15/09/13

Organ Preservation

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Organ Preservation
Author: Erik B Finger, MD, PhD; Chief Editor: Ron Shapiro, MD more...
Updated: Sep 5, 2013

Overview
According to data from the United Network for Organ Sharing (UNOS), more than 400,000 renal transplantations
have been performed since the first successful renal transplantation in the 1950s. With improved surgical
techniques and immunosuppressive medications, outcomes after renal and extrarenal (liver, pancreas, lung, heart)
transplantation have continued to improve.
Most solid-organ transplantations are now performed as the therapeutic option of choice. In many cases,
transplantation offers definitive treatment for a given disease entity. As a result, the list of indications for solidorgan transplantation has expanded considerably, placing increasing pressure on an already limited supply of
donor organs.
The growth in the number of patients wanting or waiting for a transplant has outpaced the supply of available
organs. As of April 2004, 96,060 patients were awaiting deceased donor organ transplantation in the United
States, compared with half as many in 1995.[1, 2] The UNOS reported that, as of July 2000, 45,600 people on its
national patient list were waiting for a kidney.[3] The average waiting time for a deceased donor kidney transplant is
approaching 3 years, and that for heart transplants 18 months.[2] Each year, more patients are placed on the
waiting lists than receive transplants, causing the waiting time to increase. With such constraints, preservation of
organs for transport between centers becomes crucial.
The technology of organ preservation has improved considerably. Several organ-preservation solutions are
available, and these are being constantly modified to provide improved organ storage and outcomes.
This article discusses the pathophysiology, techniques, and principles of organ preservation, and it describes
various preservation solutions currently used for kidney, liver, pancreas, small-bowel, lung, and heart
transplantations.

Pathophysiology of Organ Preservation

The removal, storage, and transplantation of a solid organ from a donor profoundly alters the homeostasis of the
interior milieu of the organ. These effects manifest in the degree to which the return of normal organ function is
delayed or prevented after transplantation is completed. The injury an organ sustains during recovery, preservation,
and transplantation occurs primarily as a result of ischemia and hypothermia. Techniques for organ preservation
serve to minimize this damage to promote optimal graft survival and function.

Phases of Organ Damage During Transplantation

Damage to organs during transplantation occurs in 2 phases.

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The first, the warm ischemic phase, includes the time from the interruption of circulation to the donor organ to the
time the organ is flushed with hypothermic preservation solution. In multiorgan recovery, the organs are cooled
before they are removed.
The second, the cold ischemic phase, occurs when the organ is preserved in a hypothermic state prior to
transplantation into the recipient.

Mechanisms of Tissue Injury

Integrity of the cell structure
The cell membrane plays a structural role for the cell and provides an active interface with the extracellular
environment. Receptors, ion regulation, and enzyme systems linked to the cell-membrane complex contain
extracellular, transmembrane, and intracellular components essential to their function.
The stability of the membrane to chemical and water permeability depends on the integrity of the lipid bilayer and
on tight control of temperature, pH, and osmolarity.[4] Organ ischemia and preservation disrupt all these relations.
Lowering the temperature causes a phase transition of lipids and results in profound changes in membrane
stability. In addition, it drastically alters the function of membrane-bound enzymes.[4] Hypothermia-induced
structural changes in the membrane increase permeability, which contributes to cell swelling. Therefore, organpreservation solutions are hypertonic to minimize these alterations.
Ionic composition of the cell
The sodium-potassium adenosine triphosphatase (Na-K ATPase) pump functions to maintain the ionic
composition of the cell. The pump is disrupted because of the lack of adenosine triphosphate (ATP) production
and by excessive production of hydrogen ions because of anaerobic metabolism during ischemia. When the
sodium-potassium ATPase pump is paralyzed, potassium moves out of the cell and diffuses down its
concentration gradient to the extracellular space, whereas sodium, which is normally kept at a low concentration
in the cell, pours in. This ionic shift causes cell swelling and disruption of the cell if unchecked. Current
preservation solutions have electrolyte compositions similar to the milieu inside the cell, with high potassium and
low sodium concentrations to minimize the osmotic gradients.
Hydrogen-ion production continues in ischemic organs and causes intracellular pH to decrease without
replenishment of buffering capabilities. Under conditions requiring a switch from aerobic to anaerobic glycolysis,
the production of lactic acid also increases. The liver appears to be especially susceptible to this type of injury.
Calcium ion permeability is increased with ischemia, and a rapid influx of calcium overpowers the intracellular
buffering capacity. Calmodulin activity increases and, in turn, causes upregulation of phospholipases. Subsequent
production of prostaglandin derivatives results in mitochondrial and cell-membrane injury. Increased cellular
calcium concentrations also initiate myofibrillar contraction of the vascular smooth muscle, causing vasospasm
and subsequent ischemic damage.
Endothelin, a 21amino acid peptide with potent vasoconstrictor properties, is another factor that plays a major
role in ischemia by inducing vasospasm, which delays recovery of organ function after revascularization.[5, 6]
Investigators have evaluated the use of endothelin A and B receptor antagonists to improve results after solid-organ
transplantation, reporting favorable results.
ATP generation
A combination of the anaerobic enzymatic breakdown of glucose (glycolysis) and aerobic cellular respiration
provides for the energy requirements of aerobic cells. These processes encompass the transfer of electrons from
organic molecules to molecular oxygen. Hypothermia decreases the metabolic rate and slows enzymatic
degradation of cellular components, but metabolism is not completely suppressed. Cooling from 37C to 0C
reduces cellular metabolism 12-fold.[4] Although metabolism and utilization of cellular energy stores are slowed,
ATP and adenosine diphosphate (ADP), the major sources of cellular metabolic energy, are gradually depleted
during hypothermia. This depletion is due to residual energy requirements of the cell that exceed the capacity of
the cell to produce ATP.
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During ischemia and organ preservation, the glycolytic pathway is shunted to lactate production with generation of
2 ATP, as the Krebs tricarboxylic acid cycle (TCA) cycle and mitochondrial respiration are impaired. Therefore,
mitochondrial dysfunction is responsible for most of the changes in cellular energy associated with ischemia and
organ preservation.
Hypothermic preservation reduces the activity of mitochondrial enzymes.[7] Cellular respiration, which requires
adenine nucleotide substrates, is reduced. For ADP to be transported into the mitochondrion as a substrate for
conversion to high-energy ATP, a membrane adenine nucleotide translocase is required. Hypothermia impairs the
function of the translocase because amounts of ADP available in the mitochondria for conversion to ATP are
decreased.[8] Phospholipid hydrolysis by phospholipases increases levels of free fatty acids, which also affect
function of the translocase. Adenylate kinase converts excess ADP accumulating in the cytoplasm to ATP, and
adenosine monophosphate accumulates as a by-product. This effect reduces purine synthesis and results in the
loss of ATP precursors from the cell.
Vascular renal resistance during hypothermic machine perfusion has been found to be an independent risk factor
for 1-year graft failure. Renal resistance must be taken into account when evaluating graft quality and predicting a
successful outcome; however, renal resistance on its own cannot be used to precisely predict the outcome.[9]
Reperfusion injury
Much of the injury to transplanted organs occurs not during ischemia, but during reperfusion. This finding has led
to many advances in organ preservation aimed at preventing this type of injury. Furthermore, some of the events
that occur during reperfusion may result in enhanced immunogenicity of the graft.[10] Oxygen free-radicals
generated during reperfusion are the main cause of the reperfusion injury, but cytokines and nitric oxide also play
a role.[10, 11]
Oxygen free-radicals are the most important mediators of reperfusion injury and act by means of various
mechanisms. During ischemic states, increased intracellular calcium levels activate cytosolic enzymes, resulting
in the conversion of xanthine dehydrogenase to xanthine oxidase.[10] Both xanthine dehydrogenase and xanthine
oxidase catabolize hypoxanthine and xanthine to uric acid, and xanthine oxidase uses molecular oxygen as an
electron acceptor, forming superoxide as a result.[10] Superoxide anion rapidly reacts with itself to form hydrogen
peroxide, a potent oxidant capable of injuring the cell by oxidizing lipid membranes and cellular proteins. Hydrogen
peroxide then produces a cascade of oxygen free-radicals, including hydroxyl radical and singlet oxygen, that are
even more potent than the others. The damaging effects of oxygen free-radicals begin on reperfusion of the organ.
During ischemic conditions, tissue oxygen levels fall below the threshold needed to allow xanthine oxidase to
metabolize xanthine and hypoxanthine. This decrease allows the intracellular concentration of these metabolites
to rise. On reperfusion, oxygen is suddenly available, and metabolism proceeds rapidly, resulting in a sudden
production of reactive oxygen intermediates. The cellular pathways to scavenge oxygen free-radicals are
overwhelmed, and cellular injury ensues.
Allopurinol, an inhibitor of xanthine oxidase, has protective effects when it is used before the ischemic insult, as
shown in various experimental systems. Lipid peroxidation is another consequence of free radical generation.[11] In
this process, interaction of highly reactive oxygen species with polyunsaturated fatty acids in the cell membrane
starts a chain reaction that may ultimately destroy cellular integrity and result in cell death. The magnitude of lipid
peroxidation appears to be inversely related to levels of glutathione, which functions as an endogenous free-radical
scavenger.[11] Therefore, glutathione and other agents that protect against peroxidation are useful in organ
preservation solutions to attenuate reperfusion injury.
Production of oxygen free radicals also initiates production of prostaglandins, including leukotriene B4, by means
of direct activation of phospholipase A210. This chemoattractant causes leukocyte adherence to vascular
endothelium. These neutrophils may contribute to local injury by plugging the microcirculation and by
degranulation with resulting proteolytic damage to the organ.
Cytokines are intercellular messenger molecules that may be produced in various normal and pathophysiologic
states. Ischemia and reperfusion are associated with marked release of tumor necrosis factor (TNF)-alpha,
interferon-gamma, interleukin-1, and interleukin-8.[12] These cytokines cause upregulation of adhesion molecules
and cause leukocyte adherence and platelet plugging after revascularization, resulting in graft failure and rejection.
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Nitric oxide (NO) is an extremely labile autocoid generated by nitric oxide synthase from L-arginine. Reports
indicate that NO production is induced by inflammatory cytokines, such as TNF-alpha, interferon-gamma, and
interleukin-1. Increased NO synthesis also correlates with acute rejection.[13]

Preservation Solutions and Their Pharmacology

Various flush solutions are used for organ preservation. Each substantially differs in their composition, but the
purposes of each are similar: to prevent cellular edema, to delay cell destruction, and to maximize organ function
after perfusion is reestablished.

Euro-Collins solutions
The development of solutions of intracellular electrolyte composition allowed for organ preservation to be
attempted. These early solutions, called Collins solutions, contained high concentrations of potassium,
magnesium, phosphate, sulphate, and glucose. Euro-Collins solution was developed as a modification of the
original Collins solution and contained high concentrations of potassium (110 mM), phosphate (60 mM), and
glucose (180 mM). Organ preservation improved with the use of Euro-Collins solution. When it was used for kidney
preservation, delayed renal function after implantation was significantly reduced. The solution was adequate for use
in preserving the heart, liver, and lung.

Ross-Marshall citrate solutions

Ross-Marshall citrate solutions were developed as alternatives to the Collins solutions. Their electrolytic
compositions are similar except that citrate replaces phosphate, and mannitol replaces glucose. The citrate acts
as a buffer and chelates with magnesium to form an impermeable molecule that helps stabilize the extracellular
environment. It is not commonly used in clinical practice.

Bretschneider histidine tryptophan ketoglutarate solution

Initially developed as a cardioplegia solution for the use in open heart surgery, Bretschneider histidine tryptophan
ketoglutarate (HTK) solution was found to be effective in liver and kidney preservation. Its contents include histidine
(200 mM), mannitol (30 mM), tryptophan and alpha-ketoglutaric acid. It also contains low concentrations of
sodium, potassium, and magnesium. Histidine serves as a buffer, and tryptophan, histidine, and mannitol act as
oxygen free-radical scavengers. The solution improved renal function after transplantation compared with EuroCollins solution. It has become increasingly popular in recent years, but some concern exists regarding an
increased risk for pancreatitis when the pancreas graft is preserved with HTK solution. This has not been
confirmed in randomized studies.

Phosphate-buffered sucrose solution

This solution contains sucrose 140 mmol/L and sodium hydrogen and dihydrogen phosphate as buffers. In
experimental studies, it preserved dog kidneys for 3 days. It is not commonly used today.

University of Wisconsin solution

University of Wisconsin (UW) solution was developed for liver, kidney, and pancreas preservation. It has been
considered the standard for renal and hepatic preservation, effectively extending the ischemic time for kidneys and
livers and allowing them to be transported considerable distances to waiting recipients. UW solution has also been
successfully applied to small-bowel and heart preservation.
The composition of the solution is complex. Analysis of its various components has shown that some may be
omitted or replaced with results similar to that of the original solution.
The solution has an osmolality of 320 mmol/kg and pH 7.4 at room temperature and is composed of the following:
Potassium 135 mmol/L
Sodium 35 mmol/L
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Magnesium 5 mmol/L
Lactobionate 100 mmol/L
Phosphate 25 mmol/L
Sulphate 5 mmol/L
Raffinose 30 mmol/L
Adenosine 5 mmol/L
Allopurinol 1 mmol/L
Glutathione 3 mmol/L
Insulin 100 U/L
Dexamethasone 8 mg/L
Hydroxyethyl starch (HES) 50 g/L
Bactrim 0.5 ml/L
HES conveys no advantage to the solution when used for cold storage, and it, in fact, adds to the viscosity of the
solution as well as to the expense. HES-free derivatives of the solution have given similar, if not better, clinical
results than those of the original formulation.
The lactobionate is the major effective component of the solution. Its insoluble nature maintains the colloid oncotic
pressure of the solution, delaying or preventing equilibration of the solution across the cell membrane, and thus
delaying the development of cellular edema.
The lowered concentration of potassium improves the flushing efficiency of the solution by removing the
vasoconstrictive effect of the high potassium solution.
Glutathione is unstable in solution and effective as an oxygen free-radical scavenger only if it is added immediately
before use. Adenosine and allopurinol help in this function.

Celsior solution
Celsior is a recently developed extracellular-type, low-viscosity (due to the absence of HES) preservation solution
that couples the impermeant, inert osmotic carrier from UW solution (by using lactobionate and mannitol) and the
strong buffer from Bretschneider HTK solution (by using histidine). The reduced glutathione in Celsior solution is
the best antioxidant available. The solution was specifically designed for heart transplantation. It is being currently
used in clinical lung, liver, and kidney transplantations and it is under investigation for pancreas transplantation.
The contents of Celsior solution are as follows:
Sodium 100 mmol/L
Potassium 15 mmol/L
Magnesium 13 mmol/L
Calcium 0.25 mmol/L
Lactobionate 80 mmol/L
Glutathione 3 mmol/L
Glutamate 20 mmol/L
Mannitol 60 mmol/L
Histidine 30 mmol/L

Kyoto ET solution
Researchers at Kyoto University developed a new solution that contains a high sodium concentration, a low
potassium concentration, trehalose, and gluconate. The solution is chemically stable at room temperature. It is
being investigated for skin storage and lung preservation in a rat model. ET Kyoto solution is also being actively
investigated in clinical trials for transplantation of the lungs, heart, and other organs.
Its constituents include the following:
Sodium 100 mmol/L
Potassium 44 mmol/L
Phosphate 25 mmol/L
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Trehalose 41 mmol/L
HES 30 gm/L
Gluconate 100 mmol/L

Techniques of Organ Preservation

Because most transplanted organs are from deceased donors, the organ must inevitably be stored after its
removal from the donor until it can be transplanted into a suitable recipient. The donor and recipient are often in
different locations, and time is needed to transport the donor organ to the hospital where the recipient is being
prepared for transplantation. Effective, safe, and reliable methods are needed to preserve the organ ex vivo until
transplantation can be performed. Acceptable preservation times vary with the organ. Most surgeons prefer to
transplant the heart within 5 hours of its removal; the kidney can safely be stored for 40-50 hours, but earlier
transplantation is preferred. Most pancreas transplants are performed after 5-15 hours of preservation. Liver
transplantations usually are performed within 6-12 hours.

Hypothermic preservation
Hypothermia is the preferred technique of organ preservation because it is simple, does not require sophisticated
expensive equipment, and allows ease of transport. Hypothermia is beneficial because it slows metabolism.[4, 14,
15] Organs exposed to normothermic ischemia remain viable for relatively short periods, usually less than 1 hour.
In warm ischemia, the absence of oxygen leads to a rapid decline in ATP levels in the cells, to a redistribution of
electrolytes across the cell membrane, and to a decrease in biosynthetic reactions. However, biodegradable
reactions continue; these include the accumulation of lactic acid, a decrease in intracellular pH, proteolysis,
lipolysis, and lipid peroxidation.
With hypothermia, the degradative reactions are considerably slowed but not halted. A 10 C decrease in
temperature slows the metabolic rate approximately by a factor of 2. Cooling an organ from 37 C to
approximately 0 C slows metabolism by a factor of 12-13. Hypothermia alone is not sufficient for adequate
preservation because of the time necessary for optimal use of deceased donor organs. Therefore, the organ must
also be flushed with an appropriate preservation solution.
Two techniques of hypothermic preservation are used: simple cold storage and continuous hypothermic perfusion.
With simple cold storage, the organ is flushed with cold preservative solution and placed in a sterile bag immersed
in the solution. The sterile bag is placed inside another bag that contains crushed ice. Advantages of simple cold
storage include universal availability and ease of transport. With continuous hypothermic perfusion, which Belzer
developed in 1967, a machine is used to continuously pump perfusion fluid through the organ.[16] In this way,
oxygen and substrates are continuously delivered to the organ, which maintains ion-pump activity and metabolism,
including the synthesis of ATP and other molecules.
For kidneys, machine perfusion offers superior results compared with simple cold storage.[17] With simple cold
storage, approximately 25-30% of transplanted kidneys have delayed graft function, but with machine perfusion,
the rate can be less than 10%. The perfusate is similar to the UW solution, except for the impermeant. For
continuous perfusion, gluconate is used in place of lactobionic acid.[16]

Freezing and thawing

Cryopreservation has long fascinated scientists, who have made many attempts at cryopreserving organs and even
full bodies by means of conventional freezing and thawing.[18] These efforts usually focused on simple transferring
techniques that have worked for cell preservation to organs.
Notable problems are associated with this approach. For instance, the packing density of cells in an organ can
approach 80%, but preservation of isolated cells becomes technically difficult at a cell concentration above 20%.
[19] In addition, the presence of many different cell types, each with its own requirements for optimal
cryopreservation limits the recovery of each when a single thermal protocol is imposed on all cells. Moreover,
extracellular ice can cause mechanical damage to the structural integrity of the organ, particularly the vascular
component, where ice is likely to form.[18] Mechanical fractures occur in the vitreous solids that exist between ice
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crystals when thermal stresses occur at low temperatures. These fractures separate parts of the organ from each
other. The attachments that form between cells and between cells and their basement membranes are disrupted.
Last, osmotic movement of interstitial water causes mechanical stresses.
Each of the problems is a formidable source of damage, above those already well known from studies of cells in
suspension. Cryopreservation of whole organs is not possible using current technology.

Vitrification
Perhaps the most promising approach to the cryopreservation of whole organs lies with the process of vitrification.
[19] This is the process of taking an aqueous solution and making it into an amorphous solid.
A liquid can be cooled past its melting point without a phase change. The formation of ice first requires nucleation,
a stochastic process by which an ice nucleus (cluster of water molecules that reaches a critical size) forms
spontaneously. With lowered temperatures, the critical size of a nucleus decreases and eventually approaches the
size of the clusters in the liquid. The solution can be cooled to the homogeneous nucleation temperature
(temperature at which the probability of nucleation equals 1) in a supercooled state, but below this point
crystallization occurs. The supercooled liquid exists in a metastable state until the transition temperature is
reached. At this temperature, the time required for the molecular translations needed in nucleation or crystalline
growth becomes infinite; therefore, the amorphous solid is stable below this point.
Vitrification can also be achieved by adding solutes that develop a structure in water that must be broken down for
crystalline growth. The solute molecules impede this growth simply by blocking other water molecules and
interfering with hydrogen bonding necessary for ice formation. Both the kinetic approach and the solute approach
are additive. Therefore, as the solute concentration is increased, the cooling rate necessary to achieve vitrification
is lowered.
The problem with vitrifying organs is that about half of the water in an organ must be replaced with solute
molecules for vitrification to occur at reasonable cooling rates. The difficulties in developing successful vitrification
techniques include infusing high concentrations of vitrification solutes into the organ and removing them on thawing
and preventing fracturing of the organs during cryogenic storage and warming the organs fast enough to prevent
devitrification, among other problems. Vitrification is not currently being used in clinical transplantation.
Table. Constituents and Their Functions (Open Table in a new window)
Constituent

Function

Example

Osmotic
active agents

Prevent cell swelling

Lactobionate, raffinose, citrate, gluconate

Electrolytes

Exert an osmotic effect

Na+, K+, Ca+, Mg+

H+ ion buffers

Regulate extracellular H+

Phosphate, histidine, N -(2-hydroxyethyl)-piperazine-N'-2ethanesulfonic acid (HEPES) buffer

Colloid

Initial vascular flush out and

perfusion

Albumin, HES

Metabolic
inhibitors

Suppresses degradation of cell

constituents

Allopurinol, antiproteases, chlorpromazine

Metabolites

Facilitate restoration of
metabolism on reperfusion

Adenosine, glutathione

Antioxidants

Inhibit oxygen free-radical injury

Amino steroids, vitamin E, deferoxamine (Desferal)

Principles of Organ Preservation

Preservation of the organ begins when a donor is identified, and the donor's hemodynamic status must be
adequately maintained to prevent organ injury before its recovery and preservation. An organ can be injured
because of cardiovascular instability and hypotension. During the operation to remove the organ, the warm
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ischemia time must be minimized, and the organ must be cooled rapidly in situ or by means of well-timed backtable flush out.[20] Thereafter, the organ is maintained in hypothermic state and transported in this state until it is
ready to be transplanted. Cold ischemia time must be kept within the limits prescribed for the particular organ.

Donor Maintenance
Tissue perfusion
Because most donors are treated initially with a minimum of fluids to prevent increased cerebral edema, one of the
first priorities in donor maintenance is the prompt restoration of intravascular volume. Volume resuscitation with 310 L may be required, and pressor agents may be needed to support blood pressure.[20]
Crystalloids may be used, and lactated Ringer's solution is often given because its low sodium concentration
counteracts the sodium-increasing effects of diabetes insipidus. If the latter condition has resulted in severe
hypernatremia, free water may need to be added, and desmopressin may also be used selectively in severe
cases. Colloid and blood should be used to restore and maintain osmotic pressure and normovolemia.
The hematocrit should be kept at approximately 35% by volume to replace traumatic losses and maintain oxygencarrying capacity. Enough volume should be administered to achieve a urine output of at least 100 mL/h and a
systolic arterial pressure of 90-120 mm Hg. Arterial blood pressures higher than this are usually unnecessary
because of the loss of sympathetic tone that accompanies brain death.
Oxygenation and ventilation
Arterial blood gases should be checked regularly, and the ventilator should be adjusted to optimize gas exchange
and acid-base balance. The oxygen supply should be adequate to maintain an arterial oxygen saturation of greater
than 95%, and, if available, a mixed venous oxygen saturation above 70%. Low levels of positive end-expiratory
pressure may facilitate balance of the oxygen supply and demand.
Inotropic support
Most donors are hypovolemic at brain death and are receiving inotropic support in lieu of volume to maintain their
blood pressure. Dopamine hydrochloride is the most commonly used agent. High doses of dopamine maintained
for long periods before organ recovery may be associated with increased rates of acute tubular necrosis and
hepatic allograft failure. Cardiac recovery is often abandoned if high doses of inotropic support are required despite
adequate volume status.
Other inotropic agents, such as isoproterenol, epinephrine, norepinephrine, and phenylephrine, are occasionally
used, but use of these agents should be discouraged because of their peripheral vasoconstrictive effects.
Dobutamine is occasionally used in conjunction with low doses of dopamine.
Prevention of hypothermia
Thermoregulatory homeostatic mechanisms are destroyed with brain death, and severe hypothermia may lead to
ventricular arrhythmia and cardiac arrest. Warming blankets should be placed above and below the donor to keep
the body temperature above 35 C. If maintenance of normal body temperature is problematic, intravenous fluids
may be prewarmed before their administration, and a heated humidifier circuit can be added to the ventilator.
Hypothermia and the composition of the organ-preservation solution are key factors in successful organ
preservation. In the cold storage of organs, the organ is rapidly cooled to approximately 4 C by flushing out the
vascular system with an appropriate organ-preservation solution; this is the Starzl method of rapid cooling. The
flushing should remove the blood as completely as possible, and the solution be delivered at a pressure that is not
damaging to the organ (usually 60-100 cm H2 O) and in a volume that is not excessive. The volume used for each
organ varies, but the liver usually is flushed with approximately 2-3 L, the kidney is flushed with 200-500 mL, and
the pancreas with 200-500 mL. The organ is then placed in a sterile container and kept cold at 4-6 C.

Multiple-Organ Recovery
After brain death is declared, the deceased is identified as a suitable organ donor, and the next of kin gives
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permission, the organs must be recovered. Techniques of multiple organ recovery allow for the removal of the
heart, lungs, kidneys, liver, intestine, and pancreas from a single donor for transplantation into 6 or more
recipients.
The heart-beating donor is brought to the operating room from the intensive care unit or emergency department,
with appropriate hemodynamic and electrocardiographic monitoring. Oxygen is delivered by means of manual bagvalve mask with 100% inspired concentration. Inotropic drug infusions are continued during transport and recovery.
The anesthesiologist should maintain close communication with the recovery teams to prevent cardiac arrhythmia,
hypotension, and hypoxemia.
Steps in the procedure can be categorized as follows: (1) incision, (2) exploration and inspection, (3) mobilization
of individual organs, (4) in situ perfusion, (5) removal of organs, and (6) closure of the incision. Postrecovery
processing, packaging, and transport to the recipient centers are the final steps.
Incision, exploration, and inspection
The entire torso is prepared with an iodine-containing solution, and a field is draped from the neck to the pubis.
General exploration is carried out to confirm that unexpected conditions that preclude donation, such as tumor,
infection, or specific organ damage, are absent. A complete midline incision from suprasternal notch to pubis is
made for multiple-organ recovery. The sternum is split. If necessary, cruciate abdominal incisions are added to
facilitate exposure of the intra-abdominal organs.
Mobilization of individual organs and in situ perfusion
In the rapid technique of organ procurement, little mobilization of individual organs is necessary. Preparation for in
situ perfusion consists of a complete Kocher maneuver with a Cantrell maneuver. The aorta is exposed from the
bifurcation distally to the level of the left renal vein proximally. The inferior mesenteric artery is divided. Lumbar
branches may be ligated and divided at this point. The inferior vena cava is similarly exposed.
Next, the left triangular ligament of the liver is taken down, exposing the crural muscle at the aortic hiatus. The
aorta is encircled with tape at the diaphragm. In situ perfusion through the distal aorta and cross-clamping of the
proximal aorta begin immediately in the event the donor becomes hemodynamically unstable or sustains cardiac
arrest. In situ perfusion prevents warm ischemia. Stability of the donor allows for further preparation before in situ
flushing.
The inferior mesenteric vein is isolated as it enters the retroperitoneum behind the pancreas. This vein provides
convenient access for in situ portal flushing by means of a small catheter, such as a Javid shunt. The pars flaccida
of the lesser omentum should be inspected for evidence of a replaced left hepatic artery arising from the left gastric
artery, and minimal dissection of the hepatic artery is necessary.
The course of the ureters should be identified. Gerota's fascia is widely incised to allow topical cooling with iced
slush solution to supplement the in situ perfusion. Complete mobilization of the kidneys before in situ flushing is
unnecessary and poses a risk of damage to the renal vessels or inadvertent division of accessory renal arteries.
Removal of organs
A team working simultaneously with the abdominal-retrieval team can prepare the heart and lungs for removal. The
superior and inferior vena cava are mobilized, and the aortic arch is dissected sufficiently for the placement of a
crossclamp at the time of infusion of aortic root cardioplegia. Preliminary mobilization of the lungs is usually
performed, and access to the pulmonary artery is necessary for pulmonary preservation. When all teams are
ready, a coordinated sequence of events ensures that all organs are simultaneously cooled and protected.
The donor is given systemic heparin. A Javid shunt is advanced through the inferior mesenteric vein near the
pancreas and advanced into the portal vein. A cardioplegia needle is positioned in the aortic arch. The distal
abdominal aorta is cannulated for in situ perfusion of the kidneys, liver, and pancreas, and an exsanguination
cannula is placed in the distal inferior vena cava. As an alternative, the inferior vena caval-right atrial junction may
be divided in the chest with suction catheters placed in the caval lumen and right thoracic cavity to decompress
the venous circulation at the moment of aortic cross-clamping.
Another cannula is placed in the distal vena cava for venous decompression and exsanguination. The aortic arch
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and the abdominal aorta at the diaphragm are simultaneously cross-clamped. (In the case of simultaneous
liver/small bowel allograft procurement, the supraceliac aorta is not clamped because of the need to preserve the
donor thoracic aorta with the graft without intimal injury from the clamp).
Cardioplegia solution is infused under pressure into the aortic root, perfusing the coronary arteries and arresting
the heart. Ventilation is ceased. Portal and distal aortic perfusion are initiated with ice-cold preservation solution.
Topical iced slush is placed in the abdomen and chest to assist the cooling process. The heart and lungs are then
removed. The clamp is removed from the distal vena caval cannula for exsanguination and to preclude venous
congestion.
The liver and pancreas and/or intestine are removed en bloc. The diaphragm surrounding the suprahepatic inferior
vena cava and adjacent to the bare area of the liver is divided. The infrahepatic inferior vena cava is divided just
cephalad to the left renal vein. The liver, pancreas and intestine unit is now attached by only the distal superior
mesenteric vessels coursing to the small bowel and by the aortic origins of the superior mesenteric artery and
celiac axis. The liver, pancreas, and intestine are separated as a bench procedure; the celiac axis is retained with
the liver.
The process of separation depends, at this point, on the allocation of organs. If the intestine and pancreas have
been placed separately, the superior mesenteric arterial and venous branches emerging from the uncinate process
are divided, ligating the pancreatic side. If the liver/small bowel graft has been allocated to the same recipient, no
further dissection is performed. If only the liver and pancreas have been allocated, the superior mesenteric artery
and vein are divided distal to the pancreas (often with a vascular load from a stapling device), and the cylinder of
aorta between the superior mesenteric artery and celiac axis is divided.
The splenic artery is divided at its origin. This vessel and the superior mesenteric artery are reconstructed with a
bifurcated donor iliac artery graft. The gastroduodenal artery is ligated and divided. The portal vein is divided
approximately 1 cm from the superior edge of the pancreas, and the common bile duct is divided just superior to
its entrance into the pancreas.
The kidneys are also removed en bloc. The ureters are mobilized with a generous amount of periureteral tissue to
avoid devascularization and are divided near their entrance into the bladder. Dissection is carried out posterior to
the aorta and vena cava in the plane of the prevertebral fascia. Once removed, the left renal vein is divided with a
small cuff of vena cava. The aorta is opened in the midline to identify the orifices of the renal arteries from within
the lumen. In this way, multiple renal arteries can be readily identified and kept on a single aortic (Carrel) patch.
Closure of the incision
After the abdominal and thoracic organs are removed, a sampling of lymph nodes and spleen is taken for tissue
typing and crossmatch testing. The chest and abdomen are closed, and standard postmortem care is given. If the
intestine has been allocated, use of antilymphocyte globulin to avoid graft versus host disease from the lymphoidrich bowel graft is perfused in the donor. Lymph nodes should be procured prior to initiation of the antilymphocyte
globulin because difficulty in collecting adequate viable lymphocytes for the crossmatch has been noted in the
past when they are procured after procurement of the solid organs.

Preservation Solutions
Two requirements of any ideal preservation solution are (1) impermeant molecules that suppress hypothermically
induced cell swelling and (2) an appropriate biochemical environment. Impermeants are agents that remain outside
the cells and that are sufficiently active osmotically to retard the accumulation of water by the cell. Constituents of
an ideal solution and their individual function are detailed below and in Preservation Solutions and their
Pharmacology above.

Current Preservation Techniques

Kidney, liver, and pancreas
Until relatively recently, the primary solution used for cold-storage preservation of the kidneys was Euro-Collins
solution.[21] Its formulation provides a hyperosmolar environment with an intracellular electrolyte composition
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intended to reduce cellular swelling. In combination with hypothermia, kidneys can be safely stored in this solution
for up to 36-48 hours before transplantation.[21]
In the 1980s, the advent of new immunosuppressive agents, such as cyclosporine, meant that, for the first time,
extrarenal organs could be transplanted with good success rates. With this development, the need for effective
preservation became apparent.
The limitations of cold ischemia to approximately 8 hours for the liver and pancreas meant that donor and recipient
teams had to be closely coordinated.[22] Complex recipient operations that required a multitude of ancillary support
services had to be organized in the middle of the night, and all personnel involved in the procedure, including the
surgeons, were starting the operation in a suboptimal fatigued condition.
Researchers at the University of Wisconsin developed a solution that simplified the practice of hepatic and
pancreatic transplantation at most centers in North America and Europe.[3] The solution, UW cold-storage
solution, is based on lactobionate, raffinose, HES, and a host of other ingredients designed to provide high-energy
phosphate precursors, hydrogen-ion buffering capacity, and antioxidant properties.[22]
Lactobionate, an impermeant anion to prevent cellular swelling, was used in place of the glucose contained in
Euro-Collins solution. Raffinose, a naturally occurring trisaccharide of fructose, glucose, and galactose, provides
additional osmotic activity; and HES is a colloid intended to prevent an increase in the extracellular space, though
it makes the solution viscous.
Most teams that perform hepatic and pancreatic transplantation prefer UW solution as the preservation method of
choice.[22] Both the liver and pancreas can reliably be stored for 12-18 hours, and isolated clinical cases with total
cold ischemia times in excess of 30 hours have been reported.[23] However, evidence is accumulating that cold
ischemia times longer than 12 hours may be associated with a high incidence of biliary strictures.[23]
Whether the UW cold-storage solution has any significant advantages over Euro-Collins solution for the
preservation of kidneys is unclear. In a large, randomized, multicenter European trial, patient and graft survival
rates were similar among recipients of the 2 solutions, but the incidence of delayed graft function requiring dialysis
was reduced by approximately one third in the UW group. Results of ongoing trials are needed before a definitive
statement can be made about the relative merits of the 2 solutions in renal preservation.
New preservative solutions, including Celsior solution, are emerging and may have advantages over UW solution,
[23, 24] though results are conflicting. [25] The Kyoto solution was evaluated for kidney storage and found to be as
good as UW solution. Furthermore, the Kyoto solution was less viscous and stable at room temperature for as
long as 3 years, and it was cost effective as compared with UW solution.[26]
Another solution that is being increasingly used presently is Bretschneider's HTK solution (Custodiol). Originally
developed for cardioplegia, HTK is routinely used for liver, kidney, and heart transplantation. HTK solution has been
shown to be superior to Euro-Collins solution in prospective trials (Ringe, 2006; Agarwal, 2006; Nardo, 2005;
Mangus, 2006). Advantages include lower viscosity and less leucocyte adhesion. In the European multicenter trial,
HTK was shown to be equivalent to UW solution except for superior delayed graft function rates in the HTK group.
Other reports have shown better delayed graft function rates with UW solution (Agarwal, 2005).
A randomized study comparing the efficacy of UW solution versus HTK on 102 liver transplant recipients reported
that both solutions were equally effective in graft preservation.[27] Mangus et al reported from their single center
study of extended criteria liver donors that HTK and UW were clinically indistinguishable but that biliary
complications were less common with HTK.[28] However, in a retrospective single center study of living donor liver
transplantation from Korea, the incidence of preservation injury was greater in grafts treated with HTK versus UW
solution.[29]
Islet transplantation has become a feasible treatment option for patients with type 1 diabetes mellitus after
improvements were made in the diabetogenicity of immunosuppression and in the preparation of sufficient
quantities of highly viable islets for transplantation. However, a minimum of 10,000 islet equivalents per kilogram of
the recipient's body weight islet mass is required to achieve insulin independence,[30] and long-term outcomes
have been disappointing, with a 5-year insulin-independence rate of 8%.
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UW solution has proven to be effective in pancreas preservation, leading to clinically successful whole-pancreas
transplantation. In addition, human pancreatic grafts can be preserved for longer than 24 hours by using UW
solution. However, in clinical islet transplantation, prolonged cold storage in UW solution before islet isolation
significantly reduced recovery of viable islets.[31]
A 2-layer cold-storage method using perfluorochemical (PFC) and UW solution has been evaluated for wholepancreas preservation. This method continuously supplies sufficient oxygen to a pancreas during preservation and
reduces cold ischemic injury by producing ATP, which maintains cellular integrity and controls ischemic cell
swelling.[31] Canine pancreata subjected to 90 minutes of warm ischemia were resuscitated during preservation by
using the 2-layer method at 4C for 24-48 hours.[32] A prospective randomized study comparing HTK versus UW in
68 pancreas transplant recipients reported that the solutions were equally suitable for perfusion and organ
preservation. In this study, 6-month patient survival was 96.3% (HTK) versus 100% (UW) (P = 0.397).[33]

Heart and lungs

Cardiac preservation has changed relatively little in recent years. Hyperkalemic, crystalloid cardioplegia solution is
used at 4C, and 4 hours is the generally accepted limit of cold ischemia.[34] For this reason, donor and recipient
operations must be finely coordinated. Every effort is made to limit the ischemic time (the time between the initial
interruption of coronary flow by means of aortic cross-clamping in the donor and the removal of the clamp in the
recipient) to less than 4 hours. Although laboratory data and isolated clinical reports suggest that good results
may be expected with storage times of 8 hours or longer with the use of the newer preservation solutions,[34]
increased ischemic time remains a strong and important independent risk factor for poor recipient outcome.
The maximal safe interval for the lung to remain ischemic, even when cooled, has not been defined. Based on
empiric observation, 6 hours is the selected limit.[35] This constraint limits the distance that can be traveled to
recover donor lungs. The limits of donor-lung ischemia have been expanded because of efforts to develop bilateral,
sequential lung replacement. The second lung to be implanted is ischemic for longer than the first because the
lungs are not implanted simultaneously. The longest cold ischemic time was 9-10 hours, and the lung functioned
well within 24 hours after implantation. Although donor-lung dysfunction occurs in 5-10% of cases, it is usually
reversible. This problem is not correlated with prolonged donor-lung ischemic time.
Whether one type of preservation solution for lung allografts is better than another remains to be determined. The
Celsior solution may be better for early lung function than the standard Euro-Collins solution.[36] One clinical study
demonstrated less reperfusion injury, better immediate and intermediate function, and better early and long-term
survival for donor lungs preserved with Celsior than with Euro-Collins solution.[35] Core cooling of the donor with an
extracorporeal circuit has been used extensively in the United Kingdom for cardiopulmonary transplantation.
Others have used an immersion technique without flushing the pulmonary artery. Hypothermia is applied, along
with intracellular-type solutions. The Kyoto solution also appears promising in lung transplantation.[37] The optimal
preservation solution for the lungs remains unknown, and deficiencies in the quality and duration of preservation
still limit the results of pulmonary transplantation.

Small bowel
The transplantation of segments of small bowel with or without concomitant liver transplantation is being performed
with increased regularity as the treatment of choice for short-gut syndrome. The bowel is usually preserved with
UW solution, though experimental evidence does not indicate that this solution offers any advantage over simple
hypothermia.[38] Experimental studies have also reported that ex vivo application of carbon monoxide in UW
solution may also prevent reperfusion injury.[39] The use of anti-oxidative agents has also shown promise in
laboratory studies as an intervention to minimize preservation injury.[40] The same investigators reported that this
may occur due to down-regulation of pre-apoptotic and up-regulation of cytoprotective signals in the presence of a
nutrient-rich preservation solution.[41] Laboratory studies on Wistar rates have also reported better small bowel
integrity and function compared to UW solution.[42]
Most procurements of small bowel are from donors who have many useful organs. Therefore, standard intra-aortic
preservation techniques are used. The current limit of cold ischemia time for small bowel is approximately 12
hours.[43] Reports suggest that the use of luminal flush solutions, both UW and amino acid enriched solutions,
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improve mucosal barrier function, as measured by means of mannitol permeability, and decrease villous
morphologic injury.[44]

Contributor Information and Disclosures

Author
Erik B Finger, MD, PhD Assistant Professor, Department of Surgery, Division of Transplantation, University of
Minnesota School of Medicine
Disclosure: Nothing to disclose.
Specialty Editor Board
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center
College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Debra L Sudan, MD Professor of Surgery, Chief, Abdominal Transplant Surgery, Vice Chair of Clinical
Operations, Department of Surgery, Duke University School of Medicine
Debra L Sudan, MD is a member of the following medical societies: Alpha Omega Alpha, American College of
Surgeons, American Society of Transplant Surgeons, American Society of Transplantation, American Surgical
Association, Association for Academic Surgery, Association of Women Surgeons, Association of Women
Surgeons, International Liver Transplantation Society, Nebraska Medical Association, Society for Surgery of the
Alimentary Tract, and Society of University Surgeons
Disclosure: Nothing to disclose.
Chief Editor
Ron Shapiro, MD Professor of Surgery, Robert J Corry Chair in Transplantation Surgery, Associate Clinical
Director, Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center
Ron Shapiro, MD is a member of the following medical societies: American College of Surgeons, American
Society of Transplant Surgeons, American Society of Transplantation, American Surgical Association,
Association for Academic Surgery, Central Surgical Association, International Pediatric Transplant Association,
Society of University Surgeons, and Transplantation Society
Disclosure: Brystol Meyer Squibb StemCell Data Monitoring Committee Consulting fee Review panel
membership; Stem Cells, Inc Consulting fee Review panel membership; Up To Date contracted Author; Novartis
Honoraria Consulting; Genentech/Valcyte Honoraria Consulting
Additional Contributors
Juan D Arenas, MD Chair, Division of Surgical Transplantation, Univeristy of Texas Southwestern Medical
Center
Disclosure: Nothing to disclose.
Sanjeev Kaul, MD, MCh (Urol) Clinical Fellow in Laparoscopic Urology and Robotics, Department of Urology,
Henry Ford Hospital
Disclosure: Nothing to disclose.
Sandeep Mukherjee, MB, BCh, MPH, FRCPC Associate Professor, Department of Internal Medicine, Section
of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of
Gastroenterology and Hepatology, Veteran Affairs Medical Center
Sandeep Mukherjee, MB, BCh, MPH, FRCPC is a member of the following medical societies: Royal College of
Physicians and Surgeons of Canada
Disclosure: Merck Honoraria Speaking and teaching; Ikaria Pharmaceuticals Honoraria Board membership
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