypoglycemia, patients with chronic end-stage liver disease experience impaired insulin-mediated glucose uptake. Glucose metabolism may worsen during liver transplantation, and progressive hyperglycemia may ensue, especially in the reperfusion phase. Several mechanisms have been implicated, including enhanced glycogenolysis by the donor liver, decreased glucose use, and insulin resistance. [163] [212] Close observation of electrolytes is essential. Hyperkalemia/hypokalemia may be present as a result of either renal dysfunction and massive transfusion or aggressive diuresis.[213] Hyponatremia frequently is encountered in end-stage liver disease, but overzealous correction during the perioperative phase should be avoided because of the associated risk of central pontine myelinolysis. Ionized calcium levels are often significantly decreased during liver transplantation, particularly during the dissection and anhepatic phases.[163] An exogenous citrate load from transfused blood products and the decreased ability of the diseased liver to metabolize citrate are thought to be responsible for the severely depressed ionized calcium levels, and calcium infusions are frequently required. Treatment of ionic hypocalcemia can be similarly accomplished with calcium chloride or calcium gluconate.[214] After reperfusion, and with the onset of function of the grafted liver, calcium hemostasis is often corrected, and calcium supplementation generally is unnecessary.

Less consistency is found among centers regarding the monitoring of coagulation parameters. The prothrombin time, international normalized ratio, partial thromboplastin time, fibrinogen, and platelets are measured by most programs. Thromboelastography is used in approximately 33% of liver transplant centers, and the activated clotting time is used in approximately 18%.[205] Severe coagulopathy and intraoperative blood loss remain the most significant problems encountered in patients undergoing liver transplantation. Impaired hemostasis, especially after receiving an extended criteria liver, is usually multifactorial and includes hyperfibrinolysis, depletion of coagulation factors, thrombocytopenia, and platelet dysfunction.[215] Approaches to correct hemostasis vary significantly among institutions and depend partly on institutional transfusion preferences and the coagulation monitoring method. [216] [217] The administration of fresh frozen plasma, red blood cells, platelets, and cryoprecipitate remains the mainstay of therapy for blood loss and coagulopathy during liver transplantation. Overall use of blood products during liver transplantation has been significantly reduced in recent years because of improved surgical technique, intraoperative management, and patient selection. This is an important accomplishment because blood transfusion results in immunomodulation and seems to affect longterm outcome adversely.[218] Pharmacologic agents known to alter hemostasis also have been investigated as adjunctive therapies. Aprotinin, aminocaproic acid, tranexamic acid, and conjugated estrogen all have been studied in this context [219] [220] [221] [222] [223] [224]

[225]; one study showed improved hemodynamics with the administration of aprotinin.[227] These studies have produced conflicting results, however, partly because of study designs. In a meta-analysis including 1043 patients, Warnaar and colleagues[228] showed that aprotinin apparently is safe and results only in transient renal dysfunction. Aprotinin was withdrawn from the market in late 2007, however, based on complication rates in the cardiac surgery population. The true efficacy of a drug can be determined only when the optimal treatment dosage (established through rigorous dose-finding studies) is used.[229] To compare the efficacy of different drugs, knowledge of the optimal dosage of each is necessary. Similarly, the safety profile of a drug has to be taken into account. A dosage that maximally reduces blood loss and transfusion requirements during liver transplantation also may increase the risk of hepatic artery or portal vein thrombosis. It is not surprising that there is no consensus on the use of any of these hemostatic agents at liver transplant centers worldwide, despite promising studies. [229] Another drug, recombinant factor VIIa, has attracted significant attention for improving coagulopathy and reducing intraoperative blood loss.[230] Recombinant factor VIIa was initially developed for patients with hemophilia and particularly for patients unable to receive conventional therapy because of antibodies against factors VIII and IX. Recombinant factor VIIa increases thrombin generation in conjunction with activated

platelets.[231] Several case reports, case series, and noncontrolled studies have shown the potential usefulness of recombinant factor VIIa in the setting of liver transplantation. [226] [232] [233] In 2005, two prospective randomized trials in liver transplant patients resulted in disappointing results, in part because of poor patient selection. [234] [235] A small retrospective study showed that in a select group of patients with prolonged prothrombin time and high MELD score, the prophylactic application of recombinant factor VIIa at the start of orthotopic liver transplantation may reduce perioperative transfusion requirements.[236] In view of the very high cost of the drug and the lack of scientific data, it can be recommended only for compassionate use in extreme situations. As outlined earlier, liver transplantation can be divided into three stages: dissection, anhepatic, and reperfusion (neohepatic) phases. The surgical goals of the dissection phase are to mobilize the vascular structures around the liver (suprahepatic vena cava, infrahepatic vena cava, portal vein, and hepatic artery) and isolate the common bile duct. Frequently, adhesions between the liver, diaphragm, and retroperitoneal areas must be dissected to allow full mobilization of the liver within the right upper quadrant. Manipulation of the liver can impede venous return and result in hypotension. Similarly, acute decompression of ascites early during the dissection phase can result in hypotension. During this phase, adequate fluid replacement is crucial, and colloids frequently are used.

Diuresis should be established early during the procedure to facilitate fluid management, and it may produce some renal protection in anticipation of relative renal ischemia during the anhepatic period. Commonly used drugs to maintain good urine output are loop diuretics, dopamine, mannitol, and, more recently, fenoldopam. It has not yet been established which regimen, if any, is the most protective during liver transplantation. As for dopamine, sound scientific data on the beneficial effect of fenoldopam are lacking in the liver transplant population. In a review article on fenoldopam, only two small studies were referenced that showed potential renal protective properties during liver transplantation under defined study conditions. [237] [238] The comparably high cost probably excludes fenoldopam as a first-line drug for renal protection in routine liver transplantation. However, interventions frequently used for perioperative renal protection either are without beneficial effect[239] or are possibly harmful in the noncardiac patient population. [240] During the end of the dissection stage, the donor organ, which is stored in preservation solution, is flushed with crystalloid or colloid solution on a separate table (back table). During the anhepatic stage, the new liver is primarily implanted by either infracaval interposition or piggyback technique. The choice of surgical technique has important anesthetic implications. During infracaval interposition, complete vascular occlusion is established by clamping the hepatic artery, portal vein, infrahepatic vena cava, and suprahepatic

vena cava ( Fig. 67-4A ). Because the inferior vena cava is occluded, cardiac preload becomes dependent on collateral flow, and severe hypotension can occur. Cardiac output often decreases significantly with an accompanying increased heart rate. If VVBP is not used, volume loading with a target CVP of 10 to 20 mm Hg and occasionally small infusions of vasopressors (e.g., phenylephrine) are needed before the infrahepatic and suprahepatic caval clamps are placed to prepare for the anhepatic phase. In a retrospective study, Schroeder and colleagues[241] suggested that a low CVP during liver transplantation may decrease the rate of blood transfusion, but it increases postoperative renal failure and 30-day mortality. The results have to be interpreted with caution, however, because of significant shortcomings in the study design. Massicotte and associates[242] showed in a prospective study that reducing CVP (e.g., phlebotomy) reduces blood loss, but does not result in increased adverse outcomes.

Figure 67-4 A, With the use of a caval interpositional technique immediately before the anhepatic phase, the suprahepatic vena cava, the infrahepatic vena cava, and the portal vein are clamped. The hepatic artery is frequently clamped late in the dissection phase. B, Anastomoses during liver transplantation. The donor's suprahepatic vena cava and infrahepatic vena cava are anastomosed to the recipient, followed by the portal vein. Frequently, the hepatic artery and bile duct are anastomosed in the reperfusion phase. A Roux-en-Y loop of the small intestine is an alternative biliary drainage conduit. Reconstruction of the hepatic artery, portal vein,

or bile duct is occasionally necessary. Placement of a Ttube for drainage of the bile duct is not mandatory and is increasingly not being done. IVC, inferior vena cava. (From Hardy JD: Hardy's Textbook of Surgery, 2nd ed. Philadelphia, JB Lippincott, 1988.)

Because the response to caval occlusion may differ among patients, a temporary test clamp on the inferior vena cava may help guide management before vascular clamps are permanently placed for the anhepatic phase. Alternatively, VVBP can be instituted before vascular exclusion of the liver is established. Bypass is usually accomplished by cannulation of the femoral and portal veins with diversion to the suprahepatic vena cava through the axillary, subclavian, or jugular vein. [243] [244] Extensive research was conducted in the 1980s and 1990s to understand the advantages and disadvantages of VVBP, particularly after one group reported a 10% intraoperative mortality without VVBP that was attributed to hemodynamic instability during the anhepatic phase. Advantages of VVBP include improved hemodynamic

stability, improved perfusion of organs during the anhepatic phase, decreased red blood cell and fluid requirements, splanchnic decompression, reduced renal impairment, limited metabolic impairment, and a reduced incidence of pulmonary edema.[243] Several disadvantages also were reported, with complications related to cannula placement being the most significant. Lymphocele, hematoma, major vascular injury, nerve injury, pulmonary air embolism, and death have been associated with VVBP; in one study, the complication rate was reported to be 10% to 30%. A more recent retrospective study noted that VVBP can be initiated during liver transplantation with acceptable risks.[245] More recent North American studies have reported, however, that most centers rarely use VVBP, if at all. [205] [246] [247] Even centers not routinely using VVBP may consider it for selected patients, such as patients with significant preexisting cardiac disease, severe pulmonary hypertension, significant hemodynamic instability, or when the anesthesiologist is unfamiliar with caval clamping. [247] [248] In the past, a greater than 50% reduction in cardiac output after vena cava clamping was considered an indication for VVBP. This indication has been challenged in a study in which it was shown that a reduction in cardiac output of more than 50% after vena cava clamping was not associated with increased perioperative morbidity and mortality compared with patients with a less pronounced reduction in cardiac output.[249]

Alternatively, a piggyback technique can be used. During this approach, the vena cava is either partially or entirely occluded during the anhepatic phase. Although improved hemodynamics has been shown (with partial occlusion) with this technique, it is considered surgically more difficult than caval interposition, and may lead to greater technical complications.[250] The anhepatic stage begins with excision of the native liver and control of bleeding. The ice-cold liver donor graft is placed into the surgical field. The suprahepatic, infrahepatic, and portal vein anastomoses are completed in that order. The hepatic artery anastomosis can be performed before reperfusion or after restoration of blood flow ( Fig. 67-4B ). Profound acidosis and hypocalcemia frequently develop during the anhepatic stage, so laboratory parameters should be monitored closely. Fluid management can be challenging during this phase, and the return of significant volume when the clamps are released at completion of the vascular anastomoses must be anticipated. Overly aggressive fluid management to maintain adequate blood pressure during the anhepatic phase may result in fluid overload with possible cardiopulmonary compromise and considerable liver and intestinal swelling. An engorged liver and intestines may pose a significant technical challenge for the surgeon during the reperfusion phase, especially when performing a Roux-en-Y choledochojejunostomy. At the end of the anhepatic phase, the vascular clamps are removed in staged fashion, and each anastomosis is inspected for leakage. The return of preload by

establishment of continuous caval flow results in normal or supranormal filling pressure. Removal of the portal vein clamp allows blood flow from the splanchnic circulation into the donor liver and constitutes the beginning of the reperfusion phase. The most critical part of the reperfusion phase is the period immediately after the vascular clamps are removed from the liver graft. Significant hemodynamic instability and cardiac arrest can occur within seconds to minutes of unclamping, particularly after unclamping the portal vein. Reduced cardiac contractility,[251] arrhythmias, severe bradycardia, profound hypotension, and hyperkalemic arrest all have been reported, and anesthetic management is directed at maintaining or recovering cardiovascular stability. This goal may require immediate pharmacologic intervention, such as the administration of epinephrine, atropine, calcium, or occasionally sodium bicarbonate. Methylene blue has been shown in one small study to attenuate hemodynamic changes of the reperfusion syndrome.[252] Preoperative placement of external pads may be helpful for immediate postreperfusion cardiac arrest. The physiologic perturbations seen in the immediate reperfusion phase are often described as reperfusion syndrome. The exact mechanism is unknown and remains elusive.[253] Several factors alone or in combination are postulated to produce this hemodynamic instability, including high potassium concentrations[254] in the preservative solution (UW solution), donor demographics, [255] the surgical technique,[256] and decreased systemic vascular resistance.[257] Less well established, and in part controversial, factors, such as hypothermia,

metabolic acidosis, endogenous vasoactive peptides from the intestine, and sudden atrial stretching in response to unclamping and reperfusion, are some mechanisms that have been postulated to cause the observed hemodynamic changes. After the initial reperfusion phase, the hepatic artery anastomosis is completed, the gallbladder (in liver grafts from deceased donors) is removed, and the bile duct is reconstructed. Hepatic artery reconstruction is mostly done by end-to-end anastomosis and, in select cases (with unfavorable anatomy), by a jump graft from the aorta. Bile drainage is usually accomplished by choledochocholedochostomy and occasionally by Rouxen-Y choledochojejunostomy. Attention should be paid to the diagnosis and management of significant coagulopathy (e.g., dilution and consumption of clotting factors, platelet entrapment, endogenous heparinoid-like substances, primary fibrinolysis) and resultant bleeding in the reperfusion phase. Laboratory analysis (with consideration of its limitations) and clinical evidence of surgical bleeding should guide management of the coagulopathy. The immediate function of the newly transplanted liver can be assessed by monitoring obtainable parameters in the operating room. Intraoperative parameters associated with prediction of the outcome of liver transplantation include transfusion requirements, intraoperative bile and urine production, technical complications, and total operating time. The lack of bile production, the need for platelet transfusion, and decreased urine output seem to

be associated with a significant increase in ICU and hospital stay.[258] When adequate hemostasis is established, the abdomen is closed. Hypertension may develop toward the end of the procedure in some patients, and treatment should be initiated before leaving the operating room. Postoperative Care Postoperative tracheal intubation is no longer mandatory as long as significant respiratory compromise or concern for airway protection is absent, and established criteria for extubation are fulfilled. Immediate postoperative extubation of liver transplant patients while still in the operating room was reported in 1997 in a cooperative study between the University of Colorado and the University of California at San Francisco.[259] A small group of patients with characteristics associated with few postoperative complications were studied. The successful outcome of this study was followed by reports of immediate or early extubation from institutions in the United States and Europe. [260] [261] [262] [263] [264] More recent studies have reported that 75% of first-time deceased liver transplant patients without fulminant failure could be extubated in the operating room by physicians who had experience with early extubation protocols. [263] [265] A prospective multicenter study confirmed that early extubation in liver transplantation patients is safe when strict guidelines are followed.[266]

Fluid shifts or blood loss per se should not be considered an indication for postoperative intubation. The standard criteria for extubation in addition to some patient-specific considerations (e.g., significant preoperative hepatic encephalopathy, fulminant hepatic failure) suffice to assist in determining whether a patient should be considered for extubation. Nevertheless, regardless of whether the patient is extubated in the operating room, most centers admit patients to the ICU for close monitoring purposes. There have been more recent reports of uncomplicated cases with patient disposition to the postoperative anesthesia care unit and subsequent floor admission. Postsurgical pain control is not generally a problem. Several studies have shown that analgesic requirements in patients with end-stage liver disease undergoing liver transplantation appear to be significantly decreased compared with other major abdominal surgery. [267] [268] [269] In one study, the neuropeptide metenkephalin, which is involved in pain modulation, was shown to be significantly elevated in liver transplant patients compared with the control population. The exact mechanism of this clinical observation is unknown, and preoperative administration of large doses of steroids may play some role. Whether this applies to transplant patients with hepatocellular carcinoma and preserved synthetic liver function is unknown. The postoperative course of patients who have undergone liver transplantation is primarily dictated by the degree of immediate liver function and recovery of organs that

were compromised before transplantation (e.g., hepatorenal syndrome, hepatopulmonary syndrome). Recovery can range from uncomplicated to extremely complex. Frequent assessment of cardiac and pulmonary function, serum glucose and electrolytes, renal and liver function, and coagulation and the blood count is crucial. In most cases, therapy is supportive and follows the guidelines established for all ICU patients. Certain aspects require special attention, however. Patients occasionally need fresh frozen plasma therapy postoperatively to offset an initially low graft liver function. Fresh frozen plasma requirements also are considered an indirect measure of postoperative liver function. The need for administering platelets or cryoprecipitate postoperatively is low, and such administration is reserved for selected cases. One should have a low threshold for reexploration. Leakage from vascular anastomosis sites, or bleeders, and diminished flow or thrombosis in the hepatic artery or portal vein should always be considered. Patients who have adequate postoperative liver function and have received steroids tend to be hyperglycemic, which may warrant an infusion of insulin. Anesthesia for Patients after Liver Transplantation Liver transplant recipients occasionally return to the operating room shortly after the procedure for exploratory laparotomy. Reasons for exploration include bleeding, biliary leak, bowel obstruction, and abscess formation. Liver function may not have returned to

baseline in the immediate post-transplant period, and additional surgical stress may result in significant worsening of hepatic function. Coagulation studies should be monitored carefully throughout the case, and fresh frozen plasma should be made readily available. The most common reason to operate after liver transplantation is for biliary reconstruction. At this point, liver function is generally normal, and anesthetic considerations (including regional techniques such as epidural catheters) are similar to those for any abdominal procedure. These patients have been receiving powerful immunosuppressive therapy, however, which leads to an increased risk for infectious complications, drug toxicity, and adverse drug interaction. Placement of any intravenous or epidural catheters should be done under strict sterile conditions with maximum barrier protection. The patient's drug regimen should be reviewed and screened for known interactions with drugs used during the perioperative period. The medical history and physical examination done at this point should include screening for these adverse immunosuppressive drug effects, including, but not limited to, neurotoxicity and renal toxicity. Intestine Transplantation Intestinal transplantation is done much less frequently than transplantation of other solid organs. In 2007, 198 intestinal transplants were done in the United States, and there were approximately 222 patients on the waiting list.

Short-gut syndrome accounted for more than 60% of these transplants, and half the recipients were younger than 6 years.[144] The overall graft survival rate at 1 year was 66% and at 5 years was 20%. These outcomes are markedly improved compared with earlier years, when early universal graft failure was very common. Changes in immunosuppressive therapy are thought to be responsible for the improved graft survival.[270] Only a few centers perform this procedure as either an isolated intestinal transplantation or a combined liver-intestinal transplantation. Dependence on total parenteral nutrition can lead to steatotic liver disease with hepatic failure requiring combined liver-intestinal transplantation. Optimization of hepatosplanchnic blood flow is essential for these cases. Fluid loading and inotropic support may be beneficial.[271] No studies have investigated the perioperative anesthetic management and graft and patient outcome. Infection after Abdominal Solid Organ Transplantation After transplantation, organ recipients are at significant risk for various complications, including bacterial, fungal, and viral infections. Infections in this patient population are associated with increased morbidity and mortality because transplant recipients have unique infectious risks compared with immunocompetent ICU patients. Studies of patients receiving different transplanted abdominal organs show the importance of postoperative infection in

transplant recipients. In the first month after transplantation, the sources of infection are primarily nosocomial secondary to the surgical technique or technical complications. After transplantation of any abdominal organ, there is a risk of surgical site infections, intra-abdominal abscesses, and infected hematomas. Multidrug-resistant microorganisms are increasingly seen in this population and are likely to represent a significant challenge in the future. In liver transplantation, surgical complications such as biliary leaks can lead to subsequent infections, including peritonitis, cholangitis, and hepatic abscesses.[272] The risk of fungal infections after orthotopic liver transplantation increases with renal failure, transfusions, retransplantation, repeat laparotomy, and creation of a Roux-en-Y biliary duct anastomosis. Surgical site infections of the soft tissue are usually diagnosed clinically by the presence of erythema, tenderness, purulence, and crepitus around the wound. [9] Often, superficial surgical site infections can be treated with antibiotics only; however, any rapidly progressing soft tissue infection requires prompt surgical treatment. Gram-positive organisms usually cause superficial surgical site infections, but necrotizing infections are often polymicrobial. Surgical site infection involving deeper tissue structures may be more difficult to recognize. Diagnostic procedures include culturing and Gram staining of any fluid from the wound or drains, ultrasound or CT scanning to localize possible fluid collections, and possible repeat laparotomy.

Laparotomies are associated with an increased mortality, but are often necessary in critically ill transplant patients, especially patients with sepsis and multiorgan failure. [273] CT-guided drains successfully treat 80% of abdominal abscesses in general surgical patients.[274] Intra-abdominal abscesses in orthotopic liver transplantation are often near the biliary tract, especially if a Roux-en-Y choledochojejunostomy was used for the biliary reconstruction. Renal allograft recipients with high serum creatinine, urinary fistulas or leaks, and prolonged urinary bladder catheterization have a higher risk for wound infections. [275] After simultaneous pancreas and kidney transplant, the risk of an intra-abdominal surgical site infection may be increased slightly if pancreatic exocrine secretions are drained enterically, rather than drained via pancreatic duct anastomosis to the bladder.[276] Additionally, kidney transplant recipients with a peritoneal dialysis catheter present before transplantation may have increased risk for intra-abdominal, bloodstream, and wound infections.[275] Frequently, transplant patients require extensive postoperative critical care with prolonged intubation and indwelling central venous and urinary catheters. These devices are significant risk factors for ventilatorassociated pneumonia, urinary tract infections, and catheter-related bloodstream infections in a significantly immunocompromised patient population.

Comorbidities, such as diabetes and persistent renal dysfunction, can contribute to increased susceptibility to infections. Renal failure incurs a 15-fold to 21-fold increased risk of invasive fungal infection. Pneumonia accounts for 41% of febrile episodes in the ICU in the first 7 days postoperatively; the risk of catheter-related bloodstream infections increases threefold after the first week. Patients are often taking multiple immunosuppressants that act through multiple inhibitory mechanisms and may facilitate infection. Immunosuppression Recognition of a foreign alloantigen after organ transplantation triggers an immune response in the host. An immediate goal of immunosuppressive therapy is to prevent the rejection of grafts from genetically nonidentical donors. Various immunosuppressive drugs have been developed to diminish the immunologic attack on grafts and target T-cell activation, which triggers the predominant form of acute rejection. Individual immunosuppressants inhibit different steps in T-cell activation, which is a very complex process that can be divided into two stagesa sensitization phase and an effector stage. The first stage of T-cell activation involves interaction between antigen-presenting cells of the graft and host T cells, such as CD3. The second stage involves participation of costimulatory receptors such as B7, CD28, and CD40, which also activate the T-cell response, and subsequent secretion of cytokines by activated T cells. An interaction of intracellular adhesion molecules and cytokines (e.g., interleukin-2, interferon-?, and tumor

necrosis factor-) activates the transcription cascade, which further amplifies T-cell activation through DNA synthesis and T-cell proliferation, and plays a central role in graft rejection. Graft rejection reactions have various time courses: hyperacute rejection occurs within the first 24 hours after transplantation, acute rejection reactions usually begin in the first few weeks after transplantation, and chronic rejection can occur months to years after transplantation. [277] [278] Immunosuppressive drugs are used for the prevention or treatment of acute and chronic rejection of a transplanted organ. The growing success of organ transplantation is closely linked to the evolution of immunosuppressive therapy. The first immunosuppressive drug, azathioprine, was introduced in 1962 and increased the possibilities for successful human transplants, earning a Nobel Prize for innovative pharmacologic progress. In the last 20 years, important medical breakthroughs, such as tissue typing and the introduction of calcineurin inhibitorbased immunosuppression, have dramatically improved the survival rate of transplant recipients. In 1983, the calcineurin inhibitors era was ushered in after the discovery of cyclosporine (1979). Transplantation of extrarenal organs became routine, with excellent outcomes for liver, pancreas, heart, and lung transplants. [279] Immunosuppressive therapy is increasingly being tailored to the specific organs transplanted and their individual risk factors. Patients who are presensitized or who receive a blood groupincompatible organ are, from an

immunologic point of view, considered to be high-risk patients. They are likely to require more potent, aggressive immunosuppressive therapy than needed for other transplant patients.[280] Frequently, the type of immunosuppressive drug (e.g., calcineurin inhibitors) or increased doses of immunosuppressive drugs are linked, however, to increased end-organ toxicity, such as neurotoxicity or nephrotoxicity. In patients with delayed renal graft function after transplantation, initial omission of calcineurin inhibitors is crucial to avoid further renal damage. Immunosuppressive drugs are frequently combined to take advantage of additive or synergistic immunosuppressive interaction and to limit drug-specific toxicity ( Table 67-2 ).[281]

Table 67-2 -- Immunosuppressive Drugs Used in Solid Organ Transplantation and Their Side Effects Mechanism of Action Side Effects Inhibition of T-cell interaction Prednisolone As with all steroids: osteoporosis, diabetes mellitus, glaucoma, infections Muromonab-CD3 (Orthoclone OKT3) Fever, lymphoproliferative disease, pulmonary edema, anaphylactic reaction, neoplasia 15-Deoxyspergualin Bone marrow suppression, gastrointestinal syndromes, paresthesia Inhibition of adhesion molecules

Rabbit/horse antithymocyte globulin Fever, nausea, anaphylactic reaction, higher incidence of cytomegalovirus and Epstein-Barr virus infection Antilymphocyte globulin Fever Enlimomab Fever, hypertension, chills, nausea, vomiting OKT4A Unknown Inhibition of cytokine synthesis Cyclosporine Nephrotoxicity, hepatotoxicity, neurotoxicity, hypertension, hyperlipidemia, hirsutism, tremor, gingival hyperplasia, diabetes Tacrolimus (FK506) Nephrotoxicity, neurotoxicity, hypertension, hyperlipidemia, hyperglycemia Sirolimus (rapamycin) Hyperlipidemia, myelosuppression, infections SDZ-RAD (everolimus) Hyperlipidemia, myelosuppression, infections Inolimomab Headache, leukopenia, thrombocytopenia Basiliximab No major adverse effects Daclizumab No major adverse effects Inhibition of DNA synthesis Azathioprine Myelosuppression, hepatotoxicity, development of malignancy Mycophenolate mofetil Leukopenia, gastrointestinal syndromes

Therapy must be maintained lifelong, although isolated cases without graft loss after complete withdrawal of all immunosuppressive drugs have been reported. A typical regimen consists of different phases, starting with the induction phase, therapy during hospitalization, the maintenance phase, and, if necessary, antirejection treatment. Each phase may consist of different drugs or doses and is constantly adjusted as dictated by the medical condition of the patient. The major limitation of current immunosuppressive drugs is that no currently available therapy is entirely effective in preventing rejection.[280] The use of multiple immunosuppressive drugs predisposes patients to a host of infectious and malignant complications. Long-term survival of patients after solid organ transplantation has improved with adequate immunosuppressive therapy. Modification of the immune system also has increased the risk of malignancy, however, especially types of malignancy involving viruses.[282] Azathioprine has been associated with a significant increase in skin cancer, and prolonged cyclosporine administration has been associated with Kaposi's sarcoma. Malignancy is now responsible for substantial morbidity and mortality in this patient population. With many different available immunosuppressant combinations, acute rejection rates are acceptable, and the focus of interest in transplantation has significantly shifted and expanded toward tolerability and long-term

graft and patient survival. The goals of therapy for new immunosuppressants drugs should include (1) prevention of the immune response (i.e., acute and chronic rejection and vascular remodeling); (2) prevention of the complications of immunodeficiency, such as opportunistic infections and malignancies; and (3) minimization of drug-induced toxicity. Many new trials are under way to identify the best immunosuppressant regimen. Because the therapeutic range of most immunosuppressive drugs is narrow, perioperative monitoring of drug levels is important. Several immunosuppressives (e.g., cyclosporine, tacrolimus, and sirolimus) are substrates or modulators (or both) of cytochrome P4503A and P-glycoprotein. [283] [284] Pglycoprotein is a member of the ABC (adenosine triphosphate [ATP]binding cassette) transport protein family. It is found in various tissues, including the bloodbrain barrier, gastrointestinal tract, kidneys, adrenal cortex, and several more. One of the functions of Pglycoprotein is the energy-dependent transport of drug acquired from the cytoplasm or plasma membrane into the extracellular space.[285] Several other drug classes (e.g., antifungals, calcium channel blockers, HIV protease inhibitors) administered to transplant patients also are substrates or modulators (or both) of cytochrome P4503A and P-glycoprotein. These drugs themselves may interact with drugs commonly administered during the perioperative period. [286] [287] Although interactions between immunosuppressive and anesthetic drugs are likely to occur, few studies have

examined in a prospective randomized fashion the impact of immunosuppressive drugs on selected anesthetics. In animal studies, cyclosporine was shown to alter barbiturate, fentanyl, and isoflurane requirements. [288] [289] [290] [291] However, the clinical relevance of these interactions remains to be investigated, however. Similarly, cyclosporine seems to enhance the effects of neuromuscular blockade, as shown in several animal studies and case reports. [292] [293] [294] [295] Despite the lack of adequate trials in humans, it seems to be reasonable to anticipate reduced requirements of nondepolarizing muscle relaxants in patients taking cyclosporine. Azathioprine, in contrast, produced a small and transient antagonism to nondepolarizing muscle blockade in patients with renal failure that was considered clinically insignificant. An animal study also showed no effect of azathioprine on atracurium requirements. The complexity of the immunosuppressive regimen in conjunction with adjunct therapies makes clinically relevant drug-drug interactions likely. A detailed preoperative review of the patient's medication should focus on possible side effects, drug-drug interactions, and potential implications for the anesthetic plan.[296] References