**2. Historical timeline**

**1. Introduction**

154 Organ Donation and Transplantation - Current Status and Future Challenges

affected by T1D.

preserved [7, 8].

Since Kelly and colleagues performed the first whole pancreas transplant in 1966, significant advancements in pancreas transplantation have been made. [1] There was a gap following the first series of whole pancreas transplants due to poor graft outcomes with significant impact from poor organ preservation of the pancreas playing a major role. It took almost 20 years for the development of newer surgical techniques including use of newly developed perfusion solutions, segmental grafts, advances in ductal drainage including bladder drainage, and effective immunosuppression regimens such that whole organ transplantation burgeoned, with great advances made by Sutherland and colleagues at the University of Minnesota [2]. However, it was not until much later following many years of experimental research that pancreata for islet cell isolation and transplantation became a reality. Over the past two decades in particular a great deal of effort has underpinned making islet cell transplantation a viable therapy for a broader range of patients with type 1 diabetes (T1D). Clinical results have progressively improved, now demonstrating outcomes on par with other organ transplants, specifically in terms of insulin independence, and graft and patient survival [3]. We are now at the point where islet cell transplantation, in the form of allotransplantation, like its forebear whole organ transplantation, has become widely accepted as a clinical therapy for patients

Now more than five decades on and with many organ donor operations having been performed since the advent of organ donor procedures as we know them, we have refined and perfected the organ donor process since the first organ retrieval of a brain dead donor in 1963 [4] and the subsequent adoption of the "Acceptance of Brain Death for Organ Donation" issued by the Ad Hoc Committee of the Harvard Medical School [5]. We have seen an increasing emergence of specialized organ retrieval teams with focus on the overwhelming need to improve organ donor rates for the ever increasing recipient patient population [6]. Always a dedicated surgical pursuit, research into organ donation and the surgical retrieval process for the pancreas and most other organs has often been overlooked in favor of recipientrelated research into the prevention of rejection, and improving immunosuppression and tissue matching. This is particularly problematic when it comes to whole pancreas and islet transplantation as the pancreas is a less retrieval tolerant organ than other solid organs, and requires extra attention both during and after retrieval to ensure that the organ's valuable islets, which are especially susceptible to hypoxia and the ischemic insult, are effectively

In this chapter we provide a general overview of Pancreas Retrieval for both Whole Organ and Islet Cell Transplantation, but it should be noted that there are clear overlaps in this process for both whole organ and cellular transplantation. As such the way the processes are performed can be utilized for retrieval for either type of subsequent transplant. Overall, we have seen significant improvements to pancreas transplantation results, in particular in the islet cell arena, due to the significant research undertaken to improve graft outcomes by improving donor selection and organ procurement and preservation [9]. On the recipient side we have also further improved outcomes with changes to the transplant and to the The original retrieval processes of the modern era were initially developed for and used in kidney only retrieval surgery. As per **Figure 1** the procedure first introduced in 1963 utilized cold lactated Ringer's or low-molecular-weight dextran solutions infused directly into the renal artery of the retrieved kidneys, performed only after their removal from the donor [11]. These were the beginnings of modern donor retrieval but they were less than ideal techniques due to the time taken to perfuse the organs, and therefore a number of more active and by far more effective methods of perfusion and cooling of organs were subsequently developed in order to minimize ischemic insult and subsequent damage to organs. These techniques were based upon the concepts from cardiothoracic surgery, involving active patient cooling during procedures to prevent ischemic damage [12, 13]. The transplant fraternity quickly adopted these intravascular perfusion-related cooling techniques, which were standardly utilized as a first step in the preservation of all whole-organ grafts. The currently accepted modern cadaveric donor procedure is performed using some basal form of the *ex situ* techniques developed and performed in the mid to late 60's by Starzl and colleagues [14] for not only kidneys but also incorporating the pancreas and liver. Further refinements saw the perfusion and addition of heparin to the perfusate solutions and also the donor. Ensuring removal of blood by *ex situ* perfusion as described by Belzer et al. [15] resulted in improved but only satisfactory kidney preservation of several days. However, this technique was eventually abandoned in most kidney transplant centers when it was learned that the quality of 2-day preservation was no better than with the simpler *"iced slush"* methods [16].

The underpinning method of *iced slush* for shipping was based around experimental work on kidneys [17]. This research and practice focused on perfusion fluids of differing intracellular and extracellular fluids consisting of electrolytes with varying osmotic and oncotic effects that were infused into the allograft before placing it in a cold storage container. Collins

et al. [20], using the Collins-Terasaki solution, and de Gruyl et al. [21] using cryoprecipitated plasma perfusion preservation of duct-ligated pancreatic allografts, along with Wall et al. [22] using similar plasma-like solution. This led directly to great improvements in pancreas and liver preservation and allowed organ sharing amongst transplant centers, although the pres-

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The development of University of Wisconsin (UW) solution for organ preservation by Belzer, Jamieson, and Kalayoglu in the 1980s was a game changer in static organ preservation for transplantation [23]. This new flushout solution for preservation of the pancreas was tested in the dog model of segmental pancreas autotransplantation. The solution has an osmolality of 320 mOsm/L (K+ = 120 mM, Na + = 30 mM), and contains lactobionate, and raffinose as impermeants. The role of hydroxyethyl starch (HES), the colloid component of UW solution, was shown to be particularly important for pancreas preservation, in comparison to the liver and kidney [24]. UW perfusate solution preservation almost tripled the time of safe preservation of the various organs, including the pancreas, making national sharing of most organs a

However, despite significant success the preservation or extended preservation of the pancreas still required further refinement, and significant research using animal models of static perfusion were pursued, in particular for use in islet cell transplantation. Along with perfusion fluids a number of standardly used retrieval techniques became more readily adopted [19]. However, until 1981 transplantation of the extra-renal organs was an unusual event such that the focus of perfusion only really focused on kidneys. By the mid-1980s, it became apparent that multiple organs would start to become transplanted in earnest, with liver, pancreas and thoracic organ transplant procedures becoming more widely accepted. A safe and effective method for multi-organ procurement and preservation was required by which the abdominal organs, kidneys, liver, and pancreas, could all be suitably retrieved using the same solution. At this stage Starzl and colleagues published an in-depth method on their "flexible procedure for multiple cadaveric organ procurement" [26], which was adopted by many centers worldwide. However, even at this point the pancreas was often over-looked with the focus on the kidneys and liver as the principal organs to be retrieved. Starzl's publication stated "*If the whole pancreas is transplanted as we recommend, the combination of liver and pancreas removal is incompatible*" and it was often the case when surgical teams were procuring the liver and pancreas together that there were issues relating to the suitable separation of their vasculature [27]. At this time, our own surgical team also retrieved the pancreas with the liver, but always removed liver to the back-table before the pancreas and kidneys. The major perceived reason for this was the need for the lifesaving liver to take priority. Furthermore, as the portal vein and the branches of the celiac trunk, drain or supply both organs, preference was given to sacrificing the pancreas' vessels instead of

the live**r**. It was a number of years before this routine surgical practice would change.

Whole organ research utilized canine models as the dog pancreas is more anatomically similar to humans in comparison to the tri-lobed porcine pancreas. These models allowed replication of the clinical situation and further refinement of the retrieval and transplant procedures [28, 29]. From these came the widespread implementation of newer perfusion fluids such as UW solution, and the utilization of vascular extension grafts to the pancreatic vasculature helped resolve the situation of shortened pancreatic inflow and outflow conduits due to preference to

ervation period was still limited to less than 8 hours.

viable and practical process [25].

**Figure 1.** A time line in the significant development of transplantation over the years with focus on the techniques used for whole pancreas and islet cell transplantation.

and colleagues developed a relatively simple technique (infusion of mannitol, phenoxybenzamine, and their Collins perfusate) providing good preservation in kidneys stored for up to 30 hours [17]. Other perfusates, such as Ringer's lactate and 10% invert-sugar solutions, gave inferior results. The new perfusate solution and technique extended the time of simple ice storage from 12 hours to 30 hours. Continuous hypothermic perfusion saw further additions by Ackerman and Snell [18] and Merkel, Jonasson, and Bergan [19] who following many organ donor studies developed the widely accepted and much more simplified core cooling. These utilized cold perfusion solutions with the infusion of the fluids being performed directly to the vascular bed of all the organs via the distal aorta and demonstrated significant improvement for the pancreas but they were still less than ideal for this most sensitive organ. However, the development of these techniques used throughout the 70's meant that organs could generally be removed without causing issues when retrieving multiple organs, which included the liver and sometimes pancreas. Kidney preservation became more feasible along with the other abdominal organs seeing times of 1 to 2 days, long enough to allow tissue matching and sharing of organs between hospital units even interstate or in Europe between countries. However, these were purely focused still on the kidneys rather than the other abdominal organs and as such a number of groups undertook experiments focusing on other organs including the pancreas and liver; landmark papers included those by Benichou et al. [20], using the Collins-Terasaki solution, and de Gruyl et al. [21] using cryoprecipitated plasma perfusion preservation of duct-ligated pancreatic allografts, along with Wall et al. [22] using similar plasma-like solution. This led directly to great improvements in pancreas and liver preservation and allowed organ sharing amongst transplant centers, although the preservation period was still limited to less than 8 hours.

The development of University of Wisconsin (UW) solution for organ preservation by Belzer, Jamieson, and Kalayoglu in the 1980s was a game changer in static organ preservation for transplantation [23]. This new flushout solution for preservation of the pancreas was tested in the dog model of segmental pancreas autotransplantation. The solution has an osmolality of 320 mOsm/L (K+ = 120 mM, Na + = 30 mM), and contains lactobionate, and raffinose as impermeants. The role of hydroxyethyl starch (HES), the colloid component of UW solution, was shown to be particularly important for pancreas preservation, in comparison to the liver and kidney [24]. UW perfusate solution preservation almost tripled the time of safe preservation of the various organs, including the pancreas, making national sharing of most organs a viable and practical process [25].

However, despite significant success the preservation or extended preservation of the pancreas still required further refinement, and significant research using animal models of static perfusion were pursued, in particular for use in islet cell transplantation. Along with perfusion fluids a number of standardly used retrieval techniques became more readily adopted [19]. However, until 1981 transplantation of the extra-renal organs was an unusual event such that the focus of perfusion only really focused on kidneys. By the mid-1980s, it became apparent that multiple organs would start to become transplanted in earnest, with liver, pancreas and thoracic organ transplant procedures becoming more widely accepted. A safe and effective method for multi-organ procurement and preservation was required by which the abdominal organs, kidneys, liver, and pancreas, could all be suitably retrieved using the same solution. At this stage Starzl and colleagues published an in-depth method on their "flexible procedure for multiple cadaveric organ procurement" [26], which was adopted by many centers worldwide.

and colleagues developed a relatively simple technique (infusion of mannitol, phenoxybenzamine, and their Collins perfusate) providing good preservation in kidneys stored for up to 30 hours [17]. Other perfusates, such as Ringer's lactate and 10% invert-sugar solutions, gave inferior results. The new perfusate solution and technique extended the time of simple ice storage from 12 hours to 30 hours. Continuous hypothermic perfusion saw further additions by Ackerman and Snell [18] and Merkel, Jonasson, and Bergan [19] who following many organ donor studies developed the widely accepted and much more simplified core cooling. These utilized cold perfusion solutions with the infusion of the fluids being performed directly to the vascular bed of all the organs via the distal aorta and demonstrated significant improvement for the pancreas but they were still less than ideal for this most sensitive organ. However, the development of these techniques used throughout the 70's meant that organs could generally be removed without causing issues when retrieving multiple organs, which included the liver and sometimes pancreas. Kidney preservation became more feasible along with the other abdominal organs seeing times of 1 to 2 days, long enough to allow tissue matching and sharing of organs between hospital units even interstate or in Europe between countries. However, these were purely focused still on the kidneys rather than the other abdominal organs and as such a number of groups undertook experiments focusing on other organs including the pancreas and liver; landmark papers included those by Benichou

**Figure 1.** A time line in the significant development of transplantation over the years with focus on the techniques used

for whole pancreas and islet cell transplantation.

156 Organ Donation and Transplantation - Current Status and Future Challenges

However, even at this point the pancreas was often over-looked with the focus on the kidneys and liver as the principal organs to be retrieved. Starzl's publication stated "*If the whole pancreas is transplanted as we recommend, the combination of liver and pancreas removal is incompatible*" and it was often the case when surgical teams were procuring the liver and pancreas together that there were issues relating to the suitable separation of their vasculature [27]. At this time, our own surgical team also retrieved the pancreas with the liver, but always removed liver to the back-table before the pancreas and kidneys. The major perceived reason for this was the need for the lifesaving liver to take priority. Furthermore, as the portal vein and the branches of the celiac trunk, drain or supply both organs, preference was given to sacrificing the pancreas' vessels instead of the live**r**. It was a number of years before this routine surgical practice would change.

Whole organ research utilized canine models as the dog pancreas is more anatomically similar to humans in comparison to the tri-lobed porcine pancreas. These models allowed replication of the clinical situation and further refinement of the retrieval and transplant procedures [28, 29]. From these came the widespread implementation of newer perfusion fluids such as UW solution, and the utilization of vascular extension grafts to the pancreatic vasculature helped resolve the situation of shortened pancreatic inflow and outflow conduits due to preference to the liver in combined retrievals [30]. The other major change to the procedure was the adoption of an *en bloc* liver pancreas retrieval technique, where both organs were rapidly removed in a bloodless field post perfusion, then separated on the back-table. Furthermore, the sharing of organs from a common donor by recipient teams from different units became routine by the early-1990s, in particular due to the use of UW solution, which had clearly been shown to be a real advantage in pancreas retrieval both experimentally and clinically [31].

of procured pancreata [37]. The organ must be procured without any parenchymal and/or capsular breach, and its arterial inflow and venous outflow vessels must be clearly identified (tagged) and maintained for subsequent back-table reconstruction when used for whole pancreas [38]. The extent of organ and vascular dissection depends upon whether the retrieval is from a brain-dead (DBD) or circulatory death (DCD) donor; a large proportion of pancreas dissection can be undertaken in the warm phase for DBD donors, whilst pursuit of the DCD pathway necessitates wholly cold-phase dissection, which is potentially more difficult

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The pancreas is situated in the retroperitoneum, nestled within the curvature of the duodenum. Important relations are both kidneys posteriorly, the spleen laterally and attached to the pancreas via its pedicle contained within the lienorenal ligament, the superior mesenteric vessels, bile duct, and portal vein in the region of the pancreatic head/neck, the inferior vena cava (IVC) deep to the head and portal vein, and the aorta, left suprarenal gland and left renal vein deep to the body. Pancreatic blood supply is primarily derived from the celiac artery in origin via the splenic and superior mesenteric arteries (via the inferior pancreaticoduodenal artery), and also the gastroduodenal artery (via the superior pancreaticoduodenal artery). The celiac trunk gives off the splenic artery, which emerges at the upper pancreatic border and runs along this border in a tortuous fashion until turning towards the splenic hilum within the lienorenal ligament. The superior mesenteric artery (SMA) emerges from the aorta inferior to the celiac trunk, and is directed inferiorly on the posterior aspect of the pancreatic neck, to then lie on the uncinate process and then the 3rd part of the duodenum prior to entering the root of the mesentery. Venous drainage occurs via the splenic vein for a large part of the pancreas, whilst the superior and inferior pancreaticoduodenal veins drain the head into the superior mesenteric vein (SMV) and portal vein confluence. It is the shared vasculature of the pancreas with the liver that often causes retrieval issues as the origin of the splenic artery is from the celiac, and the outflow of the splenic vein is through the portal vein, necessitating delicate surgical dissection and care in separation to ensure shared and usable

Pancreas retrieval in the DBD donor is a controlled process that allows significant preliminary organ and vascular pedicle dissection. The Cattell-Braasch maneuver is utilized to expose the aorta and IVC distally, with the proximal extent of dissection limited by the SMA overlying the left renal vein; this maneuver will incorporate mobilization of the small bowel mesentery and pancreatic head/duodenum [40]. Our approach to exposure and dissection of the remaining pancreas [41] is to access the lesser sac by mobilization of the greater curvature of the stomach; the greater omentum is detached at its origin using ultrasonic shears (Harmonic Scalpel) as per **Figure 2**. The short gastric vessels are also detached using this method at the upper portion of the greater curvature. The splenic flexure of the large bowel can thence be mobilized onto the lower pole of the spleen. Once the spleen is free of its surrounding attachments, it can be lifted and used as a handle to mobilize the tail and body of the pancreas without directly

as appropriate anatomy is harder to identify.

*4.1.1. Anatomical considerations*

vasculature for both organs [39].

*4.1.2. DBD retrievals—pancreas-specific considerations*

In the 1990's the focus on research and advances relating to the retrieval process started to shift, with attention once again shifting to the perfusate solutions, which were thought to be especially impactful for islet cell transplantation. A number of groups also investigated additives to the perfusate solutions such as the use of antibodies to reduce inflammation and further improve graft outcomes, although this was met with limited success [32]. In the 2000's it became generally accepted this was achieved via cannulation of the aorta alone, with or without additional access to the portal venous system with variations that have been seen specifically in relation to multiorgan retrieval where some groups chose to perform 'dual' perfusion technique which are all discussed in greater detail later in this chapter [33, 34].
