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Liver transplantation can be generally 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 will be described in more detail.
Patients who are candidates for liver transplantation will have undergone a rigorous preoperative evaluation by multiple medical specialists. 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. Documentation of the expected pathophysiologic changes in such patients is absolutely essential. 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. However, because it has a poor positive predictive value, catheterization of the right side of the heart is frequently recommended to confirm portopulmonary hypertension.[213]
It is likely that most tests will 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). Emphasis during the preoperative evaluation should be placed on the cardiopulmonary system, with the goal being detection of conditions associated with prohibitively high morbidity and mortality when liver transplantation is performed. Knowledge and documentation of preoperative testing are essential because the results of such testing dictate the perioperative management of the patient. For example, 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. Conversely, immediate preoperative right cardiac catheterization with no evidence of pulmonary hypertension may render placement of a perioperative pulmonary artery catheter for monitoring pulmonary hypertension unnecessary. 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 their evaluation process may not reflect the progression or new onset of organ-specific disease. For example, preoperative renal dysfunction has shown to be an independent risk factor for postoperative morbidity and mortality in patients undergoing liver transplantation.[203] Longitudinal assessment is crucial because previously diagnosed borderline renal function may have progressed to renal failure requiring intraoperative interventions such as continuous venous-venous hemofiltration or dialysis[214] or even a combined liver-kidney transplant. Screening for any new infections on the day of surgery is also crucial because new-onset or uncontrolled ongoing infections may require postponement of surgery.[215]
The intensity of intraoperative resource and personnel utilization varies widely between liver transplant centers and is influenced by institutional practice, caseload, and personal experience. Standardization of clinical practice has not been 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 between transplant centers, as does the use of venous-venous bypass (VVBP) during the anhepatic phase. In a recent survey of 62 transplant centers in the United States performed by Schumann, a pulmonary artery catheter was used in approximately 30%, TEE in 11.3%, and VVBP in roughly half of adult transplants. A tendency toward decreased use of pulmonary artery catheters and VVBP was shown with increasing case volume.[216] It is evident that binding recommendations with regard to resource utilization are difficult to make and will depend on various factors.
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 and progress of the procedure. Blood can be sampled for analysis as often as every 30 minutes during crucial phases of the operation.
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 type of procedure because a significantly prolonged perioperative coagulopathy can persist. Placement of an arterial line to monitor blood pressure or a central line/pulmonary catheter line before induction is not essential. 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, along with opioids and short- or intermediate-acting 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.[184] Several studies in patients with end-stage liver disease have demonstrated changes in the pharmacokinetics and pharmacodynamics (PK/PD) of drugs commonly used in anesthesia, including nondepolarizing muscle relaxants and benzodiazepines. However, extrapolation of this information to intraoperative management is somewhat difficult in view of the rather dynamic nature of the procedure (anhepatic phase, major blood loss, hypothermia). Most importantly, a functioning liver will be implanted at a given point, which will make longitudinal PK/PD studies very difficult to interpret. Most PK/PD studies have focused on one particular aspect of liver transplantation, for example, 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. [217] [218] Based on existing knowledge, it is reasonable to choose cisatracurium or atracurium over vecuronium as the muscle relaxant of choice for liver transplantation. The PK/PD of vecuronium has been shown to be substantially altered by liver disease, whereas cisatracurium and atracurium are cleared independently of liver function.[219] [220] On the other hand, muscle relaxants have been used as a probe to evaluate the function of the newly implanted liver.[221] [222] [223] [224] 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 rapid-sequence induction is often warranted because patients frequently have significant ascites or experience delayed gastric emptying, which indicates that they should be considered to have a full stomach. Postinduction hypotension may occur as a result of the very low systemic vascular resistance and relative hypovolemia of these patients, and it can usually 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. 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. However, when pulmonary hypertension is suspected or known, a pulmonary catheter should be placed and PAP determined before induction or incision. Newly diagnosed moderate to severe pulmonary hypertension should be considered a reason to abort the procedure. It is important to recognize that 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. It should be kept in mind that patients are frequently severely coagulopathic and that the placement of a nasogastric tube may result in significant bleeding. On rare occasion, 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 between medical centers, and clear communication is crucial for delivery of appropriate immunosuppressive therapy to the patient. The patient should be kept normothermic
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, as well as total intravenous anesthesia with propofol, has also 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 performed 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 as well as base deficits. Correction of the base deficit is one indirect indicator that the donor liver is functioning adequately.
The glucose-insulin pathway is frequently impaired in patients with end-stage liver disease. Unlike patients with acute liver failure who may have hypoglycemia, patient with chronic end-stage liver disease experience impaired insulin-mediated glucose uptake. Glucose metabolism may worsen during liver transplantation and progressive hyperglycemia, especially in the reperfusion phase. Several mechanisms have been implicated, including enhanced glycogenolysis by the donor liver, decreased glucose use, and insulin resistance.[174] [225] Close observation of electrolytes is essential. Hypokalemia/hyperkalemia may be present as a result of either renal dysfunction and massive transfusion or aggressive diuresis. Hyponatremia is frequently 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.[174] 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 thus frequently required. Treatment of ionic hypocalcemia can be similarly accomplished with calcium chloride or calcium gluconate.[226] During the reperfusion phase and with the onset of function of the grafted liver, calcium hemostasis is often corrected and calcium supplementation is not generally necessary.
Less consistency is found between centers regarding the monitoring of coagulation parameters. The prothrombin time, INR, 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%.[216] Severe coagulopathy and intraoperative blood loss remain the most significant problems encountered in patients undergoing liver transplantation. Impaired hemostasis, especially after receiving a suboptimal or marginal liver, is usually multifactorial and includes hyperfibrinolysis, depletion of coagulation factors, thrombocytopenia, and platelet dysfunction.[227] Approaches to correct hemostasis vary significantly from institution to institution and are partly dependent on institutional transfusion preferences and the coagulation monitoring method.[228] [229]
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. Pharmacologic agents known to alter hemostasis have also been investigated as adjunctive therapies. Aprotinin, epsilon-aminocaproic acid, tranexamic acid, and conjugated estrogen have all been studied in this context [230] [231] [232] [233] [234] [235] [236] ; however, these studies have produced somewhat conflicting results, partly because of study designs. One study even demonstrated improved hemodynamics with the administration of aprotinin.[244] Hence, the true efficacy of a drug can be determined only when the optimal treatment dosage (established through rigorous dose-finding studies) is used.[249] To compare the efficacy of different drugs, knowledge of the optimal dosage of each is necessary. Similarly, the safety profile of a drug also has to be taken into account. A dosage that maximally reduces blood loss and transfusion requirements during liver transplantation may also increase the risk of hepatic artery or portal vein thrombosis. Therefore, it is not surprising that there is no consensus on the use any of these hemostatic agents at liver transplant centers worldwide, despite promising studies.[249] Another drug, recombinant factor VIIa, has recently attracted significant attention for improving coagulopathy and reducing intraoperative blood loss.[250]
Recombinant factor VIIa was initially developed for patients with hemophilia and particularly for those unable to receive conventional therapy because of antibodies against factors VIII and IX. Recombinant factor VIIa increases thrombin generation in conjunction with activated platelets.[251] Several case reports, case series, and noncontrolled studies have demonstrated the potential usefulness of recombinant factor VIIa in the setting of liver transplantation. [243] [252] [253] As of today, however, no prospective randomized study in liver transplantation has been published that has investigated the potentially beneficial effect of recombinant factor VIIa. In view of the very high cost of the drug and the lack of scientific data at present, it can be recommended only for compassionate use in extreme situations.
As outlined earlier, liver transplantation can be divided into three stages: the 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
During the anhepatic stage, the new liver is implanted by either infracaval interposition or a piggyback technique. The choice of surgical technique has important anesthetic implications. During infracaval interposition,
Figure 56-4
A, With the use of a caval
interpositional technique immediately before the anhepatic phase, the suprahepatic
and 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 and infrahepatic
venae cavae 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 T-tube for drainage of the bile duct is not mandatory and is increasingly not
being performed. (From Hardy JD: Hardy's Textbook of Surgery, 2nd ed.
Philadelphia, JB Lippincott, 1988.)
Extensive research was conducted in the 1980s and 1990s to understand the advantages and disadvantages of VVBP, particularly after one group reported 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
Alternatively, a piggyback technique can be used. During this approach, the vena cava will be either partially or entirely occluded during the anhepatic phase. Although improved hemodynamics has been demonstrated (with partial occlusion) with this technique, it is considered surgically more difficult than caval interposition and may lead to greater technical complications.[261]
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 then completed in that order. The hepatic artery anastomosis can be performed before reperfusion or after restoration of blood flow ( Fig. 56-4B ). 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.[262] Reduced cardiac contractility,[263] arrhythmias, severe bradycardia, profound hypotension, and hyperkalemic arrest have all 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 to attenuate hemodynamic changes of the reperfusion syndrome.[264]
The physiologic perturbations seen in the immediate reperfusion phase are often described as reperfusion syndrome. The exact mechanism is not known and remains elusive.[265] Several factors alone or in combination are postulated to produce this hemodynamic instability: high potassium concentrations[266] in the preservative solution (UW solution),[267] donor demographics,[268] the surgical technique,[269] and decreased systemic vascular resistance.[270] 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.
During the reperfusion phase, the hepatic artery anastomosis is completed, the gallbladder (in liver grafts from cadaveric 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 Roux-en-Y choledochojejunostomy. Attention should be paid to the diagnosis and management of significant coagulopathy (dilution/consumption of clotting factors, platelet entrapment, endogenous heparinoid-like substances, primary fibrinolysis) and resultant bleeding. Laboratory analysis and surgical bleeding should guide management of the coagulopathy. The immediate function of the newly transplanted liver can be assessed by monitoring easily 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 appear to be associated with a significant increase in intensive care and hospital stay.[271]
Once 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 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.[272] A small group of patients
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 will admit patients to the ICU for close monitoring purposes. However, there have been 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. Interestingly, several studies have demonstrated that analgesic requirements in liver transplant patients are significantly decreased when compared with other major abdominal surgery.[279] [280] [281] In one study, the neuropeptide metenkephalin, which is involved in pain modulation, was shown to be significantly elevated in liver transplant patients when compared with the control population. The exact mechanism of this clinical observation remains unknown, and preoperative administration of large doses of steroids may play some role. 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/electrolytes, renal and liver function, and coagulation and the blood count is of great importance. Therapy is, in most cases, supportive and follows the guidelines established for all ICU patients. Certain aspects, however, require special attention. Patients occasionally need fresh frozen plasma therapy postoperatively to offset an initially "sluggish" liver function. Fresh frozen plasma requirements are also considered an indirect measure of postoperative liver function. The need for administering platelets or cryoprecipitate postoperatively is relatively low and reserved for selected cases. One should have a low threshold for re-exploration. Leakage from vascular anastomosis sites, or "bleeders," and diminished flow/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.
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. Hence, coagulation studies should be monitored carefully throughout the case and fresh frozen plasma 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. However, these patients have been receiving powerful immunosuppressive therapy, which leads to an increased risk for infectious complications, malignancy, drug toxicity, and adverse drug interaction. Hence, placement of intravenous, epidural catheters should be performed under absolute 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.
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