© Springer Science+Business Media New York 2017Kathirvel Subramaniam and Tetsuro Sakai (eds.)Anesthesia and Perioperative Care for Organ Transplantation10.1007/978-1-4939-6377-5_41
41. Anesthesia for Multivisceral Transplantation
Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, 33136, FL, USA
Department of Anesthesiology and Pain Medicine, University of Washington Medical Center, 1959 NE Pacific Street, Seattle, WA 98195, USA
KeywordsMultivisceral transplantationAnesthesiaPatient selectionTotal parenteral nutrition (TPN)Airway managementFluid management
Multivisceral transplantation has its roots in the “cluster of organs” concept developed by Dr. Starzl [1, 2]. According to this notion, intra-abdominal viscera resemble a cluster of grapes on a “grapevine,” wherein each individual grape is removable without disturbing the integrity of the vine itself. Thus, as long as the nutrient central stem of the celiac axis, superior mesenteric artery, superior mesenteric vein, and portal vein are preserved, various organs can be removed from the cluster, thereby customizing the transplanted organ complex to the recipient’s needs. Therefore, multiple combinations of transplanted organs—ranging from an isolated intestine to a large cluster containing the stomach, pancreas, duodenum, small and large intestine, liver, spleen, and kidneys—could be offered depending on the individual patient’s needs.
Intestinal transplantation is an adaptation of this concept to patients with isolated intestinal failure. Development of concomitant liver failure (such as secondary to total parenteral nutrition) might necessitate addition of a hepatic graft (i.e., intestinal and liver transplantation). Complications of severe portal hypertension, thrombosis of splanchnic arterial and/or portal circulation, and catastrophic pathology of the alimentary tract may require replacement of native dysfunctional units in the course of multivisceral transplantation. Profound disease of the alimentary tract such as locally aggressive nonmetastatic neoplasms, advanced gastrointestinal (GI) dysmotility disorders, severe trauma of the GI tract, multiple adhesions after prior surgery (especially if complicated by the development of enterocutaneous fistulas), or radiation enteritis affecting the pancreas and stomach may all require multivisceral transplantation [3, 4]. Concomitant chronic renal insufficiency and failure may require additional kidney transplantation, especially in the setting of frequent episodes of dehydration and the attendant renal toxicity of antimicrobial, antifungal, and immunosuppressive therapy.
Thus, intestinal transplant can be seen at the core of multivisceral transplantation. Inclusion of additional organ grafts usually reflects the individual patient’s pathophysiologic needs to replace dysfunctional and affected organs.
Even though Drs. Lillehei and Starzl developed a successful surgical technique more than 50 years ago, intestinal transplantation achieved practical recognition only with the advent of modern immunosuppressive therapy, namely, tacrolimus, in 1989 [4–6]. Refractory graft rejection and sepsis that befuddled prior attempts at intestinal transplantation were attributed to strong intestinal expression of histocompatibility tissue antigens, and the presence of numerous resident leukocytes and microorganisms. Fortuitously, inclusion of additional organ grafts, such as the liver and spleen, appeared to confer more tolerance [6, 7], an important benefit of multivisceral transplantation. Further technical benefits of multivisceral transplantation include its orthotopic nature, maintenance of minute vascular networks, and the replacement of the native stomach and pancreaticoduodenal complex affected by adhesions and portal hypertension. Lower risks of technical complications, such as biliary leaks and vessel thrombosis, make multivisceral transplantation the procedure of choice for children with extensive pathology in some centers .
Intestinal allograft has been described as the Achilles heel of multivisceral transplant.  The pivotal importance of intestinal engraftment and prevention of allograft rejection lead to the introduction of novel immunosuppressive/immunomodulatory regimens. Perioperative partial depletion of recipient lymphoid cells with antibody induced immunosuppression with monoclonal IL-α2 receptor blockers or polyclonal antilymphocyte agents was demonstrated to improve allograft tolerance, decrease the need for long-term post-transplant immunosuppression, moderate the frequency and severity of rejection and septic episodes, and contribute to improved patient and graft survival [4, 5].
With steady improvements of surgical and immunosuppression/immunomodulation techniques, multivisceral transplantation was increasingly viewed as a practical therapeutic option, particularly in patients with extensive portomesenteric and splenic venous thrombosis [5–7]. Out of 1859 intestinal transplants reported to United Network of Organ Sharing (UNOS) until 2009, 37 % were intestine-only, 24 % included the intestine and liver, and 30 % included the intestine, liver, and pancreas. One-, 5-, and 10-year graft survival rates were 62, 45, and 36 %, respectively, for the intestine and liver, and 69, 48, and 33 %, respectively, for intestine, liver, and pancreas transplantation . The longest survival of intestinal transplants was reported in recipients of combined intestinal and liver cadaveric transplants: 19 years in an adult and 18 years in a child.
Recipient age and transplantation in patients waiting at home as opposed to the hospital are associated with improved allograft and patient survival . These factors probably reflect the recipients’ functional status, and support the need for preemptive assessment in patients still tolerating parenteral nutrition. Additional factors contributing to longer allograft and patient survival include perioperative antibody induction immunosuppression with monoclonal IL-α2 receptor blockers or polyclonal antilymphocyte agents (such as antithymocyte globulin), and surgical center experience (at least 10 cases). Center experience has proven to be extremely heterogeneous, reflecting the complexity of the integrated medical care required for these patients. Around the world, the vast majority (83 %) of intestinal and multivisceral transplants were performed by ten centers (out of 61 programs in 19 countries). More than three quarters of these were performed in the United States . In the United Sates, out of a total of 43 programs, only 8 reported having performed 100 or more cases; the Miami Transplant Institute-Jackson Memorial Hospital, The Nebraska Medical Center, and the University of Pittsburgh Medical Center were reported as the most active United States centers, each performing more than 300 cases, and together contributing to half of all procedures worldwide .
Overview of the Surgical Aspects of Multivisceral Transplant
The intestine, liver, and pancreas with their intact donor circulation are retrieved simultaneously (“cluster of organs”) from the same donor. The duodenum and parts of the stomach may be retained in continuity with the graft jejunum to avoid biliary reconstruction. Frequently, the enteric and celiac ganglia are preserved to lessen postoperative graft dysmotility. The colonic segment may be included en bloc with the intestine in some cases [5, 7]. The graft is infused with University of Wisconsin (UW) solution in situ and is immersed in UW solution for transport; that safely preserves the grafts for approximately 10 h . If the recipient’s liver, pancreas, or spleen are to be retained, these organs are removed from the “cluster” so that the liver could be used in another recipient (modified multivisceral transplant).
Intestinal graft availability is significantly constrained by its high sensitivity to ischemia, particularly in brain-dead donors requiring vasoactive infusions, and by potential size mismatches between the donor and recipient . Consequently, waiting times for patients in need of intestinal, intestinal-liver, or multivisceral transplants have been long. To alleviate the problem of size mismatch, reduced-size allografts may be used, particularly in children , or plastic surgery techniques may be needed to close the abdomen. Alternatively, part of the abdominal wall and intact inferior epigastric vessels may be harvested en bloc with the iliac vessels  to be used to close abdominal wall defects, especially in patients whose abdominal wall was damaged by multiple prior surgeries.
The recipient procedure is conceptually and broadly divided into two phases: abdominal exenteration (resection of native organs) and graft implantation [2, 7]. Similar to liver transplantation, the latter is further subdivided into anhepatic, reperfusion, and reconstruction periods. The selection of native organs to be removed, particularly the liver and kidneys, is based not only on the primary pathological process, but also on the extent of alimentary tract dysfunction due to portal hypertension, abdominal sepsis, adhesions, and the effects of nephrotoxic medications, parenteral nutrition and associated hypovolemia and episodes of septicemia.
Recipient surgery usually commences with lysis of multiple adhesion upon entry into abdominal cavity. During abdominal exenteration of affected intra- and retroperitoneal organs, the celiac axis and superior mesenteric artery are clamped and divided early to achieve dearterialization. This greatly facilitates mobilization and resection of the native viscera; sometimes the entire foregut, including distal stomach, duodenum, proximal jejunum, liver, and spleen are removed en bloc.
If the native liver is retained and a modified multivisceral transplant is planned, the hepatic artery and its branches are carefully dissected and preserved, allowing nutrient arterial hepatic flow during the time of portal venous flow interruption. The common bile duct and arterial supply (including the gastroduodenal and splenic arteries) are divided and all organs to be removed are dearterialized.
Hepatectomy during multivisceral transplant could be performed conventionally, (i.e., en bloc with the inferior vena cava [IVC]), or using the “piggy-back” technique (i.e., stripping the liver from the retrohepatic vena cava, leaving the IVC intact, and mitigating the hemodynamic consequences of caval flow interruption). In the “piggy-back” technique, partial IVC clamp occlusion allows systemic blood return. Veno-venous bypass can be used to facilitate venous blood return from mesenteric, portal, and systemic lower body basins to the axillary vein in patients who cannot tolerate the loss of portal and IVC venous return. The great majority of multivisceral transplantation in the United States is performed without veno-venous bypass [5–7, 9]. In intestinal-liver transplants , a porto-caval shunt may be performed to facilitate venous drainage of the retained native organs.
During the anhepatic stage , the vascular targets for graft revascularization are prepared. Rearterialization of the composite graft is usually achieved from the recipient’s infrarenal aorta to the donor’s infrarenal aorta directly or by using an interposition graft. Venous drainage of the en bloc multivisceral transplantation is usually through the donor IVC or through a cuff of the hepatic vein to the host IVC. In a modified multivisceral transplant, venous drainage is created by anastomosis of the graft and host portal veins. Subsequently, the porto-caval shunt constructed earlier in the procedure may be taken down to facilitate blood flow to the liver graft. Thus, every effort is exerted to reconstruct graft vascular inflow, venous outflow, and exocrine drainage as close to normal as possible. However, the risks of porto-caval shunts disconnection and construction of porto-portal anastomoses may be substantial, and porto-caval shunts are frequently left in place without detriment to graft outcomes [5, 6, 9].
In preparation for reperfusion, the preservation solution is flushed out with sterile albumin and Lactated Ringer’s solution from the composite graft, particularly the liver, in an attempt to lessen the severity of hemodynamic changes and risk of collapse. Reperfusion usually commences with unclamping of the suprahepatic IVC, infrahepatic IVC, and portal vein, and ends with an aortic conduit. That is the time of the most significant hemodynamic and metabolic changes, discussed in more detail further.
The reconstruction period after multivisceral transplantation may be extensive and prolonged; remaining adhesions are taken down, and targets for restoring intestinal and biliary continuity are chosen. Sites of proximal anastomosis may include the stomach (gastrostomy), duodenum, or proximal native jejunum; distal targets may include the colon with diverting ileostomy, or creation of a permanent ileostomy in patients without a colon. Following gallbladder removal, Roux-en-Y choledochojejunostomy may be required for biliary continuity in patients with intestinal and liver transplantation; if the duodenum was retained en bloc in a composite graft, no biliary anastomosis may be required.
Closing of the abdominal cavity may be difficult for many reasons, such as size mismatch, loss of abdominal domain, and abdominal and graft swelling. Therefore, consideration is frequently given to the use of smaller than recipient donors, smaller grafts, and plastic surgery techniques. Additionally, cadaveric grafting of the abdominal wall with intact inferior epigastric vessels has been used successfully to facilitate abdominal closure, particularly in recipients whose abdominal wall has been damaged by multiple prior surgeries, fistulas, or trauma .
Physiologic Challenges: Special Considerations in Multivisceral Transplantation
As it is evident from this brief description, the procedure may be prolonged, associated with significant blood loss, metabolic abnormalities, temperature, fluid and electrolyte shifts, and coagulopathy. These challenges may be more difficult to overcome in malnourished and frequently dehydrated patients with significantly reduced physiologic reserves due to long-standing intestinal failure, complications of parenteral nutrition, and liver dysfunction. Prior episodes of central venous thrombosis with loss of central venous sites for cannulation, infections, abdominal sepsis, and renal insufficiency add to the complexity of perioperative care.
In the initial stage of surgery, in addition to the usual concerns related to multiple reentries into the abdominal cavity and lysis of adhesions, the exenteration of abdominal organs is itself associated with a rapid and progressive deterioration of systemic hemodynamics (cardiac preload and output), as well as derangements in oxygen, lactate, and glucose metabolism . Therefore, hemodynamic and metabolic compromise due to blood loss and fluid shifts during the dissection and pre-anhepatic stage is frequently exaggerated by shock-like “centralization” of diminished cardiac preload and output associated with exenteration.
The physiologic concerns during the anhepatic, reperfusion, and reconstruction phases are similar to those in liver transplantation , with the proviso that they are exaggerated by the poorer physiologic state of the recipients, larger fluid and electrolyte shifts, and by the increased complexity and duration of the procedure. Particularly worrisome is intestinal ischemia-reperfusion injury with severe graft edema, bacterial translocation, and hemodynamic shock due to production and release of multiple vasoactive and pro-inflammatory gut hormones [12, 13]. Cotemporaneous liver and intestinal reperfusion may lead to an increased severity of post-reperfusion syndrome.
The reconstruction period of the intestine and biliary complex is often longer than in liver transplantation alone, and may be associated with greater third-space losses and intestinal edema. This period may coincide with the phase of delayed ischemia-reperfusion reactions, such as neutrophil chemotaxis and late release of pro-inflammatory mediators. Indeed, pathological examination of intestinal grafts at the end of the transplantation suggests changes associated with ischemia-reperfusion injury . Concomitant hypothermia, acidosis, and hypoxia may potentiate intestinal mucosal swelling, bacterial translocation, and systemic release of pro-inflammatory molecules , which all result in a systemic inflammatory response and sepsis-like clinical presentation. Conversely, rapidly improving hemodynamic, metabolic, and coagulation parameters during the reconstruction period may indicate graft well-being and recovery [14, 15].
Anesthetic Considerations in Multivisceral Transplantation
The described pathophysiologic considerations underpin the anesthetic plan and preparations required for the perioperative care of patients undergoing multivisceral transplantation. The procedure will tax the severely diminished physiologic reserves of these patients. The ability of the patient’s cardiac and pulmonary systems to respond to severe perioperative stress and to maintain oxygen delivery and tissue oxygenation in face of a highly variable cardiac preload and afterload, hemoglobin concentration, and pulmonary resistance is paramount for survival. In addition to “anesthetizing” the patient, the anesthesiologist assumes the role of critical care specialist in a highly volatile intraoperative milieu. Assuring the safe conduct of anesthetic care, intraoperative life support, and critical care are complimentary priorities of the anesthesia team caring for patients undergoing multivisceral transplantation.
Patients presenting for multivisceral transplantation are typically critically ill, and frequently at the point of exhaustion of all available therapeutic options. Dehydration, central compartment contraction, ascites, pleural effusions and anasarca, hepatic dysfunction, portal hypertension and concomitant renal insufficiency all profoundly affect the pharmacodynamics and pharmacokinetics of perioperatively administered medications [16, 17]. Intestinal insufficiency impairs the absorption of oral medications. Hepatic dysfunction due to paucity and diminished activity of hepatocytes reduced liver flow, and porto-caval shunting markedly decreases hepatic clearance, while impaired secretion of bile acids, bilirubin, and organic anions impair biliary excretion of medications. Low serum concentrations and qualitative changes in albumin and α1-acid glycoproteins (due to malnutrition and impaired synthesis) lead to reduced plasma protein binding of circulating medications. An increased serum bilirubin concentration may further impair plasma protein binding of circulating medications. The presence of ascites in the context of low protein binding results in a large volume of distribution. Similarly, a low muscle mass and reduced metabolism of creatine to creatinine may render calculated creatinine clearance rates inaccurate, and lead to an under-appreciation of renal insufficiency and to a significant overestimation of glomerular filtration rate  and renal elimination of intravenously administered medications, such as antibiotics. Overall, some of the most important effects reported include decreased therapeutic efficacy of loop diuretics, and significantly increased patient sensitivity to the central effects of analgesics, opioids, anxiolytics, and sedatives.
Nonpharmacodynamic epiphenomena may influence the patient’s clinical responsiveness to medications as well. For example, the presence of encephalopathy significantly potentiates the central nervous system effects of opioids and sedatives, presumably due to accumulation of endogenous nonbenzodiazepine GABAA receptor ligands. Diminished response to β-antagonists may be directly related to the degree of liver dysfunction and hyperdynamic pattern of circulation in patients with liver cirrhosis . Additionally, variable hepatopetal blood flow during the initial dissection, coupled with blood loss, transfusions, large intraoperative fluid shifts, absence of hepatic metabolism during the anhepatic stage, and uncertain graft recovery during reconstruction, all compound the complexity of multivisceral transplantation pharmacokinetics.