Ex vivo and in situ hypothermic hepatic resection

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Chapter 94 Ex vivo and in situ hypothermic hepatic resection


The limits of liver surgery are constantly evolving, propelled by advances in surgical technique and imaging. Extended right and left hepatectomies, previously considered to be pushing the boundaries of resection, have become relatively standard procedures for experienced liver surgeons. Strategies such as preoperative portal vein embolization (PVE) (see Chapter 93A, Chapter 93B ) to allow growth of the planned liver remnant allows even more aggressive resections to be performed with a morbidity similar to that of less extensive resections. Advances in surgical technique have been paralleled by advances in hepatic imaging, giving the liver surgeon greater ability to assess tumor position in relation to the intrahepatic vascular and biliary structures. Over the same period, liver transplantation has thrived and proliferated, and more recently the development of living donor liver transplantation (LDLT) has led to a variety of techniques that also can be applied in nontransplant liver surgery. Standard components of LDLT include resection and reconstruction of portal venous, hepatic arterial, biliary, and hepatic venous structures (see Chapters 90D and 98B). These same techniques are now more frequently being considered for the resection of hepatic tumors by surgeons experienced with liver resection and transplantation techniques.

The principal difficulty of vascular reconstruction during hepatic resection is the resulting period of hepatic ischemia. The liver can tolerate short periods of ischemia surprisingly well. During standard liver resections, the use of hepatic inflow occlusion is often used during the parenchymal transection to control excessive blood loss. The use of a combination of inflow occlusion with maintenance of low central venous pressure (CVP) allows relatively bloodless transection of the liver. Intermittent hepatic inflow occlusion for 15 minutes with 5 minutes of reperfusion at the end of each 15-minute interval can reduce the degree of liver injury (Man et al, 1997) and may be particularly useful in more complex resections.

Ischemic preconditioning seems to protect the liver from subsequent ischemic injury (Clavien et al, 2003) and is performed by applying a Pringle maneuver for 10 minutes, then reperfusing the liver for at least 10 minutes before reapplying inflow occlusion. The mechanisms by which ischemic preconditioning protects the liver from subsequent ischemia have not been fully elucidated, but even longer periods of ischemia are relatively well tolerated. The normal liver can tolerate 60 minutes or more of continuous inflow occlusion and warm ischemia (Huguet et al, 1994; Azoulay et al, 2005), but patients with cirrhosis or altered liver function from biliary obstruction or prolonged chemotherapy may tolerate significantly less ischemic insult before sustaining irreversible injury (Hannoun et al, 1996); the same may be true of older patients (Selzner et al, 2009). Even with normal liver function, the risk of irreversible liver damage following prolonged periods of continuous ischemia is significant.

Beyond inflow occlusion, tumors that involve the retrohepatic inferior vena cava (IVC) or that involve the hepatic veins at their junction with the vena cava may require total vascular isolation (see Chapter 91A). Total vascular isolation may increase the degree of ischemic injury to the liver more than inflow occlusion alone, as there is some evidence that backward diffusion of hepatic venous blood into the liver attenuates ischemic injury (Smyrniotis et al, 2003). In most cases, however, the procedure can be planned such that most of the hepatic parenchymal division is performed without total vascular exclusion, and caval clamping is reserved for the relatively short time that is required to deal with the IVC or hepatic veins.

In fact, most resections involving hepatic vascular structures can be dealt with using techniques that do not involve protective strategies, such as hypothermic perfusion of the liver. Tumors that involve hilar vessels usually can be dealt with by temporary occlusion of the hepatic artery or portal vein with relatively short ischemic times. Blood flow to the liver is maintained by the artery, if the portal vein is reconstructed, or the portal vein, if the artery is reconstructed. In the rare case that the hepatic artery and the portal vein require reconstruction, the reconstructions can be performed sequentially, maintaining flow through one vessel or the other.

Based on the previous information, it would seem that standard liver resection techniques can be applied to almost every liver resection, without the need to consider the use of techniques that require hypothermic perfusion; however, a minority of patients will have lesions that seem truly unresectable by any conventional technique. Lesions that are centrally placed and involve all three main hepatic veins, with or without involvement of the retrohepatic IVC, are essentially unresectable using standard liver resection techniques. These few patients who require complex reconstruction of venous outflow may benefit from ex vivo or in situ hypothermic perfusion of the liver with hepatic resection and vascular reconstruction.

History of Hypothermic Perfusion and Ex Vivo Techniques

Fortner and colleagues (1974) first described the use of hypothermic perfusion during liver resection to protect the liver from ischemic injury in a series of 29 patients. Technical improvements in liver surgery over the next 2 decades, along with the growing understanding of the liver’s ability to tolerate normothermic ischemia, made the use of hypothermic perfusion unnecessary in most cases. During the same period, liver transplantation had been applied to technically unresectable primary and secondary liver malignancy with dismal results (see Chapter 97A). Although the procedure was technically feasible, transplantation for large, unresectable primary liver tumors, and especially for metastatic lesions, resulted in the rapid recurrence of malignancy, either in the new liver or elsewhere shortly after transplantation.

In response to patients with unresectable tumors who were considered inappropriate for liver transplantation, Pichlmayr and associates (1988) developed hypothermic perfusion with ex vivo liver resection. During ex vivo liver resection, the liver is removed completely from the body and perfused with cold preservation solution on the back table. The liver resection is performed on the back table in a completely bloodless field such that reconstruction of hepatic venous outflow is performed under ideal conditions; however, the morbidity and mortality rates from this procedure are relatively high; as a result, in situ and ante situm hypothermic perfusion techniques have been explored.

In situ hypothermic perfusion is performed using standard liver resection mobilization techniques, but the liver is placed in total vascular isolation (see Chapter 91A) and cold perfused via the portal vein. In the ante situm procedure, the liver is cold-perfused via the portal vein, with the hilar structures left otherwise intact; but the suprahepatic IVC is divided, and the liver is rotated forward, allowing improved access to the area of the liver and IVC centered around the hepatic vein confluence. To a great extent, the three techniques—in situ hypothermic liver perfusion, ante situm hypothermic liver perfusion, and ex vivo liver resection—overlap, and all three mirror aspects of LDLT. The procedure and role for each technique are described below.

In Situ Hypothermic Perfusion

In situ hypothermic perfusion is the least technically demanding of the three techniques. In situ perfusion has been recommended (Hannoun et al, 1996) for liver resections that require total vascular isolation for periods exceeding 1 hour. More recently Azoulay and colleagues (2005) demonstrated that hypothermic perfusion of the liver is associated with better tolerance to ischemia in the setting of total vascular isolation of any duration.

The need for total vascular isolation arises when patients have tumors in close proximity to or involving the hepatic veins, retrohepatic IVC, or both. In initial descriptions, the entire hepatic parenchymal transection was performed after cold perfusion of the liver, allowing a precise dissection of the hepatic veins and IVC to occur under bloodless conditions. If caval or hepatic vein resection was required during resection of the tumor, hepatic hypothermia safely allowed the additional ischemic time to perform reconstruction of the vascular structures.

To perform in situ cold perfusion as originally described, the liver is mobilized as for total vascular isolation (see Chapter 91A) with control of the suprahepatic and infrahepatic IVC and the portal structures. The main portal vein is dissected out for insertion of a perfusion catheter. Although the portal vein can be dissected from the right of the bile duct, for in situ perfusion, it is usually easier to dissect it from the left of the bile duct after dissecting out the hepatic artery; the hepatic artery eventually requires control in any event. A sufficient length of portal vein (3 to 4 cm) is exposed to place a perfusion catheter and the portal venous cannula of venovenous bypass, if this is to be used. Most patients tolerate total vascular isolation without venovenous bypass; however, the standard use of bypass reduces the time pressures involved in these cases and reduces the gut edema associated with prolonged portal clamping. Prior to clamping, the patient is bolused with at least 5000 U of heparin intravenously. The infrahepatic cava is clamped, and the patient is placed on the caval portion of venovenous bypass.

It is generally advisable, although not absolutely necessary, to ligate and divide the right adrenal vein before clamping the infrahepatic IVC, because it otherwise has a tendency to become avulsed during some particularly inconvenient portion of the procedure. A portal clamp is placed relatively superiorly on the portal vein with bypass instituted below. The portal cannula can be inserted down toward the superior mesenteric vein after complete division of the portal vein or by dividing just the anterior wall of the portal vein and sliding the cannula down the back wall. Full venovenous bypass is started. The liver side of the portal vein is cannulated with the perfusion solution tubing, and the hepatic artery is clamped. The suprahepatic cava is clamped, and a transverse venotomy is created in the infrahepatic IVC just above the clamp. Cold perfusion of the liver is begun with preservation solution, and the effluent is suctioned from the venotomy in the infrahepatic cava (Fig. 94.1).

Preservation solution is either histidine-tryptophan-ketoglutarate (HTK) (Gubernatis et al, 1990) or University of Wisconsin (UW) solution (Kalayoglu et al, 1988). The liver resection proceeds in a bloodless field with excellent visualization of intrahepatic structures. The liver can be cooled continuously throughout the parenchymal transection by slow infusion of cooling solution (see below), or it can be cooled intermittently every 30 minutes by bolus infusion; at completion of the liver resection, the liver should be flushed of cold preservation solution, which can be done by flushing the portal vein with cold 5% albumin before restoring flow to the liver, or by allowing the initial 300 to 500 mL of venous effluent from the reperfused liver to be vented out the infrahepatic cava venotomy after reperfusion but before removing the suprahepatic cava clamp. Next, the portal bypass cannula is removed, and the portal vein is repaired or reanastomosed if divided. If the liver has been flushed with 5% albumin, the infrahepatic venotomy is closed, and the suprahepatic cava clamp is removed to assess hepatic venous bleeding, which should be controlled if present. Portal and hepatic arterial inflow is reestablished.

If the liver is warm-flushed with the initial blood flow through the liver, the sequence is altered slightly to prevent flushing of cold, high-potassium solution into the cardiac return. If a warm-flush technique is used, the portal vein is repaired, and the infrahepatic venotomy is closed with a running suture left loose and untied. Portal flow is established with the suprahepatic cava clamp in place. The initial 300 to 500 mL of blood is suctioned from the infrahepatic cava venotomy, the suture is secured, and the suprahepatic cava clamp is removed. We often cold flush the liver with 5% albumin, because it can be done in an unhurried fashion, and it allows sequential removal of clamps with separate assessment of hepatic venous and portal bleeding on reperfusion. The patient is decannulated from caval bypass if bypass has been used.

We rarely use in situ perfusion as just described. The advent of LDLT (see Chapters 90D and 98B) and the more frequent use of the anterior approach to liver resection (Liu et al, 2000) have improved the ability to divide the liver parenchyma and dissect along the hepatic veins without the need for extensive periods of inflow occlusion. In patients in whom a single hepatic vein or the vena cava requires reconstruction, most of the parenchymal transection can be performed without inflow occlusion under low CVP conditions. As the parenchymal transection is near completion, total vascular isolation is applied to divide and reconstruct the vascular structures only. This practice results in substantially shorter periods of hepatic ischemia and allows a different method of applying in situ cold perfusion that is simpler and generally does not require bypass.

In this technique, the liver is mobilized as for total vascular isolation. The portal vein is dissected to the right and left branches, and perfusion tubing is placed into the portal vein branch on the side of the liver to be removed (Fig. 94.2). The branch is divided, maintaining portal flow to the side of the liver to be left in but allowing access for cold perfusion. Alternatively, the anterior wall of the main portal vein can be used as a site of cannula insertion (Fig. 94.3). As much of the hepatic parenchyma as possible is divided under low CVP, maintaining hepatic perfusion until it becomes necessary to divide the hepatic veins or IVC that requires reconstruction.

At this point, the patient is volume loaded, and clamps are placed sequentially on the infrahepatic cava, the portal vein, hepatic artery, and the suprahepatic IVC. If only the hepatic vein requires reconstruction, caval flow can be maintained by controlling the offending hepatic vein by placing a clamp tangentially down onto the IVC, across the hepatic vein orifice, but only partially occluding the IVC (Fig. 94.4). The anterior wall of the IVC or hepatic vein is incised, and cold perfusion of the liver is instituted through the portal cannula. Only the side of the liver remaining in place is perfused. The vessels are transected, and the specimen is removed. The vessels, hepatic veins, or IVC can be reconstructed in a bloodless field without time pressures (Fig. 94.5). Before completing the anastomoses, the liver can be flushed with cold 5% albumin. Alternatively, the liver can be flushed with 300 to 400 mL of portal vein blood with the caval clamps still in place, whereupon the portal vein clamp is reapplied, the caval venotomy is closed, and all clamps are removed. With the shorter ischemic periods involved, we have not had to use venovenous bypass with this technique (Dubay et al, 2009; Hemming et al, 2002, 2004, 2008); even longer periods of total vascular isolation do not necessarily require venovenous bypass.

Ante Situm Procedure

The ante situm technique of liver resection can be used when resection of the IVC and hepatic veins is expected to be difficult, and when improved access to the hepatic veins and IVC is required. We have used this technique when combined cava and hepatic vein reconstruction is required (Azoulay et al, 2006). The ante situm technique uses the same technique as in situ cold perfusion with several caveats. The suprahepatic IVC requires more extensive dissection to achieve enough length to place a clamp on, divide, and subsequently reanastomose. Greater exposure of the suprahepatic cava can be obtained by dividing the phrenic veins and gently dissecting the IVC away from the diaphragm (Fig. 94.6). We frequently also open the pericardium directly anterior to the IVC and loop the intrapericardial vena cava; alternatively, a sternotomy provides superb exposure of the entire area (Fig. 94.7).

Control of the intrapericardial cava allows placement of the clamp on the vena cava or caudal right atrium within the pericardium as a primary option or as a secondary option in case technical difficulties arise with placement of the original suprahepatic cava clamp. We perform as much of the liver transection as possible without inflow occlusion before cold perfusing the liver. Venovenous bypass is generally recommended for this procedure; however, many patients tolerate caval clamping without difficulty. Institution of cold perfusion is as originally described for in situ perfusion; however, the perfusate is vented via the suprahepatic IVC as the suprahepatic cava is divided. Dividing the suprahepatic IVC allows the liver to be rotated forward and upward toward the abdominal wall, enabling greater access to the area immediately around the IVC–hepatic vein junction (the hepatocaval confluence) (Figs. 94.8 and 94.9).

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