So far, we have used only 3 interposition vessel grafts for hepatic artery reconstruction, namely one right gastric vein graft (Uchiyama et al., 2007), one splenic artery graft and one superior rectal artery graft. The right gastric vein graft was used to fill a gap between the graft artery and the recipient inflow artery. The Y-shaped splenic artery graft was used to reconstruct two graft arteries from one inflow artery. The superior rectal artery graft was used to taper the caliber of a large recipient inflow artery. Because the use of an interposition graft necessitates at least two anastomoses, which may increase the rate of hepatic artery complications, it should be considered a last resort for hepatic artery

In preparing the recipient arteries, the outer surrounding tissue around the recipient

Recipients with end-stage liver disease often have dense nerve fibers and lymphatic vessels around the hepatic arteries. These fibers and vessels are obstacles for hepatic artery

candidate hepatic arteries has to be meticulously removed (Fig. 8).

reconstruction and should be removed. Adequate blood flow is confirmed by releasing the proximal forceps.

Fig. 8. Preparation of the recipient hepatic artery. (A) The outer surrounding tissue is removed from the recipient hepatic artery. (B) Sometimes, nerve fibers are firmly attached to the artery. These are dissected from the artery and divided. (C) After the proximal portion of the artery is clamped, the distal end of the artery is cut open. (D) The intact arterial flow is confirmed by temporary declamping of the artery, and the recipient artery is ready to be anastomosed

Fig. 9. Hepatic artery reconstruction using a double-clip. (A) After removal of the outer connective tissue surrounding both the donor and recipient arteries, these are secured by a double-clip. Angle stitches (8-0 or 9-0 non-absorbable sutures) are placed on both edges of the arteries. (B) After the clips are moved inward so that both arteries are attached to each other, the angle stitches are tied. (C) Several stitches (usually 4 or 5 stitches) are placed between the angle stitches. The number of stitches is determined according to the diameter of the arteries. These stitches are left untied until all stitches are placed, because it is easier to place each stitch correctly before they are tied, which is called the untied suture technique (Harashina, 1977). (D) These stitches are tied one-by-one. Then, the double-clip is turned over. (E, F) Several stitches are placed on the other side of the arteries in the same manner

Microvascular Hepatic Artery Reconstruction in Living Donor Liver Transplantation 75

Sometimes, surgeons encounter a situation where a double-clip cannot grasp the arteries to be anastomosed because of the stiffness of the arteries or because the stump is too short. In such situations, hepatic arteries are reconstructed using two tension stitches placed at the 6

Daily Doppler ultrasound should be performed to check for intact hepatic arterial flows for 7 days after transplantation (Fig. 11). We use neither anti-coagulant nor anti-platelet agents for the purpose of preventing hepatic artery thrombosis. Current Doppler ultrasound machines are so accurate (Kaneko et al., 2004) that they rarely give false positive results (good pulsatile hepatic arterial flows in the graft are detected even when there is a hepatic arterial problem). Whenever there is no pulsatile hepatic arterial flow on Doppler ultrasonography, the patient should immediately undergo contrast-enhanced CT. If there is a suspicion of hepatic artery complications, invasive angiography should be performed, and any attempts to restore the hepatic arterial flow into the graft need to be made within

With regard to repairing hepatic artery complications, our first choice is surgical revision of the HA anastomosis, although there have been some reports regarding non-surgical interventional therapy or retransplantation (Maleux et al., 2005; Kodama et al., 2006;

Fig. 11. Doppler ultrasonography is used to detect the intact hepatic arterial flow in the graft

So far, we have experienced 6 hepatic artery complications (Table 3, Fig. 12). Most of them

**7. Hepatic artery complications after living donor liver transplantation**

several hours, or devastating consequences (graft failure, sepsis, etc.) will occur.

**5.2 Hepatic artery anastomosis without a double-clip**

o'clock and 12 o'clock positions (Fig. 10).

**6. Posttransplant management**

Fistouris et al., 2006).

liver

occurred in our early experience.

#### **5. Hepatic artery anastomosis**

After the preparation of both the donor and recipient hepatic arteries is complete, then the final step is to actually reconstruct the graft hepatic arteries. When considering the hemodynamics of the arterial flow, a direct end-to-end anastomosis is the preferred mode of reconstruction. All hepatic artery reconstructions we experienced were done by a direct endto-end anastomosis. A size-discrepancy up to 2 times is usually acceptable. However, anastomosing so large a recipient artery to a thin graft artery may lead to a rupture of the anastomosis. In such cases, another recipient artery should be selected. So far, we have never experienced a case that required end-to-side anastomosis.

#### **5.1 Hepatic artery anastomosis using a double-clip**

We prefer to use a disposable double-clip for performing anastomosis (Fig. 9). The desired grasp force is 45 to 60 grams. By fixing both the graft and recipient arteries, excessive forces at the anastomosis can be avoided.

Fig. 10. Hepatic artery reconstruction without a double-clip. (A) After removal of the outer connective tissue surrounding both the donor and recipient arteries, angle stitches are placed on the 6 o'clock and the 12 o'clock positions. (B) After the angle stitches are tied, these stitches are pulled in opposite directions using light clamps so that the arterial walls between the angle stitches are held horizontal with appropriate tension. (C) Several stitches (usually 4 or 5 stitches) are placed between the angle stitches. The number of stitches is determined according to the diameter of the arteries. These stitches are left untied until all stitches are placed, because it is easier to place each stitch correctly before they are tied, which is called the untied suture technique (Harashina, 1977). (D) These stitches are tied one-by-one. The arteries being anastomosed are turned over by pulling each angle stitch in the opposite direction. (E, F) Several stitches are placed on the other side of the arteries in the same manner

#### **5.2 Hepatic artery anastomosis without a double-clip**

Sometimes, surgeons encounter a situation where a double-clip cannot grasp the arteries to be anastomosed because of the stiffness of the arteries or because the stump is too short. In such situations, hepatic arteries are reconstructed using two tension stitches placed at the 6 o'clock and 12 o'clock positions (Fig. 10).

#### **6. Posttransplant management**

74 Liver Transplantation – Technical Issues and Complications

After the preparation of both the donor and recipient hepatic arteries is complete, then the final step is to actually reconstruct the graft hepatic arteries. When considering the hemodynamics of the arterial flow, a direct end-to-end anastomosis is the preferred mode of reconstruction. All hepatic artery reconstructions we experienced were done by a direct endto-end anastomosis. A size-discrepancy up to 2 times is usually acceptable. However, anastomosing so large a recipient artery to a thin graft artery may lead to a rupture of the anastomosis. In such cases, another recipient artery should be selected. So far, we have

We prefer to use a disposable double-clip for performing anastomosis (Fig. 9). The desired grasp force is 45 to 60 grams. By fixing both the graft and recipient arteries, excessive forces

Fig. 10. Hepatic artery reconstruction without a double-clip. (A) After removal of the outer connective tissue surrounding both the donor and recipient arteries, angle stitches are placed on the 6 o'clock and the 12 o'clock positions. (B) After the angle stitches are tied, these stitches are pulled in opposite directions using light clamps so that the arterial walls between the angle stitches are held horizontal with appropriate tension. (C) Several stitches (usually 4 or 5 stitches) are placed between the angle stitches. The number of stitches is determined according to the diameter of the arteries. These stitches are left untied until all stitches are placed, because it is easier to place each stitch correctly before they are tied, which is called the untied suture technique (Harashina, 1977). (D) These stitches are tied one-by-one. The arteries being anastomosed are turned over by pulling each angle stitch in the opposite direction. (E, F) Several stitches are placed on the other side of the arteries in

never experienced a case that required end-to-side anastomosis.

**5.1 Hepatic artery anastomosis using a double-clip**

**5. Hepatic artery anastomosis**

at the anastomosis can be avoided.

the same manner

Daily Doppler ultrasound should be performed to check for intact hepatic arterial flows for 7 days after transplantation (Fig. 11). We use neither anti-coagulant nor anti-platelet agents for the purpose of preventing hepatic artery thrombosis. Current Doppler ultrasound machines are so accurate (Kaneko et al., 2004) that they rarely give false positive results (good pulsatile hepatic arterial flows in the graft are detected even when there is a hepatic arterial problem). Whenever there is no pulsatile hepatic arterial flow on Doppler ultrasonography, the patient should immediately undergo contrast-enhanced CT. If there is a suspicion of hepatic artery complications, invasive angiography should be performed, and any attempts to restore the hepatic arterial flow into the graft need to be made within several hours, or devastating consequences (graft failure, sepsis, etc.) will occur.

With regard to repairing hepatic artery complications, our first choice is surgical revision of the HA anastomosis, although there have been some reports regarding non-surgical interventional therapy or retransplantation (Maleux et al., 2005; Kodama et al., 2006; Fistouris et al., 2006).

Fig. 11. Doppler ultrasonography is used to detect the intact hepatic arterial flow in the graft liver

#### **7. Hepatic artery complications after living donor liver transplantation**

So far, we have experienced 6 hepatic artery complications (Table 3, Fig. 12). Most of them occurred in our early experience.

Microvascular Hepatic Artery Reconstruction in Living Donor Liver Transplantation 77

Table 3. The hepatic artery complications in our series

Fig. 12. The hepatic artery-related complication rate in our series

Patient #17 underwent an auxiliary partial orthotopic LDLT. The case was previously reported as a case report (Uchiyama et al., 2007). The left hepatic graft had a single left hepatic artery, which was reconstructed using the right gastric artery interposed by the right gastric vein graft. There was a restriction on the use of recipient inflow arteries because the native residual liver also had to receive arterial inflows. The patient underwent a follow-up CT examination at 4 years after the LDLT without any symptoms, and an aneurysm at the vein graft was found incidentally. Six months later, the patient underwent a follow-up CT examination again, and the aneurysm was found to be growing. We performed an aneurysm resection and hepatic artery re-reconstruction using the right gastroepiploic artery. The patient is now alive and still doing well at 12 years and 3 months posttransplant.

Patient #18 suffered refractory anastomotic bile leakage after the first LDLT and had to undergo repeated drainage tube insertions to drain infected biloma. On posttransplant day 28, the serous transaminases were steeply elevated and the pulsatile hepatic arterial flows disappeared on Doppler ultrasonography. Emergency angiography was performed which revealed that there was no hepatic artery inflow into the hepatic graft. Although we tried to re-reconstruct the hepatic artery, the tissues around the hepatic hilum had become very fragile because of the infected biloma and we could not perform hepatic artery rereconstruction. The patient underwent re-LDLT and is still alive at 12 years and 2 months posttransplant.

Patient #39 experienced an unstable clinical course after LDLT, in which hypotension, atrial fibrillation, and oliguria persisted. On posttransplant day 7, the serum transaminases were steeply elevated and no pulsatile arterial flows in the hepatic graft could be detected. Emergency angiography revealed that there was a hepatic artery thrombosis at the anastomosis. An emergency operation was performed to restore the hepatic arterial flows into the graft. The thrombus partially extended into the graft from the origin at the anastomosis. After the thrombus was removed from the graft hepatic artery as much as possible, the arterial re-reconstruction was accomplished using the recipient gastroduodenal artery. Nevertheless, the patient died of multiple organ failure with intact hepatic arterial flows on postransplant day 10.

Patient #73 received a right hepatic graft and the right hepatic artery was anastomosed to the right hepatic artery of the recipient. On posttransplant day 7, the pulsatile flows on Doppler ultrasonography were shown to be weakened, and emergency angiography revealed there was an arterial wall dissection which extended 3 cm proximally from the anastomosis. The dissected wall was resected, and the graft hepatic artery was rereconstructed using the left gastric artery.

Patient #203 received a right hepatic graft with two hepatic arterial stumps. The main right hepatic artery and the accessory A6 artery were each reconstructed using the anterior branch of the right hepatic artery and the posterior branch of the posterior branch of the right hepatic artery, respectively. This was an ABO-incompatible case, and a cannulation tube was inserted into the hepatic artery for local graft infusion therapy (Egawa et al., 2008), which was considered to have caused the later hepatic artery complication. On the posttransplant day 10, the pulsatile flows on Doppler ultrasonography were shown to be weakened, and emergency angiography revealed there was an arterial wall dissection which extended proximally from the anastomosis with intact A6 arterial flow. We considered that

Patient #17 underwent an auxiliary partial orthotopic LDLT. The case was previously reported as a case report (Uchiyama et al., 2007). The left hepatic graft had a single left hepatic artery, which was reconstructed using the right gastric artery interposed by the right gastric vein graft. There was a restriction on the use of recipient inflow arteries because the native residual liver also had to receive arterial inflows. The patient underwent a follow-up CT examination at 4 years after the LDLT without any symptoms, and an aneurysm at the vein graft was found incidentally. Six months later, the patient underwent a follow-up CT examination again, and the aneurysm was found to be growing. We performed an aneurysm resection and hepatic artery re-reconstruction using the right gastroepiploic artery. The patient is now alive and still doing well at 12 years and 3 months post-

Patient #18 suffered refractory anastomotic bile leakage after the first LDLT and had to undergo repeated drainage tube insertions to drain infected biloma. On posttransplant day 28, the serous transaminases were steeply elevated and the pulsatile hepatic arterial flows disappeared on Doppler ultrasonography. Emergency angiography was performed which revealed that there was no hepatic artery inflow into the hepatic graft. Although we tried to re-reconstruct the hepatic artery, the tissues around the hepatic hilum had become very fragile because of the infected biloma and we could not perform hepatic artery rereconstruction. The patient underwent re-LDLT and is still alive at 12 years and 2 months

Patient #39 experienced an unstable clinical course after LDLT, in which hypotension, atrial fibrillation, and oliguria persisted. On posttransplant day 7, the serum transaminases were steeply elevated and no pulsatile arterial flows in the hepatic graft could be detected. Emergency angiography revealed that there was a hepatic artery thrombosis at the anastomosis. An emergency operation was performed to restore the hepatic arterial flows into the graft. The thrombus partially extended into the graft from the origin at the anastomosis. After the thrombus was removed from the graft hepatic artery as much as possible, the arterial re-reconstruction was accomplished using the recipient gastroduodenal artery. Nevertheless, the patient died of multiple organ failure with intact hepatic arterial

Patient #73 received a right hepatic graft and the right hepatic artery was anastomosed to the right hepatic artery of the recipient. On posttransplant day 7, the pulsatile flows on Doppler ultrasonography were shown to be weakened, and emergency angiography revealed there was an arterial wall dissection which extended 3 cm proximally from the anastomosis. The dissected wall was resected, and the graft hepatic artery was re-

Patient #203 received a right hepatic graft with two hepatic arterial stumps. The main right hepatic artery and the accessory A6 artery were each reconstructed using the anterior branch of the right hepatic artery and the posterior branch of the posterior branch of the right hepatic artery, respectively. This was an ABO-incompatible case, and a cannulation tube was inserted into the hepatic artery for local graft infusion therapy (Egawa et al., 2008), which was considered to have caused the later hepatic artery complication. On the posttransplant day 10, the pulsatile flows on Doppler ultrasonography were shown to be weakened, and emergency angiography revealed there was an arterial wall dissection which extended proximally from the anastomosis with intact A6 arterial flow. We considered that

transplant.

posttransplant.

flows on postransplant day 10.

reconstructed using the left gastric artery.

Table 3. The hepatic artery complications in our series

Fig. 12. The hepatic artery-related complication rate in our series

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this tiny A6 artery could not sustain the right hepatic graft, and a reoperation was performed. The dissected wall was resected, and the graft main right hepatic artery was rereconstructed using the recipient right gastroepiploic artery.

Patient #292 received a left lobe graft with two graft hepatic arteries. The graft replaced left hepatic artery and the graft middle hepatic artery were anastomosed to the recipient left hepatic artery and the recipient middle hepatic artery, respectively. The patient was incidentally found to have an aneurysm at the anastomosis between the graft replaced left hepatic artery and the recipient left hepatic artery. The aneurysm was resected and the graft replaced left hepatic artery was re-reconstructed.

#### **8. Conclusion**

With the technical advances made in hepatic artery reconstruction, plus our experience with the procedures, we have not recently encountered any hepatic artery-related complications. Although mastering microvascular surgical techniques is time-consuming, we think that this is the most reliable procedure for hepatic artery reconstruction, especially in LDLT for small recipients. The next issue that must be addressed is how to securely pass these techniques to the next generation.

#### **9. References**

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Patient #292 received a left lobe graft with two graft hepatic arteries. The graft replaced left hepatic artery and the graft middle hepatic artery were anastomosed to the recipient left hepatic artery and the recipient middle hepatic artery, respectively. The patient was incidentally found to have an aneurysm at the anastomosis between the graft replaced left hepatic artery and the recipient left hepatic artery. The aneurysm was resected and the graft

With the technical advances made in hepatic artery reconstruction, plus our experience with the procedures, we have not recently encountered any hepatic artery-related complications. Although mastering microvascular surgical techniques is time-consuming, we think that this is the most reliable procedure for hepatic artery reconstruction, especially in LDLT for small recipients. The next issue that must be addressed is how to securely pass these techniques to

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**8. Conclusion**

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**4**

*Japan*

**Small-for-Size Syndrome After**

*Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine,*

*Dentistry and Pharmaceutical Sciences*

**Living Donor Liver Transplantation**

Yuzo Umeda, Takahito Yagi, Hiroshi Sadamori and Toshiyoshi Fujiwara

Patients scheduled for liver transplantation frequently have portal hypertension and consequently they are likely to have a high portal blood flow in the transplanted graft. When the graft volume is small in adult living donor liver transplantation with partial liver transplantation, various problems that may affect the prognosis often occur because the partial graft cannot sustain excessive portal blood perfusion. It is widely known that liver transplant recipients can potentially develop a specific syndrome known as "small-for-size syndrome", when a small for size graft causes size mismatch in the presence of portal hypertension. The small-for-size syndrome can result in large-volume ascites, hyperbilirubinemia, and coagulopathy. The pathologic mechanism of small-for-size syndrome includes graft failure caused by excessive and destructive portal inflow into the small for size graft. The small-for-size syndrome is widely recognized by transplant surgeon as one of the important post-transplant events. Thus, sufficient graft volume is one of the important determinants of successful transplant and clinically satisfactory outcome. Particularly in the case of living donor liver transplantation, there is the added problem of insufficient donor pool and donor safety, but it is essential to maintain graft function under the given circumstances. The decision on the type of liver graft depends on various factors, such as recipients' status and donor safety: a small for size graft tends to be selected due to problems related to donor selection and to ensure the safety of the donor. In this regard, many centers stipulate the absolute lack of various pre-transplant risk factors and a minimal

graft size in order to prevent the development of this syndrome and good outcome.

Small-for-size syndrome can occur in the special situation of partial liver graft transplantation, especially in adult living donor liver transplantation, with resultant size mismatching between graft size and recipient hepato-portal circulation. Once the partial liver volume graft is subjected to excessive portal inflow, portal hyperperfusion results in the development of the small-for-size syndrome. The basic pathophysiology in this syndrome relates to graft injury after transplantation, which is caused by graft size mismatch and portal hypertension, followed by the appearance of various clinical

**2. Pathophysiological mechanisms of small-for-size syndrome**

**1. Introduction**

### **Small-for-Size Syndrome After Living Donor Liver Transplantation**

Yuzo Umeda, Takahito Yagi, Hiroshi Sadamori and Toshiyoshi Fujiwara *Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Japan*

#### **1. Introduction**

82 Liver Transplantation – Technical Issues and Complications

Wang, C.C., Lin, T.S., Chen, C.L., Concejero, A.M., Iyer, S.G. & Chiang, Y.C. (2008) Arterial

transplantation using gastric vessels. Surgery Vol. 143(No. 5): 686-690. Wei, W.I., Lam, L.K., Ng, R.W., Liu, C.L., Lo, C.M., Fan, S.T. & Wong, J. (2004)

reconstruction in hepatic artery occlusions in adult living donor liver

Microvascular reconstruction of the hepatic artery in live donor liver transplantation: experience across a decade. Arch Surg Vol. 139(No. 3): 304-307.

> Patients scheduled for liver transplantation frequently have portal hypertension and consequently they are likely to have a high portal blood flow in the transplanted graft. When the graft volume is small in adult living donor liver transplantation with partial liver transplantation, various problems that may affect the prognosis often occur because the partial graft cannot sustain excessive portal blood perfusion. It is widely known that liver transplant recipients can potentially develop a specific syndrome known as "small-for-size syndrome", when a small for size graft causes size mismatch in the presence of portal hypertension. The small-for-size syndrome can result in large-volume ascites, hyperbilirubinemia, and coagulopathy. The pathologic mechanism of small-for-size syndrome includes graft failure caused by excessive and destructive portal inflow into the small for size graft. The small-for-size syndrome is widely recognized by transplant surgeon as one of the important post-transplant events. Thus, sufficient graft volume is one of the important determinants of successful transplant and clinically satisfactory outcome. Particularly in the case of living donor liver transplantation, there is the added problem of insufficient donor pool and donor safety, but it is essential to maintain graft function under the given circumstances. The decision on the type of liver graft depends on various factors, such as recipients' status and donor safety: a small for size graft tends to be selected due to problems related to donor selection and to ensure the safety of the donor. In this regard, many centers stipulate the absolute lack of various pre-transplant risk factors and a minimal graft size in order to prevent the development of this syndrome and good outcome.

#### **2. Pathophysiological mechanisms of small-for-size syndrome**

Small-for-size syndrome can occur in the special situation of partial liver graft transplantation, especially in adult living donor liver transplantation, with resultant size mismatching between graft size and recipient hepato-portal circulation. Once the partial liver volume graft is subjected to excessive portal inflow, portal hyperperfusion results in the development of the small-for-size syndrome. The basic pathophysiology in this syndrome relates to graft injury after transplantation, which is caused by graft size mismatch and portal hypertension, followed by the appearance of various clinical

Small-for-Size Liver Graft Syndrome After Living Donor Liver Transplantation 85

Furthermore, accumulation of oxygen free radicals in the graft could possibly contribute to

The most important step is prevention of small-for-size syndrome through perioperative treatment strategies that include approaches aimed at reducing excessive portal inflow as the major cause of small-for-size syndrome, and lowering the graft perfusion pressure. Furthermore, efforts should be made to prevent hepatic venous congestion due to

An important factor in determining portal inflow volume and pressure is the blood perfusion level in the spleen, thus highlighting the benefits of splenectomy and ligation of the splenic artery. However, patients with end-stage hepatic failure exhibit a hyperdynamic state of splanchnic blood flow, compared with normal state, and are at increased risk of hemorrhage associated with seriously invasive surgical procedures. Thus, careful attention should be paid to the expansion of the dissection area during surgery, especially in patients with collateral circulation around the splenic artery, such as gastric coronary vein and spleno-renal shunt. However, the development of new surgical technique and advances in medical devices have allowed a reduction in blood loss during surgical dissection procedures and splenectomy. Although the invasiveness of surgical procedure such as splenectomy and splenic artery ligation could be diminished further, adverse events such as increased susceptibility to infection caused by low immunity and portal vein thrombosis, may occur after splenectomy. Thus, patients should be carefully

Portosystemic shunt is currently considered an efficacious procedure in the treatment of portal hypertension. Especially adequate portosystemic shunt, which achieves favorable portal decompression to below 15 mmHg, could dramatically improve the post-transplant prognosis of patients with small for size graft. The procedure has allowed lowering the cutoff value for graft weight-to-recipient body weight ratio from 0.8% to 0.6%. This procedure is anticipated to become the main strategy in the future to prevent the development of the small-for-size syndrome. However, the separation of the graft portal route, as seen in portosystemic shunt, may result in portal steal to the extrahepatic route, which sometimes leads to fatal events especially in cases with decreased graft portal vascular compliance, such as the case of steatotic liver graft or accute cellular rejection. Based on this potential complication, some centers have adopted certain precautionary measures against such

The recently introduced approach of splenic artery embolization could be an effective procedure for portal decompression instead of the conventional treatment. Splenic artery embolization is described by some investigators as a rescue treatment for post-transplant small-for-size syndrome. In this regard, we previously reported that preoperative portal decompression by splenic artery embolization efficaciously reduced blood loss during operation and shortened the operating time, and that it contributed to favorable prognosis without serious complications related to the procedure itself. In our institution, preoperative embolization is selected for patients considered at risk of development of shunt in the peri-celiac trunk. The risk assessment is based on preoperative radiography showing possible problems with safety of splenic artery ligation. In each patient scheduled

**3. Treatment strategy for small-for-size syndrome**

insufficient vascular orifices or mechanical stenosis and kinking.

selected for splenectomy and splenic artery ligation.

complications using modifications of the shunt closing technique.

graft dysfunction.

abnormalities such as excessive ascites, hyperbilirubinemia, coagulopathy, encephalopathy, and renal dysfunction. Transplant recipients develop symptoms related to the above abnormalities after transplantation and post-transplant prognosis is reported to be less than ideal.

To understand the pathophysiological mechanism of the small-for-size syndrome, several studies examined post-transplant biopsies. These studies reported histopathological evidence of mechanical injury and graft failure caused by destructive portal hyperperfusion. The main histopathological findings are: (1) Portal vein and periportal sinusoidal endothelial denudation and focal hemorrhage into the portal tract connective tissue; and (2) poor arterial flow and vasospasm, resulting in ischemic cholangitis and parenchymal infarct. Furthermore, electron microscopic examination showed sinusoidal congestion, excessive swelling of the mitochondria in hepatocytes, irregular large gaps of sinusoidal lining cells, and collapse of the space of Disse. These findings are considered to represent progressive damage of the graft resulting from microcirculatory failure due to irreversible endothelial injury after reperfusion. On the other hand, other studies examined the molecular basis of graft damage by analyzing intragraft gene expression. The results of these studies provided evidence for sinusoidal damage. Cases of small-for-size syndrome and associated graft dysfunction due to portal hyperperfusion, showed intragraft upregulation of endothelin-1 and down regulation of heme-oxigenase-1 and heat shock protein-70. Others showed low portal venous plasma nitric oxide levels. In addition, experimental studies using animal models of the small-for-size syndrome showed intragraft over-expression of endothelin-1, early growth response -1 (Egr-1) and endotherin-1A receptor and significant changes in intragraft mRNA levels as well as plasma levels of inflammatory cytokines (interleukin [IL]- 6, IL-15, tumor necrosis factor [TNF]-alpha). Furthermore, the small for size isografts and allografts, with volumes measuring 50% or 30% of the liver graft volume, demonstrated higher expression levels of vascular endothelial growth factor (VEGF) and fetal liver kinase (Flk)-1 than the whole isograft and allograft. In addition, Flk-1-positive activated macrophages were also detected in small for size isografts and allografts, which were probably induced by VEGF. In this regard, the expression of VEGF and its interaction with Flk-1 could mediate the inflammatory response, early activation of macrophages. Thus, the above changes in the small for size graft injury likely play important roles in the accelerated acute rejection process of the small for size allograft.

Previous studies indicated that liver regeneration begins in the early period after partial liver transplantation. Although the detailed mechanism remains unknown at present, the high portal flow rate and high portal pressure are considered important triggers of liver regeneration. In partial liver transplantation, a high level of liver regeneration is observed when the graft size is small, or when portal pressure is high in cirrhotic patients. On the other hand, liver tissue damage and ischemic reperfusion injury caused by high portal pressure in small-for-size syndrome result in serious interference with the process of liver regeneration. Interestingly, IL-6 and TNF-alpha play key roles in liver regeneration, though they are also considered to represent markers of acute-phase tissue damage. Local activation and excessive production of these cytokines is associated with poor liver regeneration, since they can act as negative regulators of cell proliferation. In fact, TNF-alpha could trigger the cell death pathway after binding to the TNF-receptor. Thus, although the role of these cytokines remains controversial, they are considered to function as inflammatory cytokines, rather than as liver regenerative factors, in patients with small-for-size syndrome. Furthermore, accumulation of oxygen free radicals in the graft could possibly contribute to graft dysfunction.

#### **3. Treatment strategy for small-for-size syndrome**

84 Liver Transplantation – Technical Issues and Complications

abnormalities such as excessive ascites, hyperbilirubinemia, coagulopathy, encephalopathy, and renal dysfunction. Transplant recipients develop symptoms related to the above abnormalities after transplantation and post-transplant prognosis is reported to be less than

To understand the pathophysiological mechanism of the small-for-size syndrome, several studies examined post-transplant biopsies. These studies reported histopathological evidence of mechanical injury and graft failure caused by destructive portal hyperperfusion. The main histopathological findings are: (1) Portal vein and periportal sinusoidal endothelial denudation and focal hemorrhage into the portal tract connective tissue; and (2) poor arterial flow and vasospasm, resulting in ischemic cholangitis and parenchymal infarct. Furthermore, electron microscopic examination showed sinusoidal congestion, excessive swelling of the mitochondria in hepatocytes, irregular large gaps of sinusoidal lining cells, and collapse of the space of Disse. These findings are considered to represent progressive damage of the graft resulting from microcirculatory failure due to irreversible endothelial injury after reperfusion. On the other hand, other studies examined the molecular basis of graft damage by analyzing intragraft gene expression. The results of these studies provided evidence for sinusoidal damage. Cases of small-for-size syndrome and associated graft dysfunction due to portal hyperperfusion, showed intragraft upregulation of endothelin-1 and down regulation of heme-oxigenase-1 and heat shock protein-70. Others showed low portal venous plasma nitric oxide levels. In addition, experimental studies using animal models of the small-for-size syndrome showed intragraft over-expression of endothelin-1, early growth response -1 (Egr-1) and endotherin-1A receptor and significant changes in intragraft mRNA levels as well as plasma levels of inflammatory cytokines (interleukin [IL]- 6, IL-15, tumor necrosis factor [TNF]-alpha). Furthermore, the small for size isografts and allografts, with volumes measuring 50% or 30% of the liver graft volume, demonstrated higher expression levels of vascular endothelial growth factor (VEGF) and fetal liver kinase (Flk)-1 than the whole isograft and allograft. In addition, Flk-1-positive activated macrophages were also detected in small for size isografts and allografts, which were probably induced by VEGF. In this regard, the expression of VEGF and its interaction with Flk-1 could mediate the inflammatory response, early activation of macrophages. Thus, the above changes in the small for size graft injury likely play important roles in the accelerated

Previous studies indicated that liver regeneration begins in the early period after partial liver transplantation. Although the detailed mechanism remains unknown at present, the high portal flow rate and high portal pressure are considered important triggers of liver regeneration. In partial liver transplantation, a high level of liver regeneration is observed when the graft size is small, or when portal pressure is high in cirrhotic patients. On the other hand, liver tissue damage and ischemic reperfusion injury caused by high portal pressure in small-for-size syndrome result in serious interference with the process of liver regeneration. Interestingly, IL-6 and TNF-alpha play key roles in liver regeneration, though they are also considered to represent markers of acute-phase tissue damage. Local activation and excessive production of these cytokines is associated with poor liver regeneration, since they can act as negative regulators of cell proliferation. In fact, TNF-alpha could trigger the cell death pathway after binding to the TNF-receptor. Thus, although the role of these cytokines remains controversial, they are considered to function as inflammatory cytokines, rather than as liver regenerative factors, in patients with small-for-size syndrome.

acute rejection process of the small for size allograft.

ideal.

The most important step is prevention of small-for-size syndrome through perioperative treatment strategies that include approaches aimed at reducing excessive portal inflow as the major cause of small-for-size syndrome, and lowering the graft perfusion pressure. Furthermore, efforts should be made to prevent hepatic venous congestion due to insufficient vascular orifices or mechanical stenosis and kinking.

An important factor in determining portal inflow volume and pressure is the blood perfusion level in the spleen, thus highlighting the benefits of splenectomy and ligation of the splenic artery. However, patients with end-stage hepatic failure exhibit a hyperdynamic state of splanchnic blood flow, compared with normal state, and are at increased risk of hemorrhage associated with seriously invasive surgical procedures. Thus, careful attention should be paid to the expansion of the dissection area during surgery, especially in patients with collateral circulation around the splenic artery, such as gastric coronary vein and spleno-renal shunt. However, the development of new surgical technique and advances in medical devices have allowed a reduction in blood loss during surgical dissection procedures and splenectomy. Although the invasiveness of surgical procedure such as splenectomy and splenic artery ligation could be diminished further, adverse events such as increased susceptibility to infection caused by low immunity and portal vein thrombosis, may occur after splenectomy. Thus, patients should be carefully selected for splenectomy and splenic artery ligation.

Portosystemic shunt is currently considered an efficacious procedure in the treatment of portal hypertension. Especially adequate portosystemic shunt, which achieves favorable portal decompression to below 15 mmHg, could dramatically improve the post-transplant prognosis of patients with small for size graft. The procedure has allowed lowering the cutoff value for graft weight-to-recipient body weight ratio from 0.8% to 0.6%. This procedure is anticipated to become the main strategy in the future to prevent the development of the small-for-size syndrome. However, the separation of the graft portal route, as seen in portosystemic shunt, may result in portal steal to the extrahepatic route, which sometimes leads to fatal events especially in cases with decreased graft portal vascular compliance, such as the case of steatotic liver graft or accute cellular rejection. Based on this potential complication, some centers have adopted certain precautionary measures against such complications using modifications of the shunt closing technique.

The recently introduced approach of splenic artery embolization could be an effective procedure for portal decompression instead of the conventional treatment. Splenic artery embolization is described by some investigators as a rescue treatment for post-transplant small-for-size syndrome. In this regard, we previously reported that preoperative portal decompression by splenic artery embolization efficaciously reduced blood loss during operation and shortened the operating time, and that it contributed to favorable prognosis without serious complications related to the procedure itself. In our institution, preoperative embolization is selected for patients considered at risk of development of shunt in the peri-celiac trunk. The risk assessment is based on preoperative radiography showing possible problems with safety of splenic artery ligation. In each patient scheduled

Small-for-Size Liver Graft Syndrome After Living Donor Liver Transplantation 87

graft injury. The postoperative outcome depends on the extent of graft injury immediately after the transplantation and portal decompression can protect the liver graft from destructive portal hyperperfusion and reduce the levels of these inflammatory cytokines. Our previous study reported that prophylactic splenic artery embolization and ligation decreased serum IL-6 and TNF-alpha after graft reperfusion and resulted in certain graft liver regeneration and favorable outcome. Based on these new findings, in terms of treatment strategy in small-for-size syndrome, prophylactic treatment would be favorable

Fig. 2. Box-and-whisker plots of portal vein flow and hepatic artery flow in patients of the non-portal modulation (PM) and PM groups during postoperative days (POD) 1, 3, 5 and 7

Any decision regarding the treatment strategy for small-for-size syndrome, flexible stance is often needed. Among the various approaches, either decision could be suitable depending on the individual patient. For example, the patient characteristics and institutional operative policies could influence the final decision. While portosystemic shunt is widely used for the prevention of small-for-size syndrome, there is no doubt that splenectomy and splenic artery ligation are also suitable and effective techniques to produce portal decompression. Furthermore, splenic artery embolization prior to transplantation could be an alternative effective treatment modality especially in patients with severe portal hypertension, and with established collateral circulation in the peri-celiac trunk, which makes it difficult to perform splenic artery ligation or splenectomy. In this regard, when sufficient portal decompression cannot be achieved through a single technique, a combination of two or more procedures should be applied. In essence, a proper portal decompression therapy can inhibit portal overperfusion injury and prevent small-for-size syndrome and also have beneficial effects

compared with rescue therapy.

for preoperative splenic artery embolization, abdominal angiography was performed 12 to 18 hours before transplantation. As a rule, a metallic coil was placed in the area adjacent to the root of the splenic artery and proximal to the bifurcation of the major pancreatic artery, to produce total embolization of the splenic artery trunk (Figure 1). Evaluation of posttransplantation graft hemodynamics by Doppler ultrasonography showed a significant reduction in the level of graft portal perfusion following splenic artery ligation and splenic artery embolization in the portal modulation group, compared with the non-portal modulation group (Figure 2). In the portal modulation group, the efficacy of portal decompression following splenic artery embolization was equivalent to that after splenic artery ligation. Furthermore, hepatic arterial flow was significantly higher during the postoperative phase in the portal modulation group, reflecting arterial flow shift from the spleen to the hepatic artery or hepatic arterial buffer response (Figure. 1).

Fig. 1. Preoperative splenic artery embolization as a prophylactic procedure for the prevention of small-for-size syndrome. Splenic artery was totally embolized adjacent to the root of celiac artery, 12-18 hours before liver transplantation. Splenic artery embolization reduced portal flow and increased hepatic arterial flow. Preoperative portal decompression also decreased blood loss and shortened operative time

As a result, such change in arterial blood flow could also contribute to the prevention of splenic artery steal syndrome, which causes poor arterial blood supply. Based on this procedure, none of the patients developed portal vein thrombosis or septicemia, which are sometimes observed after splenectomy.

Another issue related to liver transplantation is the post-transplant course. In this regard, high level liver regeneration is observed when the graft size is small, or when portal pressure is high in cirrhotic patients. Importantly, high serum IL-6 concentrations are considered to reflect high hemodynamic shear stress, which could lead to regenerative signaling pathway. However, in patients with extra small for size graft, regeneration of the graft liver does not occur sometimes, and liver tissue damage and ischemic reperfusion injury could result in increased release of inflammatory cytokines, such as IL-6 and TNFalpha, which lead to poor liver regeneration, i.e., these cytokines act as negative regulators of cell proliferation. Thus, although the role of these cytokines remains controversial, they are considered to function as inflammatory cytokines, rather than as liver regenerative factors, in patients with small-for-size syndrome, and thus, are considered as markers of

for preoperative splenic artery embolization, abdominal angiography was performed 12 to 18 hours before transplantation. As a rule, a metallic coil was placed in the area adjacent to the root of the splenic artery and proximal to the bifurcation of the major pancreatic artery, to produce total embolization of the splenic artery trunk (Figure 1). Evaluation of posttransplantation graft hemodynamics by Doppler ultrasonography showed a significant reduction in the level of graft portal perfusion following splenic artery ligation and splenic artery embolization in the portal modulation group, compared with the non-portal modulation group (Figure 2). In the portal modulation group, the efficacy of portal decompression following splenic artery embolization was equivalent to that after splenic artery ligation. Furthermore, hepatic arterial flow was significantly higher during the postoperative phase in the portal modulation group, reflecting arterial flow shift from the

spleen to the hepatic artery or hepatic arterial buffer response (Figure. 1).

Fig. 1. Preoperative splenic artery embolization as a prophylactic procedure for the

also decreased blood loss and shortened operative time

sometimes observed after splenectomy.

prevention of small-for-size syndrome. Splenic artery was totally embolized adjacent to the root of celiac artery, 12-18 hours before liver transplantation. Splenic artery embolization reduced portal flow and increased hepatic arterial flow. Preoperative portal decompression

As a result, such change in arterial blood flow could also contribute to the prevention of splenic artery steal syndrome, which causes poor arterial blood supply. Based on this procedure, none of the patients developed portal vein thrombosis or septicemia, which are

Another issue related to liver transplantation is the post-transplant course. In this regard, high level liver regeneration is observed when the graft size is small, or when portal pressure is high in cirrhotic patients. Importantly, high serum IL-6 concentrations are considered to reflect high hemodynamic shear stress, which could lead to regenerative signaling pathway. However, in patients with extra small for size graft, regeneration of the graft liver does not occur sometimes, and liver tissue damage and ischemic reperfusion injury could result in increased release of inflammatory cytokines, such as IL-6 and TNFalpha, which lead to poor liver regeneration, i.e., these cytokines act as negative regulators of cell proliferation. Thus, although the role of these cytokines remains controversial, they are considered to function as inflammatory cytokines, rather than as liver regenerative factors, in patients with small-for-size syndrome, and thus, are considered as markers of graft injury. The postoperative outcome depends on the extent of graft injury immediately after the transplantation and portal decompression can protect the liver graft from destructive portal hyperperfusion and reduce the levels of these inflammatory cytokines. Our previous study reported that prophylactic splenic artery embolization and ligation decreased serum IL-6 and TNF-alpha after graft reperfusion and resulted in certain graft liver regeneration and favorable outcome. Based on these new findings, in terms of treatment strategy in small-for-size syndrome, prophylactic treatment would be favorable compared with rescue therapy.

Fig. 2. Box-and-whisker plots of portal vein flow and hepatic artery flow in patients of the non-portal modulation (PM) and PM groups during postoperative days (POD) 1, 3, 5 and 7

Any decision regarding the treatment strategy for small-for-size syndrome, flexible stance is often needed. Among the various approaches, either decision could be suitable depending on the individual patient. For example, the patient characteristics and institutional operative policies could influence the final decision. While portosystemic shunt is widely used for the prevention of small-for-size syndrome, there is no doubt that splenectomy and splenic artery ligation are also suitable and effective techniques to produce portal decompression. Furthermore, splenic artery embolization prior to transplantation could be an alternative effective treatment modality especially in patients with severe portal hypertension, and with established collateral circulation in the peri-celiac trunk, which makes it difficult to perform splenic artery ligation or splenectomy. In this regard, when sufficient portal decompression cannot be achieved through a single technique, a combination of two or more procedures should be applied. In essence, a proper portal decompression therapy can inhibit portal overperfusion injury and prevent small-for-size syndrome and also have beneficial effects

Small-for-Size Liver Graft Syndrome After Living Donor Liver Transplantation 89

Variables n Odds ratio P-Value

Age ≥ 50 (vs < 50 years) 22 / 28 23.4 0.99 MELD ≥ 20 (vs < 20) 2 / 48 6.29 0.23

Cholestatic disease vs PLC 22 / 19 0.34 0.21 Acute liver failure vs PLC 9 / 19 1.39 -

Age ≥ 53 (vs < 53 years) 10 / 40 1.15 0.92 Graft type (right lobe vs left lobe graft) 38 / 12 0.29 0.46 GW/RBW < 0.8% (vs ≥ 0.8%) 12 / 38 8.44 0.02

Blood loss ≥ 50 (vs < 50ml/kg) 39 / 11 3.59 0.99 CIT ≥ 80 (vs < 80min) 16 / 34 1.16 0.91 WIT ≥ 50 (vs < 50min) 14 / 36 1.92 0.40 Operating time ≥10 (vs <10 hrs) 38 / 12 4.56 0.74 Table 1. Logistic regression analysis of post-transplant hospital mortality (the first 50 cases). PLC, Post-necrotic Liver cirrhosis; MELD, Model for End-stage Liver Disease; GW/RBW, Graft weight to recipient body weight ratio; CIT, Cold ischemic time; WIT, Warm ischemic

Fig. 3. Box-and-whisker plots of clinical factors in the first 50 cases (right side) and the later

Recipient factors

Disease

Donor factors

time

150 cases (left side)

Treatment and Operative factors

on liver generation as well as improvement of post-transplantation prognosis. In addition to the reduction in the mortality rate after the development of the technique of living donor liver transplantation, from medical and economic standpoints, the cost benefits of liver transplantation can be fully expected based on the reduced use of blood products, and shorter hospitalization through improvement of perioperative clinical condition.

#### **4. Prediction of small-for-size syndrome and hospital mortality**

Theoretically, small-for-size syndrome is expected in cases of small for size graft with high portal inflow. However, several studies have demonstrated that small-for-size syndrome does not necessarily occur even in such situations. In other words, the development of small for size syndrome and post-transplant graft function could not be predicted from the graft size only. We hypothesized that early graft function does not only depend on graft size, but also on portal hypertension, donor age and recipient status. To test our hypothesis, we determined the perioperative risk factors in small-for-size syndrome and post-transplant hospital death. In this regard, there are only a few studies that have dealt with the prediction of small-for-size syndrome in living donor liver transplantation.

We analyzed retrospectively 200 consecutive adult patients who underwent living donor liver transplantation in our hospital during the period from August 1998 to January 2010. We used multivariate analysis of hospital deaths for this purpose and various clinical, pathological and surgical parameters, after employment of cut-off values for these parameters using ROC analysis. Patients were divided into two groups according to the treatment protocol for the prevention of small-for-size syndrome. The first 50 patients had not received any prophylactic portal decompression. There were significant differences in the clinical parameters based on the time trend between the groups with and without prophylactic portal decompression. Interestingly, an aggressive operative stance was identified in the late time group and this correlated with the recipient age, donor age, MELD, and graft volume. Meanwhile, there was a significant learning curve, which seemed to reflect the development of the operative procedure, including the cold ischemic time, blood loss, and operative time (Figure 3). In the first 50 cases, the in-hospital mortality rate and 1-year survival rates of patients with a graft weight (GW)/recipient body weight (RBW) rate less than 0.8% were 27.3% and 63.6%, respectively (Figure 4). Multivariate analysis identified a single factor, which was a graft weight (GW)/recipient body weight (RBW) rate less than 0.8%, as a significant determinant of post-transplant hospital death (Table 1). From the 51th patients onward, prophylactic portal decompression was used in 70 of the 150 patients in order to prevent small-for-size syndrome. The prophylactic portal decompression consisted of splenic artery embolization in 50 patients, splenic arterial ligation in 14, splenectomy in 5, and portocaval shunt in 1 patient. After the introduction of the prophylactic portal decompression in the later 150 cases, the hospital mortality rate and 1-year survival rate of patients with GW/RBW less than 0.8% were 7.2% and 86%, respectively. After the introduction of prophylactic portal decompression, post-transplant prognosis did not correlate with a cut-off value of 0.8% for the GW/RBW ratio (Figure 4). Multivariate analysis of post-transplant hospital mortality rate in the later 150 cases identified donor age more than 54 years and MELD score more than 23, but not the GW/RBW, as significant perioperative risk factors (Table 2). In other words, the minimum GW/RBW ratio could be safely lowered to 0.68% with adequate portal modulation.

on liver generation as well as improvement of post-transplantation prognosis. In addition to the reduction in the mortality rate after the development of the technique of living donor liver transplantation, from medical and economic standpoints, the cost benefits of liver transplantation can be fully expected based on the reduced use of blood products, and

Theoretically, small-for-size syndrome is expected in cases of small for size graft with high portal inflow. However, several studies have demonstrated that small-for-size syndrome does not necessarily occur even in such situations. In other words, the development of small for size syndrome and post-transplant graft function could not be predicted from the graft size only. We hypothesized that early graft function does not only depend on graft size, but also on portal hypertension, donor age and recipient status. To test our hypothesis, we determined the perioperative risk factors in small-for-size syndrome and post-transplant hospital death. In this regard, there are only a few studies that have dealt with the

We analyzed retrospectively 200 consecutive adult patients who underwent living donor liver transplantation in our hospital during the period from August 1998 to January 2010. We used multivariate analysis of hospital deaths for this purpose and various clinical, pathological and surgical parameters, after employment of cut-off values for these parameters using ROC analysis. Patients were divided into two groups according to the treatment protocol for the prevention of small-for-size syndrome. The first 50 patients had not received any prophylactic portal decompression. There were significant differences in the clinical parameters based on the time trend between the groups with and without prophylactic portal decompression. Interestingly, an aggressive operative stance was identified in the late time group and this correlated with the recipient age, donor age, MELD, and graft volume. Meanwhile, there was a significant learning curve, which seemed to reflect the development of the operative procedure, including the cold ischemic time, blood loss, and operative time (Figure 3). In the first 50 cases, the in-hospital mortality rate and 1-year survival rates of patients with a graft weight (GW)/recipient body weight (RBW) rate less than 0.8% were 27.3% and 63.6%, respectively (Figure 4). Multivariate analysis identified a single factor, which was a graft weight (GW)/recipient body weight (RBW) rate less than 0.8%, as a significant determinant of post-transplant hospital death (Table 1). From the 51th patients onward, prophylactic portal decompression was used in 70 of the 150 patients in order to prevent small-for-size syndrome. The prophylactic portal decompression consisted of splenic artery embolization in 50 patients, splenic arterial ligation in 14, splenectomy in 5, and portocaval shunt in 1 patient. After the introduction of the prophylactic portal decompression in the later 150 cases, the hospital mortality rate and 1-year survival rate of patients with GW/RBW less than 0.8% were 7.2% and 86%, respectively. After the introduction of prophylactic portal decompression, post-transplant prognosis did not correlate with a cut-off value of 0.8% for the GW/RBW ratio (Figure 4). Multivariate analysis of post-transplant hospital mortality rate in the later 150 cases identified donor age more than 54 years and MELD score more than 23, but not the GW/RBW, as significant perioperative risk factors (Table 2). In other words, the minimum

GW/RBW ratio could be safely lowered to 0.68% with adequate portal modulation.

shorter hospitalization through improvement of perioperative clinical condition.

**4. Prediction of small-for-size syndrome and hospital mortality**

prediction of small-for-size syndrome in living donor liver transplantation.

Table 1. Logistic regression analysis of post-transplant hospital mortality (the first 50 cases). PLC, Post-necrotic Liver cirrhosis; MELD, Model for End-stage Liver Disease; GW/RBW, Graft weight to recipient body weight ratio; CIT, Cold ischemic time; WIT, Warm ischemic time

Fig. 3. Box-and-whisker plots of clinical factors in the first 50 cases (right side) and the later 150 cases (left side)

Small-for-Size Liver Graft Syndrome After Living Donor Liver Transplantation 91

functional cholestasis was defined as total bilirubin >10 mg/dL at postoperative day 14, without any other cause of cholestasis. Intractable ascites was defined as daily production of ascites of more than one liter at postoperative day 14 or >500 mL at postoperative day 28. Production of ascites represented the daily volume of ascites estimated by discharge from the abdominal drain. According to this diagnostic criterion, small-for-size syndrome occurred in 21 of 200 cases (10.5%) and 5 cases had fatal outcome. Patients with the small-for-size syndrome consisted of 11 cases (22%) in the first 50 cases and 10 cases (6.7%) in the later 150 cases, respectively. Furthermore, early hospital death was noted in 16 of 200 cases (8%).

Fig. 6. Decision tree analysis of post-transplant hospital mortality (175 cases). MELD, model for end-stage liver disease; GRWR, graft weight to recipient body weight ratio; SAM, splenic

The occurrence of small-for-size syndrome and hospital death depends on the specific combination of graft size, donor age, and MELD. Even using large-size graft, the use of grafts with high MELD and from old-age donors tended to result in the development of small-for-size syndrome and hospital mortality (Figure 5). These results indicated that the use if sufficient graft volume does not prevent the development of small-for-size syndrome graft, and that the incidence of this syndrome depends on other risk factors, which affect the post-transplant prognosis. Concerning the prediction of small-for-size syndrome or posttransplant prognosis, none of the analyses used could find significant risk factors. The decision tree analysis for hospital mortality indicated that the value of any one risk factor should affect the cut-off values of other risk factors (Figure 6). Thus, early graft function and hospital mortality are determined not only by graft size, but also by donor age and recipient status. Donor age and graft size should be matched to the recipient status when possible,

artery embolization as portal modulation

Fig. 4. Overall survival curves and hospital mortality before and after the introduction of portal modulation

Fig. 5. Correlation between graft size, MELD, and donor age in cases of small-for-size syndrome and hospital death

To evaluate the impact of small for size graft on the outcome, we defined small-for-size syndrome as both prolonged functional cholestasis and intractable ascites. Prolonged

Fig. 4. Overall survival curves and hospital mortality before and after the introduction of

1.3

SFSS Hospital death

1.1

0.9

**GW/RBW**

8 10 12 14 16 18 20 8 10 12 14 16 18 20 **MELD MELD**

*25 40 55 25 40 55*

To evaluate the impact of small for size graft on the outcome, we defined small-for-size syndrome as both prolonged functional cholestasis and intractable ascites. Prolonged

**Donor age Donor age**

Fig. 5. Correlation between graft size, MELD, and donor age in cases of small-for-size

0.7

0.5

portal modulation

1.3

1.1

0.9

**GW/RBW**

0.7

0.5

syndrome and hospital death

functional cholestasis was defined as total bilirubin >10 mg/dL at postoperative day 14, without any other cause of cholestasis. Intractable ascites was defined as daily production of ascites of more than one liter at postoperative day 14 or >500 mL at postoperative day 28. Production of ascites represented the daily volume of ascites estimated by discharge from the abdominal drain. According to this diagnostic criterion, small-for-size syndrome occurred in 21 of 200 cases (10.5%) and 5 cases had fatal outcome. Patients with the small-for-size syndrome consisted of 11 cases (22%) in the first 50 cases and 10 cases (6.7%) in the later 150 cases, respectively. Furthermore, early hospital death was noted in 16 of 200 cases (8%).

Fig. 6. Decision tree analysis of post-transplant hospital mortality (175 cases). MELD, model for end-stage liver disease; GRWR, graft weight to recipient body weight ratio; SAM, splenic artery embolization as portal modulation

The occurrence of small-for-size syndrome and hospital death depends on the specific combination of graft size, donor age, and MELD. Even using large-size graft, the use of grafts with high MELD and from old-age donors tended to result in the development of small-for-size syndrome and hospital mortality (Figure 5). These results indicated that the use if sufficient graft volume does not prevent the development of small-for-size syndrome graft, and that the incidence of this syndrome depends on other risk factors, which affect the post-transplant prognosis. Concerning the prediction of small-for-size syndrome or posttransplant prognosis, none of the analyses used could find significant risk factors. The decision tree analysis for hospital mortality indicated that the value of any one risk factor should affect the cut-off values of other risk factors (Figure 6). Thus, early graft function and hospital mortality are determined not only by graft size, but also by donor age and recipient status. Donor age and graft size should be matched to the recipient status when possible,

Small-for-Size Liver Graft Syndrome After Living Donor Liver Transplantation 93

Broering, DC; Walter, J & Bassas AF. (2005) Overcoming the portal steal phenomenon in

Dahm, F; Georgiev, P & Clavien, PA, et al. (2005). Small for size syndrome after partial liver

Eguchi, S; Yanaga, K & Sugiyama, N, et al. (2003). Relationship between portal venous flow

Eipel, C; Glanemann, M & Nuessler, AK, et al. (2005). Ischemic preconditioning impairs liver regeneration in extended reduced-size livers. *Annals of Surgery*; 241: 477-484. Hessheimer, AJ; Fondevila, C & Taurá, P, et al. (2011).Decompression of the portal bed and

Hill, MJ; Hughes, M & Jie T, et al. (2009). Graft weight/recipient weight ratio: how well does

Ikegami, T; Masuda, Y & Ohno Y, et al. (2009). Prognosis of adult patients transplanted with

Ikegami, T; Toshima, T & Takeishi, K, et al. (2009).Bloodless splenectomy during liver

Kiuchi , T; Kasahara, M & Uryuhara K, et al. (1999). Impact of graft size mismatching on

Marcos, A; Fisher, RA & Ham, JM, et al. (2000). Liver regeneration and function in donor

Navasa, M; Feu, F & Garcia-Pagan, JC, et al. (1993). Hemodynamic and humoral changes after liver transplantation in patients with cirrhosis. *Hepatology* 1993; 17: 355-360. Ogura, Y; Hori, T & El, Moghazy WM, et al. (2010). Portal pressure <15 mm Hg is a key for

Park, A & Baichwal, VR (1996). Systematic mutational analysis of the death domain of the

Piscaglia, F; Zironi, G & Gaiani S, et al. (1999). Systemic and splanchnic hemodynamic

Sterpetti, AV; Cucina, A & Morena, AR, et al. (1993). Shear stress increases the release of interleukin-1 and interleukin-6 by aortic endothelial cells. *Surgery*; 114: 911-914. Tian, Y; Graf, R & Jochum, W, et al. (2003). Arterialized partial orthotopic liver

Tian, Y; Jochum, W & Georgiev, P, et al. (2006). Kupffer cell-dependent TNF-alpha signaling

*Proceedings of the National Academy of Sciences USA* 2006; 103: 4598-4603.

outflow of the native liver. *Liver Transplantation;* 11: 1140-1143.

*American Journal of Transplantation*; 5: 2605-2610.

size" graft. *Annals of Surgery;* 253:1201-1210.

*American College of Surgeons;* 208:e1-4.

before. *Liver Transplantation*; 16:718-728.

mass. *Liver Transplantation*; 9: 789-795.

*Transplantation*; 69: 1375-1379.

*Chemistry*; 271: 9858-9862.

*Hepatology* 1999; 30: 58-64.

*Liver Transplantation*; 9: 547-551.

1630.

327.

auxiliary partial orthotopic liver transplantation by modulation of the venous

transplantation: Definition, mechanisms of disease and clinical implications.

and liver regeneration in patients after living donor right-lobe liver transplantation.

twice-baseline portal inflow are necessary for the functional recovery of a "small for

it predict outcome after partial liver transplants? *Liver Transplantation*; 15:1056-1062.

liver grafts < 35% of their standard liver volume. *Liver Transplantation;* 15:1622-

transplantation for terminal liver diseases with portal hypertension. *Journal of the*

graft prognosis in liver transplantation from living donors. *Transplantation*; 67: 321-

and recipient after right lobe adult to adult living donor liver transplantation.

successful adult living donor liver transplantation utilizing smaller grafts than

tumor necrosis factor receptor 1-associated protein TRADD. *Journal of Biological*

changes after liver transplantation for cirrhosis: A long-term prospective study.

transplantation in the mouse: A new model and evaluation of the critical liver

mediates injury in the arterialized small for size liver transplantation in the mouse.

and when not possible, portal modulation should be considered. Splenic artery embolization could help reduce the morbidity and mortality rates, as well as increase the survival rates, and should be considered along with the other perioperative risk factors.

Table 2. Logistic regression analysis of post-transplant hospital mortality (the later 150 cases). LC, post-necrotic liver cirrhosis; MELD, model for end-stage liver disease; GW/RBW, graft weight to recipient body weight ratio; CIT, cold ischemic time; WIT, warm ischemic time

#### **5. Conclusion**

Recently published clinical trials and basic research conducted by several groups have uncovered the mechanism of small-for-size syndrome, allowing the design and implementation of new treatment strategies. These advances have resulted in significant improvement in prognosis after living donor transplantation. Further improvement of liver transplantation and liver surgery techniques should result in better outcome of patients with small for size syndrome.

#### **6. Acknowledgement**

This work was supported by a Grant-in-Aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan

#### **7. References**

Botha, JF; Campos, BD & Johanning J, et al. (2009). Endovascular closure of a hemiportocaval shunt after small for size adult-to-adult left lobe living donor liver transplantation. *Liver Transplantation*; 15:1671-1675.

and when not possible, portal modulation should be considered. Splenic artery embolization could help reduce the morbidity and mortality rates, as well as increase the survival rates,

Variable n Odds

Age ≥ 54 (vs < 54 years) 78 / 72 1.54 0.59 MELD ≥ 23 (vs < 23) 24 / 126 3.66 0.001

Cholestatic disease vs PLC 21 / 115 0.61 0.73

Age ≥ 53 (vs < 53 years) 33 / 117 6.84 0.03 Graft type (Right lobe vs Left lobe graft) 80 / 70 0.47 0.44 GW/RBW < 0.68% (vs ≥ 0.68%) 26 / 124 1.41 0.72

Portal modulation 70 / 80 0.61 0.54 Blood loss ≥ 50 (vs < 50ml/kg) 101 / 49 1.90 0.61 CIT ≥ 80 (vs < 80min) 35 / 115 1.91 0.40 WIT ≥ 50 (vs < 50min) 42 / 108 1.87 0.74 Operating time ≥ 10 (vs < 10hrs) 59 / 91 3.98 0.39 Table 2. Logistic regression analysis of post-transplant hospital mortality (the later 150 cases). LC, post-necrotic liver cirrhosis; MELD, model for end-stage liver disease; GW/RBW, graft weight to recipient body weight ratio; CIT, cold ischemic time; WIT, warm ischemic time

Recently published clinical trials and basic research conducted by several groups have uncovered the mechanism of small-for-size syndrome, allowing the design and implementation of new treatment strategies. These advances have resulted in significant improvement in prognosis after living donor transplantation. Further improvement of liver transplantation and liver surgery techniques should result in better outcome of patients with

This work was supported by a Grant-in-Aid for scientific research from the Ministry of

Botha, JF; Campos, BD & Johanning J, et al. (2009). Endovascular closure of a

hemiportocaval shunt after small for size adult-to-adult left lobe living donor liver

Education, Culture, Sports, Science and Technology of Japan

transplantation. *Liver Transplantation*; 15:1671-1675.

Acute liver failure vs PLC 14 / 115 1.39

ratio P-Value

and should be considered along with the other perioperative risk factors.

Recipient factors

Disease

Donor factors

**5. Conclusion**

small for size syndrome.

**6. Acknowledgement**

**7. References**

Treatment and Operative factor

**Part 2**

**Surgical Techniques**

**Deceased Donor Liver Transplantation:**

### **Part 2**

### **Deceased Donor Liver Transplantation: Surgical Techniques**

94 Liver Transplantation – Technical Issues and Complications

Tian, Y; Jochum, W & Georgiev P, et al. (2006). Kupffer cell-dependent TNF-alpha signaling

Umeda, Y; Yagi, T & Sadamori, H, et al. (2008). Effects of prophylactic splenic artery

Yagi, S; Iida, T & Taniguchi, K, et al. (2005). Impact of portal venous pressure on

Zhong, Z; Schwabe, RF & Kai, Y, et al. (2006). Liver regeneration is suppressed in small for

cyclin D1, and defective energy supply. *Transplantation*; 82: 241-250.

*Proceedings of the National Academy of Sciences USA* 2006; 103: 4598-4603. Troisi, R & de Hemptinne, B. (2003). Clinical relevance of adapting portal vein flow in living donor liver transplantation in adult patients. *Liver Transplantation;* 9: 36-41. Umeda, Y; Yagi, T & Sadamori, H, et al. (2007). Preoperative proximal splenic artery

947-955.

*Transplantation* 15; 86: 673-80.

*Transplantation;* 11: 68-75.

mediates injury in the arterialized small for size liver transplantation in the mouse.

embolization: A safe and efficacious portal decompression technique that improves the outcome of live donor liver transplantation. *Transplantation International;* 20:

modulation on portal overperfusion and liver regeneration in small for size graft.

regeneration and graft damage after living-donor liver transplantation. *Liver*

size liver grafts after transplantation: Involvement of c-Jun N-terminal kinase,

**5**

*USA*

**Vascular and Biliary Anastomoses in Deceased**

*Oakland University William Beaumont School of Medicine / Beaumont Health System*

The purpose of this chapter is to review the various techniques of implantation for deceased donor liver transplants (DDLT). Given the overall broad nature of the topic, the focus will be exclusively on adult DDLT, without including split liver and living donor liver transplants.  These include the suprahepatic and infrahepatic vena cava, the portal vein, the hepatic artery and the bile duct. Prior to describing the various methods of implantation of the donor liver, we will briefly review the different options available for the recipient hepatectomy, as the surgeon's choice of reconstruction of the vena cava will dictate the type of hepatectomy performed. For a bicaval anastomosis, the hepatectomy involves completely dissecting out the supraand infrahepatic vena cava, mobilizing the inferior vena cava (IVC) off of the retroperitoneum, achieving full vascular isolation and subsequently removing the intrahepatic portion of the IVC with the native liver. In this scenario, the use of venovenous bypass may be required for hemodynamic stability of the patient. The traditional method involves reconstruction of the suprahepatic and infrahepatic donor cava to the corresponding structures in the recipient. A second option is to preserve the vena cava by dissecting the native liver off of the IVC completely. Subsequently, we describe several ways in which the cava is reanastomosed in the setting of caval preservation. One method is commonly known as the "piggyback" technique where two or all three recipient hepatic veins are joined together into a common orifice which is used as the site of anastomosis. Other configurations of caval anastomosis are also used, including side-to-side and end-to-side techniques. Finally, we discuss a

The remainder of the implantation is similar regardless of the method chosen for caval reconstruction. The next anastomosis is usually the portal vein (PV). For the most part, portal vein reconstruction is straightforward unless there is partial or complete thrombosis of the recipient portal vein. If thrombectomy fails, then a venous conduit may be necessary.

At this point, the liver is usually reperfused. In some situations, hepatic arterial reperfusion is performed simultaneously with portal, or even precedes portal reconstruction. Close cooperation between the surgical and anesthesia team is necessary at this critical time as

Other salvage maneuvers are used if even a conduit is not possible.

**1. Introduction**

modification of the lateral cavo-cavostomy.

reperfusion instability may result.

**Donor Orthotopic Liver Transplantation**

Steven Cohn, Julie Stein, Alan Koffron and Vandad Raofi

### **Vascular and Biliary Anastomoses in Deceased Donor Orthotopic Liver Transplantation**

Steven Cohn, Julie Stein, Alan Koffron and Vandad Raofi *Oakland University William Beaumont School of Medicine / Beaumont Health System USA*

#### **1. Introduction**

The purpose of this chapter is to review the various techniques of implantation for deceased donor liver transplants (DDLT). Given the overall broad nature of the topic, the focus will be exclusively on adult DDLT, without including split liver and living donor liver transplants.

 These include the suprahepatic and infrahepatic vena cava, the portal vein, the hepatic artery and the bile duct. Prior to describing the various methods of implantation of the donor liver, we will briefly review the different options available for the recipient hepatectomy, as the surgeon's choice of reconstruction of the vena cava will dictate the type of hepatectomy performed. For a bicaval anastomosis, the hepatectomy involves completely dissecting out the supraand infrahepatic vena cava, mobilizing the inferior vena cava (IVC) off of the retroperitoneum, achieving full vascular isolation and subsequently removing the intrahepatic portion of the IVC with the native liver. In this scenario, the use of venovenous bypass may be required for hemodynamic stability of the patient. The traditional method involves reconstruction of the suprahepatic and infrahepatic donor cava to the corresponding structures in the recipient.

A second option is to preserve the vena cava by dissecting the native liver off of the IVC completely. Subsequently, we describe several ways in which the cava is reanastomosed in the setting of caval preservation. One method is commonly known as the "piggyback" technique where two or all three recipient hepatic veins are joined together into a common orifice which is used as the site of anastomosis. Other configurations of caval anastomosis are also used, including side-to-side and end-to-side techniques. Finally, we discuss a modification of the lateral cavo-cavostomy.

The remainder of the implantation is similar regardless of the method chosen for caval reconstruction. The next anastomosis is usually the portal vein (PV). For the most part, portal vein reconstruction is straightforward unless there is partial or complete thrombosis of the recipient portal vein. If thrombectomy fails, then a venous conduit may be necessary. Other salvage maneuvers are used if even a conduit is not possible.

At this point, the liver is usually reperfused. In some situations, hepatic arterial reperfusion is performed simultaneously with portal, or even precedes portal reconstruction. Close cooperation between the surgical and anesthesia team is necessary at this critical time as reperfusion instability may result.

Vascular and Biliary Anastomoses in Deceased Donor Orthotopic Liver Transplantation 99

Dissection of the portal structures proceeds from the left or right side depending on the surgeon's preference. From the left, the gastro-hepatic ligament is divided anterior to the caudate lobe, and the lateral aspect of the portal vein is identified. Staying anterior to the PV, the proper hepatic artery is dissected out and transected. We do not routinely dissect out and divide the right and left hepatic artery individually high up in the hilum. However, some teams prefer to maintain length on the native artery if their preference is to use the bifurcation of the proper hepatic artery for reconstruction. Once the hepatic artery is divided, the only structure anterior to the PV is the common bile duct. This structure is taken down immediately distal to the insertion of the cystic duct. Finally, the only remaining structure in the hilum is the portal vein. At this time the PV is completely skeletonized from its bifurcation distally to near the first pancreatic branch proximally. One needs to ensure that the PV is completely mobilized circumferentially from the surrounding lymphatic and

The next step is mobilization of the IVC. The initial step is to dissect out and obtain control of the infrahepatic IVC. Once the plane of the IVC is established, we continue to the left and mobilize the lateral aspect of the caudate lobe off of the IVC. This is carried in a cephalad direction until the lateral aspect of the suprahepatic IVC is identified immediately above the insertion of the left hepatic vein. When the left side of the IVC is exposed, attention is then directed toward mobilizing the right lobe of the liver. The right triangular and hepatorenal ligaments are taken down and the right lobe is mobilized fully until the suprahepatic IVC is

At this point, the dissection differs between the standard and caval sparing technique.

 For the standard bicaval technique, both the suprahepatic and infrahepatic IVC are circumferentially dissected out. Generally, the right adrenal vein has to be taken down to provide for adequate infrahepatic exposure. Care is taken near the right renal vein, adrenal gland, and right hepatic vein. Gently, the surgeon's index finger is passed behind the suprahepatic IVC and the soft tissue posterior to the IVC is ensnared and retracted forward (Figure 2). This tissue is taken down either with electrocautery or tied off with silk tie if

Fig. 1. Typical bilateral subcostal incision with upper midline extension

exposed immediately superior to the insertion of right hepatic vein.

there is any concern for bleeding or retroperitoneal varices.

loose areolar tissue.

**2.1 Bicaval hepatectomy**

Hepatic arterial reconstruction probably has the most options, as anatomic variations are common, and depending on surgeon preference, different techniques of reconstruction are available. If there is inadequate inflow from the recipient's hepatic artery or its branches, an arterial conduit between the recipient aorta and donor artery may be necessary.

The last anastomosis is the biliary, which has been dubbed the "Achilles heel" of DDLT. Options for reconstructing the bile duct include common duct to common duct anastomosis for the donor and recipient. The second method is a Roux-en-Y hepaticojejunostomy. We will discuss the indications for a Roux reconstruction, and mention some controversies regarding biliary reconstruction.

While an attempt is made to mention many variations in technique, the reader should bear in mind the fact that there are numerous small modifications that are done on a case by case basis based upon the surgeon's preference and personal experience.

#### **2. Recipient hepatectomy**

Deceased donor liver transplantation (DDLT) can be divided into several distinct steps. The first is the recipient hepatectomy, followed by the anhepatic phase, and finally reperfusion of the donor graft and completion of the arterial and biliary reconstruction. It would be difficult to simply focus on the implantation of the donor graft without mentioning the recipient hepatectomy, as the choice of vascular reconstruction during the implantation essentially dictates the type of hepatectomy performed.

A key factor to improving outcomes in DDLT is minimizing the cold ischemic time especially in marginal donors or in donation after cardiac death. Therefore, we prefer to have two surgical teams. Once the procurement team has visualized the donor liver and reviewed any biopsies if indicated, the decision is made to proceed or abort the recipient case. If the donor liver is deemed suitable, the recipient is brought to the operating room in preparation for the procedure. Our preference is to have both a pulmonary artery catheter placed for close hemodynamic monitoring, as well as a large bore bypass line placed in the right internal jugular vein in case of need for venovenous bypass.

The hepatectomy can be quite challenging depending on factors such as the degree of portal hypertension, presence of adhesions, and clinical stability of the recipient. Typically, it is started by a bilateral subcostal incision with a vertical midline incision (Figure 1). Previous incisions or anatomy (e.g. presence of ostomy) may dictate where the incision is made. Also, if a combined liver and kidney transplant is planned, the subcostal portion can be made lower on the abdominal wall to facilitate placement of the kidney. With the standard incision, the right side is extended laterally to at least to the mid-axillary line to allow for adequate exposure for both dissection and placement of clamps on the IVC. The upper midline extension is carried to the xiphoid process, and, if necessary, the xiphoid is removed for better exposure of the suprahepatic IVC. The falciform ligament is then taken down and the coronary ligament is dissected until the anterior border of the suprahepatic IVC is identified. Next the left triangular ligament is divided and the left lateral lobe is mobilized. The next step is to mobilize the gastro-hepatic ligament, which would expose the left side of the IVC and the caudate lobe. If there is a replaced left hepatic artery it is ligated at this time.

Fig. 1. Typical bilateral subcostal incision with upper midline extension

Dissection of the portal structures proceeds from the left or right side depending on the surgeon's preference. From the left, the gastro-hepatic ligament is divided anterior to the caudate lobe, and the lateral aspect of the portal vein is identified. Staying anterior to the PV, the proper hepatic artery is dissected out and transected. We do not routinely dissect out and divide the right and left hepatic artery individually high up in the hilum. However, some teams prefer to maintain length on the native artery if their preference is to use the bifurcation of the proper hepatic artery for reconstruction. Once the hepatic artery is divided, the only structure anterior to the PV is the common bile duct. This structure is taken down immediately distal to the insertion of the cystic duct. Finally, the only remaining structure in the hilum is the portal vein. At this time the PV is completely skeletonized from its bifurcation distally to near the first pancreatic branch proximally. One needs to ensure that the PV is completely mobilized circumferentially from the surrounding lymphatic and loose areolar tissue.

The next step is mobilization of the IVC. The initial step is to dissect out and obtain control of the infrahepatic IVC. Once the plane of the IVC is established, we continue to the left and mobilize the lateral aspect of the caudate lobe off of the IVC. This is carried in a cephalad direction until the lateral aspect of the suprahepatic IVC is identified immediately above the insertion of the left hepatic vein. When the left side of the IVC is exposed, attention is then directed toward mobilizing the right lobe of the liver. The right triangular and hepatorenal ligaments are taken down and the right lobe is mobilized fully until the suprahepatic IVC is exposed immediately superior to the insertion of right hepatic vein.

At this point, the dissection differs between the standard and caval sparing technique.

#### **2.1 Bicaval hepatectomy**

98 Liver Transplantation – Technical Issues and Complications

Hepatic arterial reconstruction probably has the most options, as anatomic variations are common, and depending on surgeon preference, different techniques of reconstruction are available. If there is inadequate inflow from the recipient's hepatic artery or its branches, an

The last anastomosis is the biliary, which has been dubbed the "Achilles heel" of DDLT. Options for reconstructing the bile duct include common duct to common duct anastomosis for the donor and recipient. The second method is a Roux-en-Y hepaticojejunostomy. We will discuss the indications for a Roux reconstruction, and mention some controversies

While an attempt is made to mention many variations in technique, the reader should bear in mind the fact that there are numerous small modifications that are done on a case by case

Deceased donor liver transplantation (DDLT) can be divided into several distinct steps. The first is the recipient hepatectomy, followed by the anhepatic phase, and finally reperfusion of the donor graft and completion of the arterial and biliary reconstruction. It would be difficult to simply focus on the implantation of the donor graft without mentioning the recipient hepatectomy, as the choice of vascular reconstruction during the implantation

A key factor to improving outcomes in DDLT is minimizing the cold ischemic time especially in marginal donors or in donation after cardiac death. Therefore, we prefer to have two surgical teams. Once the procurement team has visualized the donor liver and reviewed any biopsies if indicated, the decision is made to proceed or abort the recipient case. If the donor liver is deemed suitable, the recipient is brought to the operating room in preparation for the procedure. Our preference is to have both a pulmonary artery catheter placed for close hemodynamic monitoring, as well as a large bore bypass line placed in the

The hepatectomy can be quite challenging depending on factors such as the degree of portal hypertension, presence of adhesions, and clinical stability of the recipient. Typically, it is started by a bilateral subcostal incision with a vertical midline incision (Figure 1). Previous incisions or anatomy (e.g. presence of ostomy) may dictate where the incision is made. Also, if a combined liver and kidney transplant is planned, the subcostal portion can be made lower on the abdominal wall to facilitate placement of the kidney. With the standard incision, the right side is extended laterally to at least to the mid-axillary line to allow for adequate exposure for both dissection and placement of clamps on the IVC. The upper midline extension is carried to the xiphoid process, and, if necessary, the xiphoid is removed for better exposure of the suprahepatic IVC. The falciform ligament is then taken down and the coronary ligament is dissected until the anterior border of the suprahepatic IVC is identified. Next the left triangular ligament is divided and the left lateral lobe is mobilized. The next step is to mobilize the gastro-hepatic ligament, which would expose the left side of the IVC and the caudate lobe. If there is a replaced left hepatic artery it is

arterial conduit between the recipient aorta and donor artery may be necessary.

basis based upon the surgeon's preference and personal experience.

essentially dictates the type of hepatectomy performed.

right internal jugular vein in case of need for venovenous bypass.

regarding biliary reconstruction.

**2. Recipient hepatectomy**

ligated at this time.

 For the standard bicaval technique, both the suprahepatic and infrahepatic IVC are circumferentially dissected out. Generally, the right adrenal vein has to be taken down to provide for adequate infrahepatic exposure. Care is taken near the right renal vein, adrenal gland, and right hepatic vein. Gently, the surgeon's index finger is passed behind the suprahepatic IVC and the soft tissue posterior to the IVC is ensnared and retracted forward (Figure 2). This tissue is taken down either with electrocautery or tied off with silk tie if there is any concern for bleeding or retroperitoneal varices.

Vascular and Biliary Anastomoses in Deceased Donor Orthotopic Liver Transplantation 101

is utilized. Once on venovenous bypass, the infrahepatic and suprahepatic IVC are clamped and the liver is explanted. Rarely, as with a very large liver (e.g. polycystic liver), the

For the caval sparing technique, the caudate and right lobes are mobilized as before. However, the right adrenal vein is left alone, and no dissection is carried out behind the cava. Instead, starting from the region of the infrahepatic cava, the liver is mobilized off the anterior surface of the IVC. Dissection proceeds either from left to right (or visa versa) depending on the anatomy. All short hepatic veins are dissected out and either tied with silk ties or oversewn with 5-0 prolene for larger branches. Larger retrohepatic veins may also be

While the PV can be left intact during most of the piggyback dissection, many surgeons prefer to create a temporary end-to-side portacaval shunt to minimize mesenteric congestion and improve hemodynamic stability (Cherqui et al., 1994; Llado´ & Figueras, 2004). Other reasons to use a shunt include decreased bleeding, improved renal function, reduced liver congestion,and improved exposure and mobility of the liver.. Shunting is more important when the patient has not developed chronic mesenteric collateralization (e.g. fulminant hepatitis). When partial clamping of the cava is used in conjunction with a shunt, both systemic and mesenteric flow are preserved without the need for venovenous bypass. If no portal decompression is used, the portal vein is left intact as long as possible prior to

Fig. 4. Caval preservation: Liver is mobilized off retrohepatic cava in a caudal to cephalad direction. Shown above right renal vein is a temporary end-to-side portal caval shunt

 The dissection is carried cephalad anterior to the IVC until the IVC ligament is identified, dissected out, and transected. We prefer to use an endovascular stapler on "thick" caval ligaments however one can clamp and cut the IVC ligament, and subsequently suture the remnant stump (large caudate lobes may increase the difficulty). Finally, the hepatic veins are isolated and completely dissected out. Many times, it helps to divide the right hepatic

If a portacaval shunt has not been created, at this time the PV is taken down, and depending on the reconstruction technique, the hepatic veins are either taken with a stapler or a Satinsky clamp is placed on the caval side of the hepatic veins, and the liver is removed. If the hepatic vein cuffs are to be used as part of the recipient anastomosis, the veins are

hepatectomy is facilitated by removing the left lateral segment of the liver first.

removing the liver in order to prevent splanchnic congestion (Lerut, 2003).

vein which facilitates exposure of the common middle and left trunk.

transected intrahepatically to preserve length. The liver is now removed.

**2.2 Caval sparing hepatectomy**

stapled.

Once the intrahepatic cava is fully mobilized a test clamp is performed. For this, the surgeon manually compresses both the infrahepatic IVC and the PV, then checks with the anesthesia team to ensure patient stability. If the patient remains hemodynamically stable, then we proceed with the hepatectomy. Initially a clamp is placed on the PV proximally and the distal aspect of the PV is tied off with a silk tie at the level of its bifurcation and transected. Subsequently a vascular clamp is place on the infrahepatic IVC. This clamp can be either placed in a horizontal or vertical position. Finally, a clamp is placed on the suprahepatic IVC. The recipient's IVC is transected between the clamps and the liver is passed off the field.

Fig. 2. Hepatectomy with mobilization of retrohepatic vena cava

While this technique avoids the extra time for going on venovenous bypass, two concerns arise. First, is that the recipient may initially be hemodynamically stable, but may become unstable during the anhepatic phase. Second, if there is concern for lack of exposure, such as edematous viscera, small recipient, or a large donor liver, proceeding in the anhepatic phase without bypass can lead to significantly worsening bowel edema and a more technically challenging implantation. For these reasons, we have a very low threshold for going on bypass. In general, however, venovenous bypass is used selectively nowadays depending on the recipient status and the bias of the surgical team (Reddy, 2005).

Fig. 3. Venovenous Scheme: Systemic and mesenteric flow travels out of patient through centrifugal pump, and is reintroduced into systemic circulation through either the axillary or jugular vein

To start systemic bypass, a femoral cannula is placed by cut-down or percutaneous technique in either groin, and the infrarenal cava is cannulated. Systemic return is through a cannula placed through cutdown in the axillary vein, or (as we prefer) through a percutaneously placed jugular cannula. Systemic bypass is then initiated while leaving the portal cannula of the circuit still clamped. Subsequently, the PV is clamped and taken down, and the PV cannula is then inserted and full venovenous bypass initiated (Figure 3). In certain situations,only the systemic and/or portal bypass portion of the venovenous circuit is utilized. Once on venovenous bypass, the infrahepatic and suprahepatic IVC are clamped and the liver is explanted. Rarely, as with a very large liver (e.g. polycystic liver), the hepatectomy is facilitated by removing the left lateral segment of the liver first.

#### **2.2 Caval sparing hepatectomy**

100 Liver Transplantation – Technical Issues and Complications

Once the intrahepatic cava is fully mobilized a test clamp is performed. For this, the surgeon manually compresses both the infrahepatic IVC and the PV, then checks with the anesthesia team to ensure patient stability. If the patient remains hemodynamically stable, then we proceed with the hepatectomy. Initially a clamp is placed on the PV proximally and the distal aspect of the PV is tied off with a silk tie at the level of its bifurcation and transected. Subsequently a vascular clamp is place on the infrahepatic IVC. This clamp can be either placed in a horizontal or vertical position. Finally, a clamp is placed on the suprahepatic IVC. The recipient's IVC is transected between the clamps and the liver is passed off the field.

While this technique avoids the extra time for going on venovenous bypass, two concerns arise. First, is that the recipient may initially be hemodynamically stable, but may become unstable during the anhepatic phase. Second, if there is concern for lack of exposure, such as edematous viscera, small recipient, or a large donor liver, proceeding in the anhepatic phase without bypass can lead to significantly worsening bowel edema and a more technically challenging implantation. For these reasons, we have a very low threshold for going on bypass. In general, however, venovenous bypass is used selectively nowadays depending

Fig. 3. Venovenous Scheme: Systemic and mesenteric flow travels out of patient through centrifugal pump, and is reintroduced into systemic circulation through either the axillary

To start systemic bypass, a femoral cannula is placed by cut-down or percutaneous technique in either groin, and the infrarenal cava is cannulated. Systemic return is through a cannula placed through cutdown in the axillary vein, or (as we prefer) through a percutaneously placed jugular cannula. Systemic bypass is then initiated while leaving the portal cannula of the circuit still clamped. Subsequently, the PV is clamped and taken down, and the PV cannula is then inserted and full venovenous bypass initiated (Figure 3). In certain situations,only the systemic and/or portal bypass portion of the venovenous circuit

Fig. 2. Hepatectomy with mobilization of retrohepatic vena cava

on the recipient status and the bias of the surgical team (Reddy, 2005).

or jugular vein

For the caval sparing technique, the caudate and right lobes are mobilized as before. However, the right adrenal vein is left alone, and no dissection is carried out behind the cava. Instead, starting from the region of the infrahepatic cava, the liver is mobilized off the anterior surface of the IVC. Dissection proceeds either from left to right (or visa versa) depending on the anatomy. All short hepatic veins are dissected out and either tied with silk ties or oversewn with 5-0 prolene for larger branches. Larger retrohepatic veins may also be stapled.

While the PV can be left intact during most of the piggyback dissection, many surgeons prefer to create a temporary end-to-side portacaval shunt to minimize mesenteric congestion and improve hemodynamic stability (Cherqui et al., 1994; Llado´ & Figueras, 2004). Other reasons to use a shunt include decreased bleeding, improved renal function, reduced liver congestion,and improved exposure and mobility of the liver.. Shunting is more important when the patient has not developed chronic mesenteric collateralization (e.g. fulminant hepatitis). When partial clamping of the cava is used in conjunction with a shunt, both systemic and mesenteric flow are preserved without the need for venovenous bypass. If no portal decompression is used, the portal vein is left intact as long as possible prior to removing the liver in order to prevent splanchnic congestion (Lerut, 2003).

Fig. 4. Caval preservation: Liver is mobilized off retrohepatic cava in a caudal to cephalad direction. Shown above right renal vein is a temporary end-to-side portal caval shunt

 The dissection is carried cephalad anterior to the IVC until the IVC ligament is identified, dissected out, and transected. We prefer to use an endovascular stapler on "thick" caval ligaments however one can clamp and cut the IVC ligament, and subsequently suture the remnant stump (large caudate lobes may increase the difficulty). Finally, the hepatic veins are isolated and completely dissected out. Many times, it helps to divide the right hepatic vein which facilitates exposure of the common middle and left trunk.

If a portacaval shunt has not been created, at this time the PV is taken down, and depending on the reconstruction technique, the hepatic veins are either taken with a stapler or a Satinsky clamp is placed on the caval side of the hepatic veins, and the liver is removed. If the hepatic vein cuffs are to be used as part of the recipient anastomosis, the veins are transected intrahepatically to preserve length. The liver is now removed.

Vascular and Biliary Anastomoses in Deceased Donor Orthotopic Liver Transplantation 103

of the middle and left hepatic veins of the recipient are sewn to the donor's suprahepatic IVC. However, joining all three hepatic veins and using a common orifice may be associated with less incidence of venous outflow obstruction (Parrilla et al., 1999; Tayar et al, 2011). Usually, it is technically difficult to place a clamp that will include all three veins during the hepatectomy phase. Therefore, in most instances, the orifice of the right hepatic vein and the common orifice of the left and middle hepatic veins are initially clamped separately. Once the liver is removed, a second clamp is placed to include all three veins The initial clamps are removed and the opening of all three veins are joined together. (Figure 6). Another technique described involves making a horizontal enlargement of the middle/left trunk to

 Fig. 5. Bicaval reconstruction: Suprahepatic anastomosis preceedes infrahepatic anastomosis

Fig. 6. Classic piggyback reconstruction: Recipient hepatic veins are joined together (all three

The donor liver is brought onto the operative field. Using 3-0 prolene, the donor's suprahepatic cava is anastomosed to the common orifice of all three hepatic veins of the recipient. Similar to the bicaval technique the posterior wall is created first. Once the suprahepatic anastomoses is complete, one liter of cold crystalloid solution is flushed through the donor's PV and the effluent is drained through the donor infrahepatic cava. Once the flush is complete, the orifice of the donor infrahepatic IVC is stapled off with a TA

decrease outflow obstruction (Lerut et al, 1997).

in this picture), and anastomosed to donor cava

Caval sparing techniques are used in large part to maintain systemic (and portal flow, if a temporary portal caval shunt is used) without requiring venovenous bypass. Thus, the dissection is carried out without disturbing systemic flow of the cava. Sometimes, however, either a partially occluding clamp, or complete caval clamping is necessary if troublesome bleeding ensues. (Belghiti et al., 2001). Also, if necessary, venovenous bypass can be used, although proponents of caval preservation usually are striving to avoid systemic bypass.

During the anhepatic phase, once the liver is explanted, the operative field is meticulously examined to ensure adequate hemostasis. This is the best opportunity to visualize the retrohepatic space before the new liver is implanted.

#### **3. Anhepatic phase**

The anhepatic phase consists of the IVC and PV reconstruction.

The initial anastomosis in the implantation of the donor liver is the IVC reconstruction. There are several different techniques which we will discuss here. These include the standard bicaval method, the piggyback technique, the lateral cavocavostomy and a modification of the cavocavostomy technique.

#### **3.1 Bicaval technique**

For the standard bicaval reconstruction, both the suprahepatic and infrahepatic IVC of the recipient are already fully clamped. Depending on the patient's clinical status and the surgeon's preference, the patient may already be on venovenous bypass. The donor liver is brought onto the operative field. Some teams prefer to maintain a slow, continuous antegrade flush through the portal vein to keep the liver cold. For the suprahepatic IVC, 3-0 prolene suture is used. Initially the corner stitches are placed on both the donor and recipient suprahepatic IVC and the liver is gently lowered into the surgical field. Both ends are tied and the posterior wall o f the IVC is anastomosed first from inside the lumen of both veins. An imbrication technique is used to prevent posterior leaks, and to exclude potentially thrombogenic adventitial surfaces. Subsequently the anterior wall is sutured.

After the suprahepatic IVC anastomosis is complete, attention is turned to the infrahepatic IVC. The anastomosis is created with 4-0 prolene in similar fashion to the suprahepatic IVC. Prior to completing the lower caval anastomoses, the liver needs to be flushed with approximately 1 liter of cold crystalloid solution to remove by products of metabolism, air, and preservation solution. This is especially true if using University of Wisconsin solution which is high in potassium and can cause arrhythmias post-reperfusion. The crystalloid is flushed through the donor's PV and the effluent is drained via the infrahepatic IVC.

When the drainage is complete, the lower IVC anastomosis is completed. Sometimes the lower caval anastomosis is left untied to allow egress of blood if the surgical team prefers to also vent the liver with blood prior to final reperfusion. (Figure 5).

#### **3.2 Classic piggyback technique**

In the case of the piggyback technique, there is no infrahepatic IVC reconstruction. In this case the orifice of the right hepatic vein can be tied or stapled off, and the common opening

Caval sparing techniques are used in large part to maintain systemic (and portal flow, if a temporary portal caval shunt is used) without requiring venovenous bypass. Thus, the dissection is carried out without disturbing systemic flow of the cava. Sometimes, however, either a partially occluding clamp, or complete caval clamping is necessary if troublesome bleeding ensues. (Belghiti et al., 2001). Also, if necessary, venovenous bypass can be used, although proponents of caval preservation usually are striving to avoid systemic bypass.

During the anhepatic phase, once the liver is explanted, the operative field is meticulously examined to ensure adequate hemostasis. This is the best opportunity to visualize the

The initial anastomosis in the implantation of the donor liver is the IVC reconstruction. There are several different techniques which we will discuss here. These include the standard bicaval method, the piggyback technique, the lateral cavocavostomy and a

For the standard bicaval reconstruction, both the suprahepatic and infrahepatic IVC of the recipient are already fully clamped. Depending on the patient's clinical status and the surgeon's preference, the patient may already be on venovenous bypass. The donor liver is brought onto the operative field. Some teams prefer to maintain a slow, continuous antegrade flush through the portal vein to keep the liver cold. For the suprahepatic IVC, 3-0 prolene suture is used. Initially the corner stitches are placed on both the donor and recipient suprahepatic IVC and the liver is gently lowered into the surgical field. Both ends are tied and the posterior wall o f the IVC is anastomosed first from inside the lumen of both veins. An imbrication technique is used to prevent posterior leaks, and to exclude potentially thrombogenic adventitial surfaces. Subsequently the anterior wall is sutured.

After the suprahepatic IVC anastomosis is complete, attention is turned to the infrahepatic IVC. The anastomosis is created with 4-0 prolene in similar fashion to the suprahepatic IVC. Prior to completing the lower caval anastomoses, the liver needs to be flushed with approximately 1 liter of cold crystalloid solution to remove by products of metabolism, air, and preservation solution. This is especially true if using University of Wisconsin solution which is high in potassium and can cause arrhythmias post-reperfusion. The crystalloid is

When the drainage is complete, the lower IVC anastomosis is completed. Sometimes the lower caval anastomosis is left untied to allow egress of blood if the surgical team prefers to

In the case of the piggyback technique, there is no infrahepatic IVC reconstruction. In this case the orifice of the right hepatic vein can be tied or stapled off, and the common opening

flushed through the donor's PV and the effluent is drained via the infrahepatic IVC.

also vent the liver with blood prior to final reperfusion. (Figure 5).

**3.2 Classic piggyback technique**

retrohepatic space before the new liver is implanted.

modification of the cavocavostomy technique.

The anhepatic phase consists of the IVC and PV reconstruction.

**3. Anhepatic phase**

**3.1 Bicaval technique**

of the middle and left hepatic veins of the recipient are sewn to the donor's suprahepatic IVC. However, joining all three hepatic veins and using a common orifice may be associated with less incidence of venous outflow obstruction (Parrilla et al., 1999; Tayar et al, 2011). Usually, it is technically difficult to place a clamp that will include all three veins during the hepatectomy phase. Therefore, in most instances, the orifice of the right hepatic vein and the common orifice of the left and middle hepatic veins are initially clamped separately. Once the liver is removed, a second clamp is placed to include all three veins The initial clamps are removed and the opening of all three veins are joined together. (Figure 6). Another technique described involves making a horizontal enlargement of the middle/left trunk to decrease outflow obstruction (Lerut et al, 1997).

Fig. 5. Bicaval reconstruction: Suprahepatic anastomosis preceedes infrahepatic anastomosis

Fig. 6. Classic piggyback reconstruction: Recipient hepatic veins are joined together (all three in this picture), and anastomosed to donor cava

The donor liver is brought onto the operative field. Using 3-0 prolene, the donor's suprahepatic cava is anastomosed to the common orifice of all three hepatic veins of the recipient. Similar to the bicaval technique the posterior wall is created first. Once the suprahepatic anastomoses is complete, one liter of cold crystalloid solution is flushed through the donor's PV and the effluent is drained through the donor infrahepatic cava. Once the flush is complete, the orifice of the donor infrahepatic IVC is stapled off with a TA

Vascular and Biliary Anastomoses in Deceased Donor Orthotopic Liver Transplantation 105

The liver can be flushed with either cold crystalloid solution through the PV prior to completing the PV anastomosis, or blood can be introduced though the completed PV anastomosis and allowed to vent through the open end of the donor cava, which is

One issue to keep in mind with this technique, is that even though the recipient IVC is not fully clamped, in order to create a longitudinal cavotomy, one needs to partially clamp the IVC and the patient's hemodynamic status needs to be carefully monitored. Advantages of the cavostomy technique include a widely patent anastomoses which minimizes outflow obstruction. Furthermore, this technique allows for better exposure and easier anastomoses in cases with difficult exposure, such as a large donor liver. The mobility and positioning of

Other variations of the piggyback technique include the end-to-side configuration (Figure 7a) which may involve enlarging the donor opening with a longitudinal cavotomy through the suprahepatic portion of the donor cava. Also, the recipient hepatic vein orifices may be included, for example, by creating a longitudinal cavotomy through the common trunk of

A final variant of the caval anastomoses is to combine the cavocavostomy incision with the orifice of the hepatic veins on both the donor and recipient. This has been referred to as a suprahepatic cavoplasty (Wu et al., 2001) or a triangulating cavocavostomy (Dasgupta et al., 2006). It is similar to the variant of the piggyback technique described above (Figure 9) but creates a much larger cavotomy. Also, this method requires full clamping of the IVC and, therefore, the hemodynamic changes are similar to the standard bicaval technique and the

However, unlike the bicaval technique there is no need for retroperitoneal dissection of the

For this method, the recipient suprahepatic and infrahepatic IVC are fully dissected out. If the patient tolerates a test clamp, we will proceed with the hepatectomy, otherwise venovenous bypass is initiated. The PV is clamped and transected at its bifurcation. The suprahepatic and infrahepatic IVC are also clamped. Using Metzenbaum scissors, the short hepatics are sharply divided until the level of the hepatic veins. A small patch of the anterior IVC can also be resected along with short hepatics. Subsequently the hepatic veins are also transected intrahepatically, creating a large "triangular" opening along the length of the

the liver may even facilitate the biliary anastomosis (Sonnenday et al., 2008).

the middle/left veins (Figure 9) (Klintmalm & Busuttil, 2005).

Fig. 9. Another variation utilizing partial caval clamping