organ preservation

15/09/13 Organ Preservation

emedicine.medscape.com/article/431140-overview 1/18

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 transplantationshave been performed since the first successful renal transplantation in the 1950s. With improved surgicaltechniques 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 solid-organ transplantation has expanded considerably, placing increasing pressure on an already limited supply ofdonor organs.

The growth in the number of patients wanting or waiting for a transplant has outpaced the supply of availableorgans. 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 thewaiting lists than receive transplants, causing the waiting time to increase. With such constraints, preservation oforgans for transport between centers becomes crucial.

The technology of organ preservation has improved considerably. Several organ-preservation solutions areavailable, 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 describesvarious preservation solutions currently used for kidney, liver, pancreas, small-bowel, lung, and hearttransplantations.

Pathophysiology of Organ Preservation

The removal, storage, and transplantation of a solid organ from a donor profoundly alters the homeostasis of theinterior milieu of the organ. These effects manifest in the degree to which the return of normal organ function isdelayed 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 preservationserve 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.

TodayNewsReferenceEducationLog InRegister

http://www.unos.org/

http://emedicine.medscape.com/article/429314-overview







http://www.medscape.com/

http://www.medscape.com/multispecialty

http://reference.medscape.com/

http://www.medscape.org/

https://login.medscape.com/login/sso/getlogin?ac=401

https://profreg.medscape.com/px/registration.do



The first, the warm ischemic phase, includes the time from the interruption of circulation to the donor organ to thetime the organ is flushed with hypothermic preservation solution. In multiorgan recovery, the organs are cooledbefore they are removed.

The second, the cold ischemic phase, occurs when the organ is preserved in a hypothermic state prior totransplantation 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 extracellularenvironment. Receptors, ion regulation, and enzyme systems linked to the cell-membrane complex containextracellular, 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-inducedstructural changes in the membrane increase permeability, which contributes to cell swelling. Therefore, organ-preservation 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 ioniccomposition of the cell. The pump is disrupted because of the lack of adenosine triphosphate (ATP) productionand by excessive production of hydrogen ions because of anaerobic metabolism during ischemia. When thesodium-potassium ATPase pump is paralyzed, potassium moves out of the cell and diffuses down itsconcentration gradient to the extracellular space, whereas sodium, which is normally kept at a low concentrationin the cell, pours in. This ionic shift causes cell swelling and disruption of the cell if unchecked. Currentpreservation solutions have electrolyte compositions similar to the milieu inside the cell, with high potassium andlow sodium concentrations to minimize the osmotic gradients.

Hydrogen-ion production continues in ischemic organs and causes intracellular pH to decrease withoutreplenishment 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 intracellularbuffering capacity. Calmodulin activity increases and, in turn, causes upregulation of phospholipases. Subsequentproduction of prostaglandin derivatives results in mitochondrial and cell-membrane injury. Increased cellularcalcium concentrations also initiate myofibrillar contraction of the vascular smooth muscle, causing vasospasmand subsequent ischemic damage.

Endothelin, a 21–amino 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-organtransplantation, reporting favorable results.

ATP generation

A combination of the anaerobic enzymatic breakdown of glucose (glycolysis) and aerobic cellular respirationprovides for the energy requirements of aerobic cells. These processes encompass the transfer of electrons fromorganic molecules to molecular oxygen. Hypothermia decreases the metabolic rate and slows enzymaticdegradation of cellular components, but metabolism is not completely suppressed. Cooling from 37°C to 0°C

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 depletedduring hypothermia. This depletion is due to residual energy requirements of the cell that exceed the capacity ofthe cell to produce ATP.



During ischemia and organ preservation, the glycolytic pathway is shunted to lactate production with generation of2 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 andorgan preservation.

Hypothermic preservation reduces the activity of mitochondrial enzymes.[7] Cellular respiration, which requiresadenine nucleotide substrates, is reduced. For ADP to be transported into the mitochondrion as a substrate forconversion to high-energy ATP, a membrane adenine nucleotide translocase is required. Hypothermia impairs thefunction 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 affectfunction of the translocase. Adenylate kinase converts excess ADP accumulating in the cytoplasm to ATP, andadenosine monophosphate accumulates as a by-product. This effect reduces purine synthesis and results in theloss of ATP precursors from the cell.

Vascular renal resistance during hypothermic machine perfusion has been found to be an independent risk factorfor 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 ledto 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-radicalsgenerated 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 variousmechanisms. 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 xanthineoxidase 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 hydrogenperoxide, a potent oxidant capable of injuring the cell by oxidizing lipid membranes and cellular proteins. Hydrogenperoxide then produces a cascade of oxygen free-radicals, including hydroxyl radical and singlet oxygen, that areeven 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 tometabolize xanthine and hypoxanthine. This decrease allows the intracellular concentration of these metabolitesto rise. On reperfusion, oxygen is suddenly available, and metabolism proceeds rapidly, resulting in a suddenproduction of reactive oxygen intermediates. The cellular pathways to scavenge oxygen free-radicals areoverwhelmed, 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] Inthis process, interaction of highly reactive oxygen species with polyunsaturated fatty acids in the cell membranestarts a chain reaction that may ultimately destroy cellular integrity and result in cell death. The magnitude of lipidperoxidation 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 organpreservation solutions to attenuate reperfusion injury.

Production of oxygen free radicals also initiates production of prostaglandins, including leukotriene B4, by meansof direct activation of phospholipase A210. This chemoattractant causes leukocyte adherence to vascularendothelium. These neutrophils may contribute to local injury by plugging the microcirculation and bydegranulation with resulting proteolytic damage to the organ.

Cytokines are intercellular messenger molecules that may be produced in various normal and pathophysiologicstates. 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 moleculesand cause leukocyte adherence and platelet plugging after revascularization, resulting in graft failure and rejection.



Nitric oxide (NO) is an extremely labile autocoid generated by nitric oxide synthase from L-arginine. Reportsindicate 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 thepurposes of each are similar: to prevent cellular edema, to delay cell destruction, and to maximize organ functionafter perfusion is reestablished.

Euro-Collins solutions

The development of solutions of intracellular electrolyte composition allowed for organ preservation to beattempted. 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 theoriginal Collins solution and contained high concentrations of potassium (110 mM), phosphate (60 mM), andglucose (180 mM). Organ preservation improved with the use of Euro-Collins solution. When it was used for kidneypreservation, delayed renal function after implantation was significantly reduced. The solution was adequate for usein preserving the heart, liver, and lung.

Ross-Marshall citrate solutions

Ross-Marshall citrate solutions were developed as alternatives to the Collins solutions. Their electrolyticcompositions are similar except that citrate replaces phosphate, and mannitol replaces glucose. The citrate actsas a buffer and chelates with magnesium to form an impermeable molecule that helps stabilize the extracellularenvironment. 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 tryptophanketoglutarate (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 ofsodium, potassium, and magnesium. Histidine serves as a buffer, and tryptophan, histidine, and mannitol act asoxygen free-radical scavengers. The solution improved renal function after transplantation compared with Euro-Collins solution. It has become increasingly popular in recent years, but some concern exists regarding anincreased risk for pancreatitis when the pancreas graft is preserved with HTK solution. This has not beenconfirmed in randomized studies.

Phosphate-buffered sucrose solution

This solution contains sucrose 140 mmol/L and sodium hydrogen and dihydrogen phosphate as buffers. Inexperimental 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 beenconsidered the standard for renal and hepatic preservation, effectively extending the ischemic time for kidneys andlivers and allowing them to be transported considerable distances to waiting recipients. UW solution has also beensuccessfully applied to small-bowel and heart preservation.

The composition of the solution is complex. Analysis of its various components has shown that some may beomitted 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/LSodium 35 mmol/L



Magnesium 5 mmol/LLactobionate 100 mmol/LPhosphate 25 mmol/LSulphate 5 mmol/LRaffinose 30 mmol/LAdenosine 5 mmol/LAllopurinol 1 mmol/LGlutathione 3 mmol/LInsulin 100 U/LDexamethasone 8 mg/LHydroxyethyl starch (HES) 50 g/LBactrim 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 thesolution as well as to the expense. HES-free derivatives of the solution have given similar, if not better, clinicalresults than those of the original formulation.

The lactobionate is the major effective component of the solution. Its insoluble nature maintains the colloid oncoticpressure of the solution, delaying or preventing equilibration of the solution across the cell membrane, and thusdelaying the development of cellular edema.

The lowered concentration of potassium improves the flushing efficiency of the solution by removing thevasoconstrictive effect of the high potassium solution.

Glutathione is unstable in solution and effective as an oxygen free-radical scavenger only if it is added immediatelybefore 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 solutionthat couples the impermeant, inert osmotic carrier from UW solution (by using lactobionate and mannitol) and thestrong buffer from Bretschneider HTK solution (by using histidine). The reduced glutathione in Celsior solution isthe best antioxidant available. The solution was specifically designed for heart transplantation. It is being currentlyused 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/LPotassium 15 mmol/LMagnesium 13 mmol/LCalcium 0.25 mmol/LLactobionate 80 mmol/LGlutathione 3 mmol/LGlutamate 20 mmol/LMannitol 60 mmol/LHistidine 30 mmol/L

Kyoto ET solution

Researchers at Kyoto University developed a new solution that contains a high sodium concentration, a lowpotassium concentration, trehalose, and gluconate. The solution is chemically stable at room temperature. It isbeing investigated for skin storage and lung preservation in a rat model. ET Kyoto solution is also being activelyinvestigated in clinical trials for transplantation of the lungs, heart, and other organs.

Its constituents include the following:

Sodium 100 mmol/LPotassium 44 mmol/LPhosphate 25 mmol/L



Trehalose 41 mmol/LHES 30 gm/LGluconate 100 mmol/L

Techniques of Organ Preservation

Because most transplanted organs are from deceased donors, the organ must inevitably be stored after itsremoval from the donor until it can be transplanted into a suitable recipient. The donor and recipient are often indifferent locations, and time is needed to transport the donor organ to the hospital where the recipient is beingprepared for transplantation. Effective, safe, and reliable methods are needed to preserve the organ ex vivo untiltransplantation can be performed. Acceptable preservation times vary with the organ. Most surgeons prefer totransplant the heart within 5 hours of its removal; the kidney can safely be stored for 40-50 hours, but earliertransplantation is preferred. Most pancreas transplants are performed after 5-15 hours of preservation. Livertransplantations 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 ofelectrolytes across the cell membrane, and to a decrease in biosynthetic reactions. However, biodegradablereactions 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 º C decrease intemperature slows the metabolic rate approximately by a factor of 2. Cooling an organ from 37 º C toapproximately 0 º C slows metabolism by a factor of 12-13. Hypothermia alone is not sufficient for adequatepreservation because of the time necessary for optimal use of deceased donor organs. Therefore, the organ mustalso 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 immersedin the solution. The sterile bag is placed inside another bag that contains crushed ice. Advantages of simple coldstorage 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 coldstorage, 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 transferringtechniques 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 canapproach 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 optimalcryopreservation 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



crystals when thermal stresses occur at low temperatures. These fractures separate parts of the organ from eachother. 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 insuspension. 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) formsspontaneously. With lowered temperatures, the critical size of a nucleus decreases and eventually approaches thesize 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 pointcrystallization occurs. The supercooled liquid exists in a metastable state until the transition temperature isreached. At this temperature, the time required for the molecular translations needed in nucleation or crystallinegrowth 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 forcrystalline growth. The solute molecules impede this growth simply by blocking other water molecules andinterfering with hydrogen bonding necessary for ice formation. Both the kinetic approach and the solute approachare additive. Therefore, as the solute concentration is increased, the cooling rate necessary to achieve vitrificationis lowered.

The problem with vitrifying organs is that about half of the water in an organ must be replaced with solutemolecules for vitrification to occur at reasonable cooling rates. The difficulties in developing successful vitrificationtechniques include infusing high concentrations of vitrification solutes into the organ and removing them on thawingand preventing fracturing of the organs during cryogenic storage and warming the organs fast enough to preventdevitrification, 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

Osmoticactive 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'-2-ethanesulfonic acid (HEPES) buffer

Colloid Initial vascular flush out andperfusion

Albumin, HES

Metabolicinhibitors

Suppresses degradation of cellconstituents

Allopurinol, antiproteases, chlorpromazine

Metabolites Facilitate restoration ofmetabolism 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 beadequately maintained to prevent organ injury before its recovery and preservation. An organ can be injuredbecause of cardiovascular instability and hypotension. During the operation to remove the organ, the warm



ischemia time must be minimized, and the organ must be cooled rapidly in situ or by means of well-timed back-

table flush out.[20] Thereafter, the organ is maintained in hypothermic state and transported in this state until it isready 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 thefirst priorities in donor maintenance is the prompt restoration of intravascular volume. Volume resuscitation with 3-

10 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 concentrationcounteracts the sodium-increasing effects of diabetes insipidus. If the latter condition has resulted in severehypernatremia, free water may need to be added, and desmopressin may also be used selectively in severecases. 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 oxygen-carrying capacity. Enough volume should be administered to achieve a urine output of at least 100 mL/h and asystolic arterial pressure of 90-120 mm Hg. Arterial blood pressures higher than this are usually unnecessarybecause 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 exchangeand acid-base balance. The oxygen supply should be adequate to maintain an arterial oxygen saturation of greaterthan 95%, and, if available, a mixed venous oxygen saturation above 70%. Low levels of positive end-expiratorypressure 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 theirblood pressure. Dopamine hydrochloride is the most commonly used agent. High doses of dopamine maintainedfor long periods before organ recovery may be associated with increased rates of acute tubular necrosis andhepatic allograft failure. Cardiac recovery is often abandoned if high doses of inotropic support are required despiteadequate volume status.

Other inotropic agents, such as isoproterenol, epinephrine, norepinephrine, and phenylephrine, are occasionallyused, 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 toventricular arrhythmia and cardiac arrest. Warming blankets should be placed above and below the donor to keepthe body temperature above 35 º C. If maintenance of normal body temperature is problematic, intravenous fluidsmay 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 organpreservation. In the cold storage of organs, the organ is rapidly cooled to approximately 4 º C by flushing out thevascular system with an appropriate organ-preservation solution; this is the Starzl method of rapid cooling. Theflushing should remove the blood as completely as possible, and the solution be delivered at a pressure that is notdamaging 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, andthe pancreas with 200-500 mL. The organ is then placed in a sterile container and kept cold at 4-6 º C.

Multiple-Organ Recovery

After brain death is declared, the deceased is identified as a suitable organ donor, and the next of kin gives



permission, the organs must be recovered. Techniques of multiple organ recovery allow for the removal of theheart, lungs, kidneys, liver, intestine, and pancreas from a single donor for transplantation into 6 or morerecipients.

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 bag-valve 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) mobilizationof individual organs, (4) in situ perfusion, (5) removal of organs, and (6) closure of the incision. Postrecoveryprocessing, 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 ismade for multiple-organ recovery. The sternum is split. If necessary, cruciate abdominal incisions are added tofacilitate 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 insitu perfusion consists of a complete Kocher maneuver with a Cantrell maneuver. The aorta is exposed from thebifurcation distally to the level of the left renal vein proximally. The inferior mesenteric artery is divided. Lumbarbranches 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. Theaorta is encircled with tape at the diaphragm. In situ perfusion through the distal aorta and cross-clamping of theproximal aorta begin immediately in the event the donor becomes hemodynamically unstable or sustains cardiacarrest. In situ perfusion prevents warm ischemia. Stability of the donor allows for further preparation before in situflushing.

The inferior mesenteric vein is isolated as it enters the retroperitoneum behind the pancreas. This vein providesconvenient access for in situ portal flushing by means of a small catheter, such as a Javid shunt. The pars flaccidaof the lesser omentum should be inspected for evidence of a replaced left hepatic artery arising from the left gastricartery, 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 icedslush solution to supplement the in situ perfusion. Complete mobilization of the kidneys before in situ flushing isunnecessary 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. Thesuperior and inferior vena cava are mobilized, and the aortic arch is dissected sufficiently for the placement of acrossclamp at the time of infusion of aortic root cardioplegia. Preliminary mobilization of the lungs is usuallyperformed, and access to the pulmonary artery is necessary for pulmonary preservation. When all teams areready, 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 thepancreas and advanced into the portal vein. A cardioplegia needle is positioned in the aortic arch. The distalabdominal aorta is cannulated for in situ perfusion of the kidneys, liver, and pancreas, and an exsanguinationcannula is placed in the distal inferior vena cava. As an alternative, the inferior vena caval-right atrial junction maybe divided in the chest with suction catheters placed in the caval lumen and right thoracic cavity to decompressthe 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



and the abdominal aorta at the diaphragm are simultaneously cross-clamped. (In the case of simultaneousliver/small bowel allograft procurement, the supraceliac aorta is not clamped because of the need to preserve thedonor 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 arrestingthe 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 thenremoved. The clamp is removed from the distal vena caval cannula for exsanguination and to preclude venouscongestion.

The liver and pancreas and/or intestine are removed en bloc. The diaphragm surrounding the suprahepatic inferiorvena cava and adjacent to the bare area of the liver is divided. The infrahepatic inferior vena cava is divided justcephalad to the left renal vein. The liver, pancreas and intestine unit is now attached by only the distal superiormesenteric vessels coursing to the small bowel and by the aortic origins of the superior mesenteric artery andceliac axis. The liver, pancreas, and intestine are separated as a bench procedure; the celiac axis is retained withthe liver.

The process of separation depends, at this point, on the allocation of organs. If the intestine and pancreas havebeen placed separately, the superior mesenteric arterial and venous branches emerging from the uncinate processare divided, ligating the pancreatic side. If the liver/small bowel graft has been allocated to the same recipient, nofurther dissection is performed. If only the liver and pancreas have been allocated, the superior mesenteric arteryand vein are divided distal to the pancreas (often with a vascular load from a stapling device), and the cylinder ofaorta 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 abifurcated donor iliac artery graft. The gastroduodenal artery is ligated and divided. The portal vein is dividedapproximately 1 cm from the superior edge of the pancreas, and the common bile duct is divided just superior toits entrance into the pancreas.

The kidneys are also removed en bloc. The ureters are mobilized with a generous amount of periureteral tissue toavoid devascularization and are divided near their entrance into the bladder. Dissection is carried out posterior tothe aorta and vena cava in the plane of the prevertebral fascia. Once removed, the left renal vein is divided with asmall cuff of vena cava. The aorta is opened in the midline to identify the orifices of the renal arteries from withinthe 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 tissuetyping and crossmatch testing. The chest and abdomen are closed, and standard postmortem care is given. If theintestine has been allocated, use of antilymphocyte globulin to avoid graft versus host disease from the lymphoid-rich bowel graft is perfused in the donor. Lymph nodes should be procured prior to initiation of the antilymphocyteglobulin because difficulty in collecting adequate viable lymphocytes for the crossmatch has been noted in thepast 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 hypothermicallyinduced cell swelling and (2) an appropriate biochemical environment. Impermeants are agents that remain outsidethe cells and that are sufficiently active osmotically to retard the accumulation of water by the cell. Constituents ofan ideal solution and their individual function are detailed below and in Preservation Solutions and theirPharmacology 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



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 effectivepreservation 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 supportservices had to be organized in the middle of the night, and all personnel involved in the procedure, including thesurgeons, 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-storagesolution, 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 inEuro-Collins solution. Raffinose, a naturally occurring trisaccharide of fructose, glucose, and galactose, providesadditional osmotic activity; and HES is a colloid intended to prevent an increase in the extracellular space, thoughit 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 thepreservation of kidneys is unclear. In a large, randomized, multicenter European trial, patient and graft survivalrates were similar among recipients of the 2 solutions, but the incidence of delayed graft function requiring dialysiswas reduced by approximately one third in the UW group. Results of ongoing trials are needed before a definitivestatement 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 asgood 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). Originallydeveloped for cardioplegia, HTK is routinely used for liver, kidney, and heart transplantation. HTK solution has beenshown 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 centerstudy 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 livertransplantation 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 afterimprovements were made in the diabetogenicity of immunosuppression and in the preparation of sufficientquantities 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 outcomeshave been disappointing, with a 5-year insulin-independence rate of 8%.



UW solution has proven to be effective in pancreas preservation, leading to clinically successful whole-pancreastransplantation. In addition, human pancreatic grafts can be preserved for longer than 24 hours by using UWsolution. 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 whole-pancreas preservation. This method continuously supplies sufficient oxygen to a pancreas during preservation andreduces 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 4°C for 24-48 hours.[32] A prospective randomized study comparing HTK versus UW in68 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 4°C, and 4 hours is the generally accepted limit of cold ischemia.[34] For this reason, donor and recipientoperations must be finely coordinated. Every effort is made to limit the ischemic time (the time between the initialinterruption of coronary flow by means of aortic cross-clamping in the donor and the removal of the clamp in therecipient) 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 torecover 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 thelungs are not implanted simultaneously. The longest cold ischemic time was 9-10 hours, and the lung functionedwell within 24 hours after implantation. Although donor-lung dysfunction occurs in 5-10% of cases, it is usuallyreversible. 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 studydemonstrated 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 anextracorporeal 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 optimalpreservation solution for the lungs remains unknown, and deficiencies in the quality and duration of preservationstill limit the results of pulmonary transplantation.

Small bowel

The transplantation of segments of small bowel with or without concomitant liver transplantation is being performedwith increased regularity as the treatment of choice for short-gut syndrome. The bowel is usually preserved withUW 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 thismay 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-aorticpreservation 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,



improve mucosal barrier function, as measured by means of mannitol permeability, and decrease villous

morphologic injury.[44]

Contributor Information and DisclosuresAuthorErik B Finger, MD, PhD Assistant Professor, Department of Surgery, Division of Transplantation, University ofMinnesota School of Medicine

Disclosure: Nothing to disclose.

Specialty Editor BoardFrancisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical CenterCollege 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 ClinicalOperations, 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 ofSurgeons, American Society of Transplant Surgeons, American Society of Transplantation, American SurgicalAssociation, Association for Academic Surgery, Association of Women Surgeons, Association of WomenSurgeons, International Liver Transplantation Society, Nebraska Medical Association, Society for Surgery of theAlimentary Tract, and Society of University Surgeons


Chief EditorRon Shapiro, MD Professor of Surgery, Robert J Corry Chair in Transplantation Surgery, Associate ClinicalDirector, 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, AmericanSociety 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 panelmembership; Stem Cells, Inc Consulting fee Review panel membership; Up To Date contracted Author; NovartisHonoraria Consulting; Genentech/Valcyte Honoraria Consulting

Additional ContributorsJuan D Arenas, MD Chair, Division of Surgical Transplantation, Univeristy of Texas Southwestern MedicalCenter


Sanjeev Kaul, MD, MCh (Urol) Clinical Fellow in Laparoscopic Urology and Robotics, Department of Urology,Henry Ford Hospital


Sandeep Mukherjee, MB, BCh, MPH, FRCPC Associate Professor, Department of Internal Medicine, Sectionof Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section ofGastroenterology and Hepatology, Veteran Affairs Medical Center

Sandeep Mukherjee, MB, BCh, MPH, FRCPC is a member of the following medical societies: Royal College ofPhysicians and Surgeons of Canada

Disclosure: Merck Honoraria Speaking and teaching; Ikaria Pharmaceuticals Honoraria Board membership

http://www.alphaomegaalpha.org/

http://www.facs.org/

http://www.asts.org/

http://www.a-s-t.org/

http://www.americansurgical.info/index.cgi

http://www.aasurg.org/

http://www.womensurgeons.org/

http://www.womensurgeons.org/

http://www.ilts.org/

http://www.nebmed.org/

http://www.ssat.com/

http://www.susweb.org/

http://www.facs.org/

http://www.asts.org/

http://www.a-s-t.org/

http://www.americansurgical.info/index.cgi

http://www.aasurg.org/

http://www.centralsurg.org/index.asp

http://www.susweb.org/

http://rcpsc.medical.org/index.php?pass=1



References

1. UNOS. United Network for Organ Sharing Web page. United Network for Organ Sharing. Available athttp://www.unos.org. Accessed May 17, 2007.

2. McBride MA, Harper AM, Taranto SE. The OPTN waiting list, 1988-2002. Clin Transpl. 2003;53-64.[Medline].

3. Gjertson DW. Look-up survival tables for living-donor renal transplants: OPTN/UNOS data 1995-2002. ClinTranspl. 2003;337-86. [Medline].

4. Belzer FO, Southard JH. Principles of solid-organ preservation by cold storage. Transplantation. Apr1988;45(4):673-6. [Medline].

5. Simonson MS, Dunn MJ. Endothelins: a family of regulatory peptides. State-of-the-art lecture.Hypertension. Jun 1991;17(6 Pt 2):856-63. [Medline].

6. Wilhelm SM, Simonson MS, Robinson AV, Stowe NT, Schulak JA. Cold ischemia induces endothelingene upregulation in the preserved kidney. J Surg Res. Jul 1999;85(1):101-8. [Medline].

7. Southard JH, Senzig KA, Belzer FO. Effects of hypothermia on canine kidney mitochondria. Cryobiology.Apr 1980;17(2):148-53. [Medline].

8. Belzer FO. Evaluation of preservation of the intra-abdominal organs. Transplant Proc. Aug1993;25(4):2527-30. [Medline].

9. Jochmans I, Moers C, Smits JM, et al. The Prognostic Value of Renal Resistance During HypothermicMachine Perfusion of Deceased Donor Kidneys. Am J Transplant. Aug 11 2011;[Medline].

10. Koyama I, Bulkley GB, Williams GM, Im MJ. The role of oxygen free radicals in mediating the reperfusioninjury of cold-preserved ischemic kidneys. Transplantation. Dec 1985;40(6):590-5. [Medline].

11. Clavien PA, Harvey PR, Strasberg SM. Preservation and reperfusion injuries in liver allografts. An overviewand synthesis of current studies. Transplantation. May 1992;53(5):957-78. [Medline].

12. Colletti LM, Burtch GD, Remick DG, Kunkel SL, Strieter RM, Guice KS. The production of tumor necrosisfactor alpha and the development of a pulmonary capillary injury following hepatic ischemia/reperfusion.Transplantation. Feb 1990;49(2):268-72. [Medline].

13. Strüber M, Harringer W, Ernst M, Morschheuser T, Hein M, Bund M. Inhaled nitric oxide as a prophylactictreatment against reperfusion injury of the lung. Thorac Cardiovasc Surg. Jun 1999;47(3):179-82.[Medline].

14. Warnecke G, Moradiellos J, Tudorache I, Kühn C, Avsar M, Wiegmann B, et al. Normothermic perfusionof donor lungs for preservation and assessment with the Organ Care System Lung before bilateraltransplantation: a pilot study of 12 patients. Lancet. Nov 24 2012;380(9856):1851-8. [Medline].

15. Izamis ML, Tolboom H, Uygun B, Berthiaume F, Yarmush ML, Uygun K. Resuscitation of ischemic donorlivers with normothermic machine perfusion: a metabolic flux analysis of treatment in rats. PLoS One.2013;8(7):e69758. [Medline]. [Full Text].

16. McAnulty JF, Vreugdenhil PK, Southard JH, Belzer FO. Use of UW cold storage solution for machineperfusion of kidneys. Transplant Proc. Apr 1990;22(2):458-9. [Medline].

17. Deng R, Gu G, Wang D, Tai Q, Wu L, Ju W, et al. Machine perfusion versus cold storage of kidneysderived from donation after cardiac death: a meta-analysis. PLoS One. 2013;8(3):e56368. [Medline]. [FullText].

18. Karlsson JO. Cryopreservation: freezing and vitrification. Science. Apr 26 2002;296(5568):655-6.[Medline].

http://www.unos.org/

http://reference.medscape.com/medline/abstract/15387097














http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724866/



http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594243/




19. Fahy GM, Wowk B, Wu J, Phan J, Rasch C, Chang A. Cryopreservation of organs by vitrification:perspectives and recent advances. Cryobiology. Apr 2004;48(2):157-78. [Medline].

20. Odom NJ. Organ donation. I--Management of the multiorgan donor. BMJ. Jun 16 1990;300(6739):1571-3.

21. Groenewoud AF, Thorogood J. A preliminary report of the HTK randomized multicenter study comparingkidney graft preservation with HTK and EuroCollins solutions. HTK Study Group. Transpl Int. 1992;5Suppl 1:S429-32. [Medline].

22. Faenza A, Catena F, Nardo B, Montalti R, Capocasale E, Busi N. Kidney preservation with university ofWisconsin and Celsior solution: a prospective multicenter randomized study. Transplantation. Oct 152001;72(7):1274-7. [Medline].

23. Cavallari A, Cillo U, Nardo B, Filipponi F, Gringeri E, Montalti R. A multicenter pilot prospective studycomparing Celsior and University of Wisconsin preserving solutions for use in liver transplantation. LiverTranspl. Aug 2003;9(8):814-21. [Medline].

24. Boggi U, Vistoli F, Del Chiaro M, Signori S, Croce C, Pietrabissa A. Pancreas preservation with Universityof Wisconsin and Celsior solutions: a single-center, prospective, randomized pilot study. Transplantation.Apr 27 2004;77(8):1186-90. [Medline].

25. Pedotti P, Cardillo M, Rigotti P, Gerunda G, Merenda R, Cillo U. A comparative prospective study of twoavailable solutions for kidney and liver preservation. Transplantation. May 27 2004;77(10):1540-5.[Medline].

26. Yoshida H, Okuno H, Kamoto T, Habuchi T, Toda Y, Hasegawa S. Comparison of the effectiveness of ET-Kyoto with Euro-Collins and University of Wisconsin solutions in cold renal storage. Transplantation. Nov15 2002;74(9):1231-6. [Medline].

27. Meine MH, Zanotelli ML, Neumann J, Kiss G, de Jesus Grezzana T, Leipnitz I, et al. Randomized clinicalassay for hepatic grafts preservation with University of Wisconsin or histidine-tryptophan-ketoglutaratesolutions in liver transplantation. Transplant Proc. Jul-Aug 2006;38(6):1872-5. [Medline].

28. Mangus RS, Fridell JA, Vianna RM, Milgrom MA, Chestovich P, Chihara RK, et al. Comparison ofhistidine-tryptophan-ketoglutarate solution and University of Wisconsin solution in extended criteria liverdonors. Liver Transpl. Mar 2008;14(3):365-73. [Medline].

29. Ko JS, Kim GS, Gwak MS, Yang M, Kim HK, Shin BS. Greater hemodynamic instability with histidine-tryptophan-ketoglutarate solution than University of Wisconsin solution during the reperfusion period inliving donor liver transplantation. Transplant Proc. Dec 2008;40(10):3308-10. [Medline].

30. Shapiro AM, Ryan EA, Lakey JR. Diabetes. Islet cell transplantation. Lancet. Dec 2001;358 Suppl:S21.[Medline].

31. Lakey JR, Warnock GL, Rajotte RV, Suarez-Alamazor ME, Ao Z, Shapiro AM. Variables in organ donorsthat affect the recovery of human islets of Langerhans. Transplantation. Apr 15 1996;61(7):1047-53.[Medline].

32. Tsujimura T, Kuroda Y, Kin T, Avila JG, Rajotte RV, Korbutt GS. Human islet transplantation frompancreases with prolonged cold ischemia using additional preservation by the two-layer (UWsolution/perfluorochemical) cold-storage method. Transplantation. Dec 27 2002;74(12):1687-91. [Medline].

33. Schneeberger S, Biebl M, Steurer W, Hesse UJ, Troisi R, Langrehr JM. A prospective randomizedmulticenter trial comparing histidine-tryptophane-ketoglutarate versus University of Wisconsin perfusionsolution in clinical pancreas transplantation. Transpl Int. Feb 2009;22(2):217-24. [Medline].

34. Michel P, Vial R, Rodriguez C, Ferrera R. A comparative study of the most widely used solutions forcardiac graft preservation during hypothermia. J Heart Lung Transplant. Sep 2002;21(9):1030-9. [Medline].

35. Bando T, Kosaka S, Liu C, Hirai T, Hirata T, Yokomise H. Effects of newly developed solutions containingtrehalose on twenty-hour canine lung preservation. J Thorac Cardiovasc Surg. Jul 1994;108(1):92-8.


















[Medline].

36. Sommer SP, Warnecke G, Hohlfeld JM, Gohrbandt B, Niedermeyer J, Kofidis T. Pulmonary preservationwith LPD and celsior solution in porcine lung transplantation after 24 h of cold ischemia. Eur JCardiothorac Surg. Jul 2004;26(1):151-7. [Medline].

37. Chen F, Fukuse T, Hasegawa S, Bando T, Hanaoka N, Kawashima M. Effective application of ET-Kyotosolution for clinical lung transplantation. Transplant Proc. Nov 2004;36(9):2812-5. [Medline].

38. Kokudo Y, Furuya T, Takeyoshi I, Nakamura K, Zhang S, Murase N. Comparison of University ofWisconsin, Euro-Collins, and lactated Ringer's solutions in rat small bowel preservation for orthotopicsmall bowel transplantation. Transplant Proc. Jun 1994;26(3):1492-3. [Medline].

39. Nakao A, Toyokawa H, Tsung A, Nalesnik MA, Stolz DB, Kohmoto J. Ex vivo application of carbonmonoxide in University of Wisconsin solution to prevent intestinal cold ischemia/reperfusion injury. Am JTransplant. Oct 2006;6(10):2243-55. [Medline].

40. Salehi P, Walker J, Madsen K, Churchill TA. Control of oxidative stress in small bowel: relevance to organpreservation. Surgery. Mar 2006;139(3):317-23. [Medline].

41. Salehi P, Walker J, Madsen KL, Sigurdson GT, Strand BL, Christensen BE, et al. Relationship betweenenergetic stress and pro-apoptotic/cytoprotective kinase mechanisms in intestinal preservation. Surgery.Jun 2007;141(6):795-803. [Medline].

42. Wei L, Hata K, Doorschodt BM, Büttner R, Minor T, Tolba RH. Experimental small bowel preservationusing Polysol: a new alternative to University of Wisconsin solution, Celsior and histidine-tryptophan-ketoglutarate solution?. World J Gastroenterol. Jul 21 2007;13(27):3684-91. [Medline].

43. Furukawa H, Casavilla A, Abu-Elmagd K, Reyes J, Nour B, Kadry Z. Basic considerations for theprocurement of intestinal grafts. Transplant Proc. Jun 1994;26(3):1470. [Medline].

44. Olson DW, Jijon H, Madsen KL, Al-Saghier M, Zeng J, Jewell LD. Human small bowel storage: the role forluminal preservation solutions. Transplantation. Aug 27 2003;76(4):709-14. [Medline].

45. Ad Hoc Committee of the Harvard Medical School. A definition of irreversible coma. Report of the Ad HocCommittee of the Harvard Medical School to Examine the Definition of Brain Death. JAMA. Aug 51968;205(6):337-40. [Medline].

46. Anadol AZ, Dursun A, Dalgiç A, Memis L, Sert S. Positive effect of low molecular weight dextrans on theearly graft function. Int Urol Nephrol. 2001;33(4):677-83. [Medline].

47. Arreola JL, Segura P, Vanda B, Vargas MH. Evaluation of the vascular permeability after 12-hourpreservation of rabbit lungs in HTK solution. Transplant Proc. Jun 2002;34(4):1105-7. [Medline].

48. Baicu SC, Taylor MJ. Acid-base buffering in organ preservation solutions as a function of temperature:new parameters for comparing buffer capacity and efficiency. Cryobiology. Aug 2002;45(1):33-48.[Medline].

49. Baron O, Fabre S, Haloun A, Treilhaud M, al Habasch O, Duveau D. Retrospective clinical comparison ofCelsior solution to modified blood Wallwork solution in lung transplantation for cystic fibrosis. ProgTransplant. Sep 2002;12(3):176-80. [Medline].

50. Brasile L, Stubenitsky BM, Booster MH, Arenada D, Haisch C, Kootstra G. Hypothermia--a limiting factorin using warm ischemically damaged kidneys. Am J Transplant. Nov 2001;1(4):316-20. [Medline].

51. Casanova D, Correas M, Moran JL, Salas E, Amado JA, Garcia Unzueta MT. Nitric oxide in cold andwarm ischemia reperfusion renal transplantation. Transplant Proc. Feb 2002;34(1):45-6. [Medline].

52. Cascales P, Fernandez V, Tomas A, Sanchez del Campo F, Gonzalez F, Tascon E. Comparison of UWand Celsior solutions in experimental liver preservation by assessment of alpha-glutathionesulfotransferase. Transplant Proc. Feb 2002;34(1):53. [Medline].





















53. de Perrot M, Keshavjee S. Lung preservation. Ann Thorac Surg. Aug 2002;74(2):629-31. [Medline].

54. Delgado DH, Rao V, Ross HJ. Donor management in cardiac transplantation. Can J Cardiol. Nov2002;18(11):1217-23. [Medline].

55. Demertzis S, Wahlers T, Schäfers HJ, Wippermann J, Jurmann M, Cremer J. Myocardial preservationwith the UW solution. First European results in clinical heart transplantation. Transpl Int. 1992;5 Suppl1:S343-4. [Medline].

56. Desrois M, Caus T, Lan C, Sciaky M, Cozzone PJ, Bernard M. Comparative effects of Celsior and a newcardioplegic solution on function, energy metabolism, and intracellular pH during long-term heartpreservation. Transplant Proc. Jun 2002;34(4):1259-61. [Medline].

57. Fabre E, Conti M, Paradis V, Droupy S, Bedossa P, Legrand A. Impact of different combined preservationmodalities on warm ischemic kidneys: effect on oxidative stress, hydrostatic perfusion characteristics andtissue damage. Urol Res. May 2002;30(2):89-96. [Medline].

58. García-Rinaldi R. Kidney transplantation from donors without a heartbeat. N Engl J Med. Nov 282002;347(22):1799-801; author reply 1799-801. [Medline].

59. Jayle C, Hauet T, Menet E, et al. Beneficial effects of polyethylene glycol combined with low-potassiumsolution against lung ischemia/reperfusion injury in an isolated, perfused, functional pig lung. TransplantProc. May 2002;34(3):834-5. [Medline].

60. Jovine E, Di Benedetto F, Quintini C, Masetti M, Cautero N, Gelmini R. Procurement technique forisolated small bowel, pancreas, and liver from multiorgan cadaveric donor. Transplant Proc. May2002;34(3):904-5. [Medline].

61. Kaneda T, Zhang ZW, Ogawa T, Otaki M, Saga T. Pretreatment of donors with endothelin receptorantagonist TAK-044 improves cardiac functional recovery following preservation with University ofWisconsin solution. Scand Cardiovasc J. Mar 2002;36(2):105-7. [Medline].

62. Lama C, Rafecas A, Figueras J, Torras J, Ramos E, Fabregat J. Comparative study of Celsior and Belzersolutions for hepatic graft preservation: preliminary results. Transplant Proc. Feb 2002;34(1):54-5.[Medline].

63. Lee CY, Zhang JX, Jones JW Jr, Southard JH, Clemens MG. Functional recovery of preserved liversfollowing warm ischemia: improvement by machine perfusion preservation. Transplantation. Oct 152002;74(7):944-51. [Medline].

64. Masters TN, Fokin AA, Schaper J, Pool L, Gong G, Robicsek F. Changes in the preserved heart that limitthe length of preservation. J Heart Lung Transplant. May 2002;21(5):590-9. [Medline].

65. Matsumoto S, Kuroda Y. Perfluorocarbon for organ preservation before transplantation. Transplantation.Dec 27 2002;74(12):1804-9. [Medline].

66. Matsumoto S, Qualley SA, Goel S, Hagman DK, Sweet IR, Poitout V. Effect of the two-layer (Universityof Wisconsin solution-perfluorochemical plus O2) method of pancreas preservation on human isletisolation, as assessed by the Edmonton Isolation Protocol. Transplantation. Nov 27 2002;74(10):1414-9.[Medline].

67. McCord JM. Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med. Jan 171985;312(3):159-63. [Medline].

68. Meneu Diaz JC, Vicente E, Nuño J, Quijano Y, Lopez-Hervás P, Bárcena R. Prospective comparativestudy of the efficacy of Celsior solution for preservation in clinical liver transplant. Transplant Proc. Feb2002;34(1):49. [Medline].

69. Meng H, Gao L, Shen H, Chen G, Cai RJ, Mu F. Morphological changes in canine lungs perfused withmodified Euro-Collins solution. Di Yi Jun Yi Da Xue Xue Bao. Oct 2002;22(10):898-901. [Medline].




















Medscape Reference © 2011 WebMD, LLC

70. Michel P, Ferrera R. Importance of calcium during hypothermic myocardial preservation with standard andmodified UW solutions. Transplant Proc. Jun 2002;34(4):1118-20. [Medline].

71. Minor T, Olschewski P, Tolba RH, Akbar S, Kocálková M, Dombrowski F. Liver preservation with HTK:salutary effect of hypothermic aerobiosis by either gaseous oxygen or machine perfusion. Clin Transplant.Jun 2002;16(3):206-11. [Medline].

72. Mueller AR, Pascher A, Schulz RJ, Rayes N, Platz KP, Schirmeier A. Clinical small boweltransplantation: focus on mucosal barrier function. Transplant Proc. May 2002;34(3):926-8. [Medline].

73. Nydegger UE, Carrel T, Laumonier T, Mohacsi P. New concepts in organ preservation. Transpl Immunol.May 2002;9(2-4):215-25. [Medline].

74. Remadi JP, Baron O, Roussel JC, Al Habash O, Treilhaud M, Despins P. Myocardial preservation usingCelsior solution in cardiac transplantation: early results and 5-year follow-up of a multicenter prospectivestudy of 70 cardiac transplantations. Ann Thorac Surg. May 2002;73(5):1495-9. [Medline].

75. Rodríguez González F, Jiménez Romero C, Rodríguez Romano D, Loinaz Segurola C, Marqués MedinaE, Pérez Saborido B. Orthotopic liver transplantation with 100 hepatic allografts from donors over 60 yearsold. Transplant Proc. Feb 2002;34(1):233-4. [Medline].

76. Rull R, García-Valdecasas JC, Momblan D, Grande L, Vidal O, Fuster J. Evaluation of potential liverdonors: expanding donor criteria?. Transplant Proc. Feb 2002;34(1):229-30. [Medline].

77. Schnitzler MA, Woodward RS, Brennan DC, Whiting JF, Tesi RJ, Lowell JA. The economic impact ofpreservation time in cadaveric liver transplantation. Am J Transplant. Nov 2001;1(4):360-5. [Medline].

78. Silva LA, Bertels IM, Paula FS, Falkenstein D, Figueiredo JF. The effect of Collin's, Euro-Collin's, andUniversity of Wisconsin solutions on the function of isolated proximal straight tubules. Transplant Proc.Jun 2002;34(4):1108-10. [Medline].

79. Sollinger HW. Organ preservation. In: Schwartz SI, ed. Principles of Surgery. 7th ed. New York, NY:McGraw-Hill Professional; 1999.

80. Sonnino RE, Cross RS, Tawfik OW. Mediators of ischemia in preserved intestinal grafts. Transplant Proc.May 2002;34(3):975-6. [Medline].

81. St Peter SD, Imber CJ, Lopez I, Hughes D, Friend PJ. Extended preservation of non-heart-beating donorlivers with normothermic machine perfusion. Br J Surg. May 2002;89(5):609-16. [Medline].

82. Stoica SC, Satchithananda DK, Charman S, Sharples L, King R, Rozario C. Swan-Ganz catheterassessment of donor hearts: outcome of organs with borderline hemodynamics. J Heart Lung Transplant.Jun 2002;21(6):615-22. [Medline].

83. Troisi R, Meester D, Regaert B, van den Broecke C, Cuvelier C, Hesse UJ. Tolerance of the porcinepancreas to warm and cold ischemia: comparison between University of Wisconsin and histidine-tryptophan-ketoglutarate solution. Transplant Proc. May 2002;34(3):820-2. [Medline].

84. Van As AB, Lotz Z, Tyler M, Adams S, Ryffel B, Kahn D. Histological assessment after different methodsof reperfusion following liver transplantation. S Afr J Surg. Aug 2002;40(3):95-8. [Medline].

85. Warnecke G, Strüber M, Hohlfeld JM, Niedermeyer J, Sommer SP, Haverich A. Pulmonary preservationwith Bretscheider's HTK and Celsior solution in minipigs. Eur J Cardiothorac Surg. Jun 2002;21(6):1073-9.[Medline].
















organ preservation

Documents

solid organ

organ preservationserve

organ preservation author

improved organ storage

phases of organ damage

solidorgan transplantations

preservation oforgans

average waiting time