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Donor Organ Management:

Literature Review

Prepared for the Forum:Medical Management to Optimize DonorOrgan PotentialFebruary 23–25, 2004

by

D.J. Kutsogiannis, MD

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Contents

Acknowledgements....................................................................................................................iv

Introduction ................................................................................................................................1

The Existing Scientific Literature................................................................................................1

The Pathophysiology of Brain Death...........................................................................................2The Cardiovascular Response in Brain Death..........................................................................2The Systemic Inflammatory Response in Brain Death.............................................................3Temporal Considerations Following Brain Death....................................................................3

Hormonal Alterations in Brain Death ..........................................................................................5Endocrine Pathophysiology after Brain Death .........................................................................5Diabetes Insipidus (DI) and Related Disorders of Antidiuretic Hormone.................................5Thyroid Dysfunction ...............................................................................................................6Disorders of Glucose Homeostasis ..........................................................................................8Adrenal Dysfunction ...............................................................................................................8Combination Hormonal Therapy.............................................................................................8

Organ-Specific Considerations..................................................................................................10Cardiovascular Considerations ..............................................................................................10Pulmonary Considerations ....................................................................................................16Renal Considerations ............................................................................................................23Hepatic Considerations .........................................................................................................30Infection Considerations .......................................................................................................37Hematological Considerations...............................................................................................38Donor Malignancy ................................................................................................................38

Logistics and Organization of Transplant Programs ..................................................................39

Conclusion................................................................................................................................41

Investigations:...........................................................................................................................43

Monitoring:...............................................................................................................................43

Abbreviations ...........................................................................................................................44

References ................................................................................................................................45

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Acknowledgements

The Steering Committee for the Forum on Medical Management to Maximize Donor OrganPotential (February 23–25, 2004) commissioned this paper, a working draft, as a backgroundinformation piece for participants attending the Forum. During the Forum, consideration will begiven to editing this working draft for wider circulation.

Sincere thanks to the following individuals who reviewed earlier drafts of this document andprovided valuable feedback for its publication:

Dr. Sam D. Shemie

Dr. Christopher Doig

Ms. Kimberley Young

Dr. Andrew Baker

Dr. Paul Greig

Dr. Joe Pagliarello

Dr. Heather Ross

Ms. Tracy Brand

The views of the paper do not necessarily reflect the official policy of the Forum host, theCanadian Council for Donation and Transplantation, and are not intended for publication in theircurrent format.

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Introduction

The gap between the number of patients added to national transplantation lists and thoseundergoing transplantation widens each year. Fundamental to this widening gap is a failure tomaintain adequate support to brain-dead donors, which accounts for at least 25% of lost donororgans.1,2 Effective medical management to optimize donor organ potential may increase thenumber of organs retrieved for transplant.3,4 The purpose of this paper is to review the literatureon the optimal management of the brain-dead (cadaveric) organ donor in preparation for anational Forum, Medical Management to Optimize Donor Organ Potential.

The purpose of this Forum is to bring together national experts in the areas of transplantation,intensive care, neurosurgery and medical administration to initiate the formulation of a nationalagreement on two aspects of organ donation: how to optimize the medical management of thepotential solid organ donor and how to expand the eligibility of organ donors while addressingthe organizational and logistical challenges from the neurological determination of death toorgan procurement. It is hoped that collegial dialogue resulting from this Forum will improve thecare of organ donors, expand the existing criteria for organ donation and ultimately result inimproved graft and recipient survival rates as well as recipient quality of life.

The Existing Scientific Literature

Citations used in this document were selected from searches of the MEDLINE database from1966 until present, using search terms “brain death”, “organ donation”, “organ donor”,“heart/kidney/lung/liver and transplant”, “thyroid/insulin/diabetes insipidus and brain death”.Other citations were extracted as references from the initial citations, from the personal databasesof the author and members of the Forum Steering Committee and from three previous consensusconference documents from the American Society of Transplant Surgeons, the American Societyof Transplantation and the Pulmonary Council of the International Society for Heart and LungTransplantation.3-6

Unfortunately, the existing scientific literature is largely comprised of small animal experiments,human case series and retrospective reviews. Although these studies have an important role inelucidating the pathophysiology of brain death and its effects on the inflammatory,cardiovascular, respiratory, renal, hepatic and hormonal systems, there are many limitations tothe existing literature:

• Many of the therapeutic strategies investigated in animal experiments and human case serieshave not been evaluated in clinical trials.

• The majority of human case series that advocate specific therapeutic interventions often failto control for the illness severity of the donor at baseline, do not adjust for the potentialconfounding effect of the quality of transplant services provided or may be selective in theirchoice of donors.

• Donor experiments involving animals utilize healthy living animals as donors, and theseanimals may not resemble the global pathophysiology of the brain-dead donor.

• Recipient risk factors for graft failure must be accounted for in any analysis of graft failurerate, and these factors are often not adjusted for in study results.

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Collectively, these methodological problems limit the inferences obtained from these studies.Recent methodological literature has demonstrated the validity of good cohort studies comparedto randomized controlled trials in determining the point estimates of treatment effect of newtherapies. Some of these studies have been possible because of the development of exceptionalregional and national registries capturing high-quality data on both organ donors and recipients,such as the United Network for Organ Renal Transplant Registry.7 These databases can providehigh-quality data that can be used both for clinical studies and for monitoring safety issuesrelated to organ procurement, infection, transplantation and the use of marginal donors.

The Pathophysiology of Brain Death

Literature on the pathophysiology of brain death can be categorized into three subject areas: thecardiovascular response in brain death, the systemic inflammatory response in brain death andtemporal considerations.

The Cardiovascular Response in Brain Death

Brain death is the consequence of raised intracranial pressure (ICP) and cerebral herniation. AsICP increases, mean arterial pressure (MAP) rises in an effort to maintain cerebral perfusionpressure. As ICP rises further, cerebral herniation into the brainstem ensues and brainstemischemia is initiated in an rostral-caudal fashion. Initial apnea, bradycardia, hypotension and adrop in cardiac output is mediated by vagal (parasympathetic) activation from midbrainischemia.8

Brainstem ischemia then progresses toward the pons, where sympathetic stimulation issuperimposed on the initial vagal response, resulting in bradycardia and hypertension (Cushing’sreflex). During this period, the EKG may be characterized by sinus bradycardia, junctionalescape beats and even complete heart block.9

Further extension into the medulla oblongata occurs, at which point the vagal cardiomotornucleus becomes ischemic, preventing tonic vagal stimuli.10 This results in unopposedsympathetic stimulation and the resulting loss of baroreceptor reflexes, which may last forminutes to hours. The unopposed sympathetic stimulation manifests as hypertension withelevated cardiac output and may also manifest as a period of sinus tachycardia and multifocalventricular tachycardia.9 This period of unopposed sympathetic stimulation is often termed“autonomic storm” and is hypothesized to be, in part, responsible for the end organ ischemia andpulmonary edema seen in some cadaveric donor organs. The vasoconstriction may be so severethat blood flow to organs may be significantly reduced, despite an elevated systemic perfusionpressure.

The magnitude of the rise of epinephrine after brain death and the extent of myocardial damagedepend on the rate of rise in ICP.11,12 Dogs given a sudden rise in ICP demonstrated a higherepinephrine surge and poorer functioning as donor hearts. A marked rise in serum catecholaminelevels has also been demonstrated in the baboon model.13 The autonomic storm also results in anincrease in cytosolic calcium, which then activates enzymes such as lipase, protease and nitricoxide synthase and generates oxygen free radicals resulting in tissue destruction.14

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Following the autonomic storm, a normotensive or hypotensive phase ensues, resulting from areduction in sympathetic flow. This stage is characterized by impaired cardiac inotropy andchronotropy, impaired vascular tone and a reduced cardiac output.14 Ultimately, this results indiminished blood flow and oxygen delivery to solid organs. During the later stages after braindeath, the EKG may manifest ischemic changes followed by a recovery to sinus rhythm withnormal ST segments and abnormal J and T waves.

In two separate series of patients suffering from severe head injury, the mean time from injury tothe progression of brain death was 17.9 and 22 hours respectively.15 In a Polish study of 27 organdonors, only 11% of donors were hemodynamically stable according to the classification systemof the United Network for Organ Sharing (UNOS), defined as requiring no catecholamines tomaintain blood pressure over 100 mm Hg.17 In a cohort study of 63 consecutive donors who diedin two Warsaw hospitals, continuous deterioration of hemodynamic stability was observeddespite the administration of intravenous fluids and inotropes.18 Prior to organ harvesting, 26(42%) of donors had evidence of progressive hypotension despite dopamine doses of greater than20 mcg/kg/min. Similarly, in a study of 77 pediatric organ donors, 41 (53.2%) suffered fromsustained hypotension, which was more common in patients treated with inotropic agents in thepresence of a low central venous pressure (CVP) and in patients with diabetes insipidus (DI) whodid not receive antidiuretic hormone replacement.19

The Systemic Inflammatory Response in Brain Death

Brain death has been identified as triggering a cascade of inflammatory mediators which mayaffect graft function.

In a prospective study of 27 donors and 50 kidney transplant recipients, donor seramalondialdehyde (a measure of lipid peroxidation) levels and total antioxidant status weremeasured as markers of free radical mediated response. Recipients with delayed renal graftfunction were associated with higher levels of malondialdehyde and lower total antioxidantstatus in the preservation solution during the time of transplant. Patients suffering from acuterejection received kidneys from donors with significantly higher levels of malondialdehyde; bothdelayed renal graft function and acute rejection predicted impaired long-term graft survival.17

An immunohistochemical study compared pretransplant donor biopsies from cadaveric kidneydonors with those from living related kidney donors. Levels of endothelial E-selectin andproximal tubular expression of HLA-DR antigens, intracellular adhesion molecule-1 andvascular cell adhesion molecule-1 were significantly higher in biopsies from the cadavericdonors.20 There was a significant association between high levels of these molecules andtraumatic death, mechanical ventilation greater than three days and infectious episodes in thecadaver donors. High levels of E-selectin expression were associated with the administration ofdesmopressin (DDAVP) to the donor prior to organ retrieval. Transient focal cerebral ischemiahas also been demonstrated to upregulate the transcriptional levels of TNF-α and IL-6.21 UrineIL-6 levels in recipients may predict early graft rejection.

Temporal Considerations Following Brain Death

The duration from brain death to organ retrieval may be associated with a differential graftsurvival in donors suffering from cerebral vascular accidents (CVA) compared to traumatic brain

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injury. A trend to poorer kidney graft survival has been observed when organs from donorssuffering from CVAs were procured between 24 and 59 hours after admission; this poorersurvival may result from higher inflammatory activity during this period.22

In a large cohort study of 1,106 renal transplant recipients, Kunzendorf demonstrated a strongassociation between the duration of brain death (defined as the time between the neurologicaldetermination of death and the beginning of the cold ischemia time before graft explantation) andthe incidence of primary renal graft dysfunction. Renal allografts retrieved from donors with alonger duration from the neurological determination of death (over 470 minutes) demonstratedsignificantly better primary graft function than those harvested from donors with fewer than 470minutes from the neurological determination of death.23 This hypothesis was tested on anotherrenal transplant recipient population of 752 in a different center, which also showed a trend toimprovement of primary graft function in those receiving a kidney from donors with longer than470 minutes duration from the neurological determination of death. Consequently, it wasconcluded that for renal allografts, a longer duration of donor brain death did not worsen short-term or long-term renal graft function.

In a cohort of 323 orthotopic liver transplants (OLTs), longer donor hospitalization (prior to,including and after the neurological determination of brain death) was not found to be associatedwith primary liver graft dysfunction using a multivariable statistical model.24

For lung transplantation, the available literature on timing of organ procurement is limited andconflicting. Although one study utilizing the California Transplant Donor Network from 1995 to1997 demonstrated an association between longer time to donor network referral and a reducedchance of lung procurement, an individual center in Australia has advocated delaying organprocurement until marginal donor lungs have been optimized with aggressive bronchial toiletusing bronchoscopy, physiotherapy, increasing tidal volume and increasing PEEP.25,26

In summary, the available evidence does not necessarily support the policy of immediate organprocurement after the neurological determination of death. In donors with marginal lung orkidney function, a delay in organ procurement may provide the necessary time required tooptimize organ function. In circumstances where marginal lung donors are considered based on a

PaO2:FIO2 ratio of < 300 with PEEP 5 and FIO2 100%, delaying organ procurement in order toenable sufficient time for bronchial toilet and adequate ventilation may improve oxygenationenough to consider an otherwise discarded lung or lungs for donation. Likewise the potentialadvantage of delaying procurement of donor hearts (to provide additional time to recover fromthe autonomic storm resulting from brain death, to titrate fluid and pharmacological therapy, andto permit serial investigation of myocardial function by echocardiography or other means) isappealing; however, the effect of such delay on recipient graft survival has yet to be formallytested in clinical experiments.

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Hormonal Alterations in Brain Death

Endocrine Pathophysiology after Brain Death

The hormonal changes that accompany brain death include those related to the catecholaminesurge during the autonomic storm, those related to posterior pituitary function (vasopressin) andthose involving anterior pituitary hormones, glycemic control and adrenal function. Althoughthere is strong evidence to suggest that dysfunction of the posterior pituitary in brain-dead donorsis common, anterior pituitary function is largely preserved.27

In a study of 32 potential organ donors by Gramm et al., 78% of the organ donors developed DI;however, none of the anterior pituitary hormones demonstrated a progressive decline in theirconcentrations. Although free triiodothyronine (FT3) values were below normal in 62% ofpatients, the authors suggested that these values are similar to those found in patients with severebrain injury who survive and are compatible with low T3 and T4 syndrome (euthyroid sicksyndrome) seen in severe nonthyroidal illness. Serum adrenocorticotropic hormone (ACTH) wasfound to be stable during the study period, and levels of thyroid stimulating hormone (TSH) andhuman growth hormone (hGH) were increased from baseline values after 30–40 hours.

Similar findings of preserved anterior pituitary function have been demonstrated by Powner etal., who compared thyroid, cortisol, insulin and lactate levels in 16 patients who became braindead to 14 patients who had traumatic brain injury and a Glasgow coma score < 7 who did notprogress to brain death.28 Low FT3 levels with high reverse T3 levels (rT3) and normal FT4 levelswere seen in most patients in both groups and were characteristic of the euthyroid sick syndrome.The level of thyroid hormones was not correlated with either systemic lactate level or the amountof vasopressors required for the maintenance of systolic blood pressure (SBP). Anterior pituitaryhormone release may be suppressed by intravenous dopamine, which has traditionally been usedas the agent of choice for hemodynamic support of the organ donor.29 Intravenous dopamineinfusions of 5 µg/kg/min directly inhibit TSH release and consequently, lower both T4 and T3

levels.30 Thus, an element of thyroid dysfunction described in previous studies of brain deathmay have been related to the use of dopamine in these patients.31

Diabetes Insipidus (DI) and Related Disorders of Antidiuretic Hormone

Arginine vasopressin (AVP) produces its physiological effects through three different receptors:V1, V2 and V3.

32 V1 receptors are located within blood vessels and mediate the vasopressor effecton vascular smooth muscle. Vasopressin also acts on V1 receptors present in the kidney toincrease urate clearance. The antidiuretic effect of vasopressin is mediated via the V2 receptorsfound on renal collecting-duct epithelia. V2 receptor stimulation increases factor VIII productionfrom vascular endothelial cells. Stimulation of ACTH secretion is mediated by vasopressin viaits effect on V3 receptors located in the anterior pituitary.

An undetectable level of vasopressin, which is responsible for the development of DI in up to87% of brain-dead donors, has been noted in 75% of brain-dead donors before cardiacprocurement.10,19,27,33 In the Warsaw database, 20% of all donors developed DI, which wasassociated with hemodynamic instability in up to 31.3% of these donors.18 The half- life ofvasopressin is approximately 15 minutes. Below plasma vasopressin levels of 5 pg/mL, there is a

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linear decrease in the body’s ability to maximally concentrate urine; with plasma levels ofvasopressin of < 1 pg/mL, urine volume increases dramatically from less than 4 L/day to 20L/day.32 The analog 1-desamino-8-D-arginine vasopressin (DDAVP) is highly selective for thevasopressin V2 receptor subtype found in the renal collecting duct, with no significantvasopressor activity in humans. Its duration of action ranges from 6 to 20 hours and may begiven at doses of 2 µg to 6 µg IV every 6 to 8 hours.8 In critically ill patients, the intravenousroute of administering DDAVP is preferred because bioavailability is ensured and the lack ofvasopressor activity ensures its safety. In a randomized trial involving 97 brain-dead donors,DDAVP therapy had no adverse effect on early or late graft function after renal transplantation.34

Intravenous vasopressin has also been demonstrated to be effective in case series of adults andchildren with DI.35–39 Other authors and committees have advocated the use of vasopressin forthe treatment of DI.3,4,8,40,41 Vasopressin may be administered intravenously, subcutaneously orintranasaly; however, if used, the intravenous route is recommended because for predictableabsorption. Dosesbetween 0.5 and 15 U/hr (8–250 mU/kg/hr) of vasopressin have beenadvocated; however, high doses may cause coronary, renal and splanchnic vasoconstriction,potentially jeopardizing cardiac, renal, pancreatic and hepatic function.8

An early study of vasopressin use in brain-dead donors suggested that its use resulted in poorfunction of transplanted kidneys.42 Despite these early concerns, other authors havedemonstrated that vasopressin can be used successfully in organ donors with no significantadverse effect on renal graft function.43 Its use in combination with epinephrine has been shownto allow prolonged hemodynamic maintenance of brain-dead patients without apparent organdamage.44 A rational approach to therapy would be to use vasopressin alone or a combination ofDDAVP (for its antidiuretic effect) in conjunction with vasopressin as a vasopressor. The safetyand efficacy of this combination on cardiovascular and laboratory endpoints has been describedpreviously.39

Although clinical trials of the optimal dosage of vasopressin in brain-dead donors are lacking,based on a rigorous review of the use of vasopressin in sepsis and with traumatic brain-injuredand brain-dead patients, a safe approach would be to limit the dose of vasopressin to 0.04 U/min(40 mU/kg/hr).45 This upper limit is within the recommendations of the TransplantationCommittee of the American College of Cardiology, which advocates the use of vasopressininfusion at 0.8–1.0 U/hr (13–17 mU/kg/hr) to treat DI.40

Thyroid Dysfunction

The use of thyroid hormone therapy in brain-dead donors appears to be largely based onexperimental animal models and small human case series.27

In a study involving 22 brain-dead donors, TSH, T4 and T3 were decreased to below normallevels in 85%, 55% and 90% of patients.33 In a brain-dead baboon model, T3 levels becamedepleted and were associated with a transition from aerobic to anaerobic metabolism, whichcould be reversed with the administration of 2 µg of T3 at hourly intervals.46 A regimen of T3 2µg, cortisol 100 mg and insulin 20 units administered intravenously at hourly intervals in brain-dead patients was found to reduce the serum lactate to pyruvate ratio, decrease bicarbonaterequirements and inotropic support, and improve the rate of cardiac graft procurement comparedto a group not receiving this hormonal regimen.47,48 However, other investigators using a similar

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regiment of T3, cortisol and insulin did not demonstrate an improvement in eitherechocardiographic function or organ retrieval rates with the use of this hormonal regimen.49

In another study of 31 consecutive brain-dead donors, all had normal or high serum reverse T3.Free T4 index was low in 29%, and TSH was low in 23%. However, in no donors were the levelsof T4 and TSH both subnormal, indicating that these patients were suffering from euthyroid sicksyndrome rather than TSH deficiency.27

In a small case-control study of the effect of vasopressin on transplant organ recovery inchildren, vasopressin was demonstrated to have a significantly beneficial effect on weaning thesechildren off other vasopressor medications; however, the infusion of thyroxine (10 µg/hr or 0.16µg/kg/hr) did not demonstrate a similar effect.50

The strongest evidence supporting the use of T3 in organ donors comes from a recent analysis ofthe UNOS database.51 Hearts harvested from donors receiving triple hormonal therapydemonstrated a significantly improved one-month survival rate (96.2%) compared to hearts fromdonors not receiving triple hormonal therapy. A multivariable model demonstrated a 46%reduced odds of death within 30 days and a 48% reduced odds of early cardiac graft dysfunction.Benefit was also found in those donors receiving corticosteroids alone or in combination withT3/T4.

Results of studies using T3 in patients undergoing coronary artery bypass grafting (CABG) havebeen conflicting. It has previously been hypothesized that T3 may attenuate ischemia-reperfusioninjury in the heart through effects on high-energy phosphate metabolism and membranestability.52–-55 In a small randomized trial of 20 patients undergoing CABG, the infusion of T3 didnot significantly improve the post-CABG levels of T3, any hemodynamic parameters or thedensity and affinity of lymphocyte β-adrenoceptors compared to controls.56 In a subsequentrandomized trial of 211 patients undergoing CABG and at high risk for requiring inotropic drugsupport, patients in the treatment arm were given a 0.8 µg/kg load followed by 0.12 µg/kg/hourof T3 for 6 hours. Control patients were administered either dopamine (5 µg/kg/min for 6 hours)or normal saline. Although T3 administration prevented a decrease in serum thyroid hormoneconcentration associated with CABG, it did not have any effect on any hemodynamic variableswithin the 24 hours after surgery.57

In contrast, two small randomized trials of T3 after CABG demonstrated improvement in cardiacfunction with T3 compared to placebo in patients with a preoperative left ventricular ejectionfraction of < 30% or > 40%.58 A randomized trial of 142 patients undergoing CABG with anejection fraction < 40% demonstrated a lower incidence of atrial fibrillation, cardioversion,anticoagulation and antiarrhythmic use in the group randomized to receive T3 as a 0.8 µg/kgintravenous bolus at the time of aortic cross-clamp followed by an infusion of 0.113 µg/kg/minfor 6 hours. In a randomized trial of 170 patients undergoing elective CABG, treated patientswere administered 0.4 µg/kg bolus of T3 followed by a 0.1 µg/kg infusion administered over a 6-hour period after cross-clamp removal. Patients randomized to T3 had a higher cardiac index,lower inotropic requirements, a lower incidence of postoperative myocardial ischemia, lowerpacemaker dependence and a lower requirement for postoperative mechanical assistance (ballonpump or left ventricular assist device) after CABG.59

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Collectively, the evidence to support the routine use of T3 in the brain-dead organ donor isconflicting. Although data from the UNOS database support the use of T3 in combination withcorticosteroids or as triple hormonal therapy (including AVP), the lack of adjustment for thepotential confounding effect of the transplant center in this analysis limits inference from itsconclusions.51

Disorders of Glucose Homeostasis

Hyperglycemia is common in brain-dead donors and is thought to be secondary to insulinresistance, as pancreatic function appears to be preserved in donors.60 The hyperglycemia may beaggravated by the use of hypotonic dextrose solutions for the treatment of hypernatremiaresulting from DI. Although the hypothesis that tight glycemic control with insulin improvesgraft survival has not been tested in brain-dead patients, it has been demonstrated in a populationof critically ill patients to improve survival primarily by reducing septic deaths. The use ofinsulin infusions to maintain glucose levels within physiological ranges is now commonplace inthe ICU.

Adrenal Dysfunction

Severe traumatic brain injury results in a stress-associated rise in serum cortisol. In one study of36 traumatic brain injury survivors, mean admission serum cortisol was 807 nmol/L.27 Comparedto this physiological response to stress, Howlett et al. noted that 50% of brain-dead donors wererelatively ACTH deficient as defined by a serum cortisol < 400 nmol/L.27 In adopting therapeuticstrategies with intravenous corticosteroids in organ donors, one must differentiate the use of thesteroids to treat relative adrenal insufficiency as opposed to their use as immunosuppressiveagents to suppress the inflammatory response noted in brain-dead patients.

The evidence for the use of immunosuppressive doses of corticosteroids is largely based on asingle retrospective analysis of 118 consecutive donors administered a non-uniform protocol ofmethylprednisolone (mean 14.5 mg/kg) compared with 38 donors not receivingmethylprednisolone; there was significant improvement in donor oxygenation (in terms ofarterial oxygen pressure/forced inspired oxygen) and lung procurement rate in themethylprednisolone group.61 In critically ill patients suffering from septic shock, serum cortisollevels in response to ACTH have been demonstrated to predict survival, and the use ofhydrocortisone at a dose of 50 mg q6hrs with fludrocortisone 100 µg once daily has beendemonstrated to improve survival in patients deemed to be relatively adrenal insufficient.62,63

Combination Hormonal Therapy

The Heart Work Group of the Crystal City Consensus Conference recommended that donorswith a left ventricular ejection fraction of less than 45% after standard donor management betreated with combination hormonal therapy.3,4 The recommended hormonal therapy consisted ofmethylprednisolone 15 mg/kg bolus, T3 bolus administration of 4 µg and then continuousinfusion of 3 µg/hr and arginine vasopressin bolus administration of 1 unit and then continuousinfusion of 0.5 to 4 units/hr (8–67 mU/kg/hr)

In a study using UNOS data and involving 10,292 consecutive brain-dead organ donors, 701 ofwhom received triple hormonal therapy and 9,591 of whom received none, one or doublehormonal therapy, significantly more organs were transplanted from donors who received triple

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hormonal therapy compared to those who did not. Also, triple hormonal therapy was associatedwith a 28% increase in the odds of a donor becoming a heart donor.41 In a subsequent study,UNOS data was analysed on 4,543 cardiac transplant recipients.51 Hearts harvested from donorsreceiving triple hormonal therapy demonstrated a significantly improved one-month survival rate(96.2%) compared to those from donors not receiving triple hormonal therapy.

A multi-variable model demonstrated a 46% reduced odds of death within 30 days and a 48%reduced odds of early cardiac graft dysfunction. Benefit was also found in those donors receivingcorticosteroids alone or in combination with T3/T4. Although these results are grounded onreliable UNOS data, no adjustment was made for the potential contribution of the quality oftransplant care or services by the individual center.

In a recent publication describing the merits of implementing a standardized critical pathway forthe management of the potential organ donor, it was noted that there were wide variationsbetween the 10 U.S. organ procurement organizations in their rates of organ donors, organprocurement, and delayed cadaveric renal graft function and survival.64 Moreover, only 394 (9%)of recipients in this database received triple hormonal therapy.

Although triple hormonal therapy has been suggested to improve both cardiac graft procurementand recipient cardiac graft survival in retrospective analyses of UNOS data, the heterogeneity ofhormonal dosing schedules and other aspects of donor and recipient care between centers limitsthe conclusions that can be obtained from this data.

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Organ-Specific Considerations

Each donor organ—heart, lung, kidney, liver—has specific considerations for effective medicalmanagement to optimize organ potential. In addition, the literature reports investigations intodonor infection, hematology and malignancy.

Cardiovascular Considerations

Cardiovascular pathophysiology following brain death

Management of the cardiovascular compromise that results from brain death is central to themaintenance of solid organ perfusion. The complete sympathectomy associated with brain deathresults in a low systemic vascular resistance that often requires the use of vasopressor agents.

Canine models of brain death have demonstrated microscopic evidence of ischemic myocardiumand subsequent myocardial dysfunction when intracranial pressure is raised rapidly compared towhen it is raised slowly. In addition, hypotension may be caused by the intravascular volumedepletion resulting from the use of osmotic diuretics in the treatment of raised intracranialpressures associated with cerebral edema as well as from DI.

Most authors recommend maintaining systolic blood pressure greater than 90 mm Hg, MAPsgreater than 60 mm Hg and heart rates less than 100 beats per minute when maintaining an organdonor. They also recommend a CVP in the range of 10 to 12 mm Hg to volume replete thosepatients in whom only abdominal organs are to be harvested, a CVP of less than 8 for potentiallung donors and a CVP of between 8 and 10 mm Hg if both thoracic and abdominal organs are tobe harvested.10 Traditionally, dopamine has been used as the initial inotrope of choice in thebrain-dead patient. However, no randomized clinical trials exist comparing the hemodynamiceffects of dopamine to other vasopressors. Moreover, a recent review of the literature has calledinto question the role of dopamine in modern critical care practice.29 The basis for this argumentis that there is no evidence that renal-dose dopamine improves renal function, alters the outcomeof acute renal failure or improves hepatosplanchnic circulation. Furthermore, dopamine has beendemonstrated to suppress the secretion and function of anterior pituitary hormones, includinggrowth hormone and TSH.

The concern over the use of alpha agonists such as norepinephrine has arisen because of the fearof inducing central and peripheral vasoconstriction and subsequent ischemia in vascular bedssupplying potentially transplantable organs. However, in studies of septic patients, whose lowsystemic vascular resistance is similar to that seen in the sympathectomized brain-dead donor,norepinephrine, compared to dopamine, was demonstrated to increase mean perfusion pressureswithout adverse effects to renal and splanchnic blood flow.65

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Sympathetic baroreceptor dysfunction and arginine vasopressin

Yoshioka has demonstrated that hemodynamic stability could be maintained after brain death foran average of 23 days with a combination of low-dose vasopressin (1–2 units/hour or 17–34mU/kg/hr) and epinephrine (0.5 mg/hr or 8 µg/kg/hr). These authors also demonstrated that theuse of low-dose vasopressin decreased the amount of epinephrine required to maintainhemodynamic stability with a preservation of renal function for a mean of 14 days after braindeath.44 The catecholamine-sparing effects of vasopressin have also been noted by otherauthors.66

Perhaps the most rigorous evidence with respect to the hemodynamic support of the brain-deadpatient through the use of vasopressin has come from Pennefather et al.39 In this study, brain-dead organ donors supported with dopamine were volume loaded with Ringer’s lactate to a CVPof 8 mm Hg and were given DDAVP, 2 mg IV in repeated boluses, if their urine output exceeded3 ml/kg/hr for 2 hours. The brain-dead donors were then randomly assigned to receive either a300 µU/kg/min infusion of vasopressin or a saline infusion, targeting a MAP of between 65 and85 mm Hg. Those randomized to therapy with vasopressin demonstrated a significant decrease inurine output (related to the mild effect on free water retention), a decrease in plasma osmolality,an increase in MAP and systemic vascular resistance (SVR) and a decrease in dopamine dose.

Similar catecholamine-sparing effects of vasopressin have been demonstrated in several caseseries of critically ill patients with low systemic vascular resistance secondary to septicshock.45,67,68 Doses of vasopressin exceeding 0.04 U/min (650 µU/kg/min or 39 mU/kg/hr )resulting in plasma levels > 100 pg/mL are associated with potentially harmful excessivevasoconstriction of the renal, mesenteric, pulmonary and coronary vasculature.45 TheTransplantation Committee of the American College of Cardiology advocates the use ofvasopressin infusion at 0.8 to 1.0 U/hr (13 to 17 mU/kg/hr) to treat DI.40

In a study of 10 brain-dead organ donors who required catecholamine vasopressors to maintain aMAP of ≥ 70 mm Hg, all patients were found to have plasma vasopressin levels < 8 pg/mL(normal serum levels of vasopressin in hypotensive patients with a serum osmolality > 290mOsm/L are > 20 pg/mL).69 These low vasopressin levels in the setting of shock were suggestiveof a defect in the baroreceptor-mediated secretion of vasopressin. Furthermore, the use of low-dose vasopressin at a dose of 0.04 to 0.1 U/min (40 to 100 mU/kg/hr) IV resulted in an increasein MAP by an average of 17 mm Hg and was of sufficient magnitude to allow completediscontinuation of catecholamine vasopressors in 40% and a reduction in vasopressor dose in anadditional 40% of patients.70

These findings in adult populations of brain-dead patients have been confirmed in a case controlstudy of 34 vasopressin treated brain-dead children and 29 age-matched controls.50 In this study,a mean dose of 41 ± 69 mU/kg/hr of vasopressin had been administered to the brain-dead casesprior to organ recovery. Average MAP after initiation of vasopressin was approximately 10 mmHg higher in the children treated with vasopressin than in their age-matched controls. Alphaagonists (norepinephrine, epinephrine or phenylephrine) were discontinued from 78% ofvasopressin-treated children versus 0% of non-vasopressin-treated children (odds ratio [OR] of7.3), and there was no significant difference in the quality of kidneys, livers and hearts recoveredfrom vasopressin-treated children versus controls.

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Based on the available evidence, the use of vasopressin at doses up to 0.04 U/min (40 mU/kg/hr)can be used to support the MAP and spare the use of catecholamines in both adult and pediatricbrain-dead organ donors. It appears that doses of this magnitude are also effective in treating theDI seen after brain death. Further clinical investigations should be performed to determine theoptimal dosage of vasopressin and its effects on organ procurement and allograft survival.

Invasive hemodynamic monitoring

Experts agree that, at the very least, brain-dead patients should undergo invasive hemodynamicmonitoring of their CVP.3,71 There is some evidence to suggest that the use of the pulmonaryartery catheter improves the rate of organ procurement. In a case series of 52 donors considered“unsuitable”, Wheeldon et al. demonstrated that 44 of these donors (92%) yielded transplantableorgans after aggressive management, including invasive monitoring with a pulmonary arterycatheter, inotropes and hormonal therapy with glucocorticoids, insulin, vasopressin and T3. Theoverall survival in the group of 89 recipients was 76% and 84% over a follow-up period of 13 to48 months.71

The Transplantation Committee of the American College of Cardiology has recommendedtitrating volume infusion to maintain a CVP at 8–12 mm Hg or PCWP 12–14 mm Hg using apulmonary artery catheter, systolic blood pressure 90 to 140 mm Hg.40 In the setting of normal orelevated cardiac output and a low systemic vascular resistance, it is logical to use a vasopressorto increase MAP rather than an inotrope, which increases myocardial work. This philosophy hasbeen espoused by Potter et al., who described the use of nomograms using physiologicalparameters recorded from a pulmonary artery catheter (right atrial pressure) and arterial line(MAP) to optimize both left and right ventricular static power and thus to maintainhemodynamic equilibrium.72

Echocardiography and angiography

Investigators have searched for hemodynamic parameters to predict successful cardiac graftfunction.

Echocardiographic parameters have been demonstrated to be beneficial in predicting successfulcardiac transplant outcomes. The fractional area changes measured by transesophagealechocardiography in the left ventricular short axis view is an independent predictor of successfulcardiac allograft procurement.73 However, echocardiography performed on the brain-dead donordoes have limitations. In a study of 66 consecutive patients with brain death, echocardiographicsystolic myocardial dysfunction was present in 42% 74 In this study, myocardial dysfunctiontended to be more often segmental in patients who had spontaneous subarachnoid orintracerebral hemorrhage and more often global in patients suffering from head trauma. In 11 ofthe 66 hearts biopsied, there was a poor correlation between pathological findings of contractionband necrosis (characteristic of neurogenic myocardial injury) and echocardiographicdysfunction.

In another case series describing serial echocardiography in 12 patients with subarachnoidhemorrhage, myocardial wall motion defects seen on echocardiography within 12 hours of theinitial event improved on repeat echocardiographic studies within two to three weeks.75 Thissuggests that one isolated echocardiogram is a valuable tool but also that it has limitations inpredicting the presence of reversible myocardial dysfunction in the brain-dead patient.

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To further the hypothesis of reversible myocardial dysfunction in a “neurogenically stunnedmyocardium”, Kono et al. studied a group of 30 brain-dead patients from the neurologicaldetermination of death until cardiac standstill (more than 7 days after the neurologicaldetermination of death).76 Patients were divided into two groups; group 1 had left ventricularfractional shortening of ≥ 30% and group 2 had left ventricular fractional shortening of < 30% oninitial echocardiography. Group 2 subsequently underwent dobutamine stress echocardiographyusing 3-minute interval increments of dobutamine at doses of 5, 10, 15 and 20 µg/kg/min. Withdobutamine infusion, the left ventricular fractional shortening improved in three patients andremained unchanged in four patients. In the subgroup of three patients with dobutamine-responsive wall motion studies, left ventricular function became normal prior to cardiac standstill(mean 15.0 ± 5.6 days), whereas left ventricular function remained decreased in the four patientswithout dobutamine-induced wall motion improvement prior to cardiac standstill (mean 3.5 ± 0.6days).

Coronary angiography is often performed on donors if they are over 40 years of age, require highinotropic support or have other risk factors for coronary artery disease such as diabetesmellitus.77, 78 The recent recommendations from the cardiac working group at the 2001 CrystalCity Consensus Conference recommended that coronary angiography should be performed inmale donors > 45 years of age and in women donors > 50 years of age and at younger ages ifthere is a history of cocaine abuse or ≥ 3 risk factors for coronary artery disease (e.g.,hypertension, diabetes, smoking).4 The committee also recommended that contrast leftventriculography be avoided in donors with technically adequate echocardiograms to avoid therisk of contrast nephropathy in the donor kidneys. If coronary angiography is performed, the useof acetylcysteine with hydration both prior to and after the angiographic procedure has beendemonstrated to reduce the risk of developing contrast nephropathy in patients with chronic renalinsufficiency.79-84 The administration of acetylcysteine and hydration was found to reduce therelative risk of contrast nephropathy by 56%.85

Although the populations of patients in these studies were not organ donors, the use ofacetylcysteine may have its most beneficial effect in preserving the renal function of marginalkidney donors such as those with age > 60, with a terminal creatinine clearance < 90 ml/L orwith a history of diabetes or hypertension.

Donor cardiac troponin

Changes in catecholamine levels resulting in an increase in peripheral resistance may result in asudden increase in myocardial work and oxygen consumption leading to myocardial ischemia orinfarction and subsequent elevation of cardiac troponin I and T. This sudden increase is welldocumented in massive subarachnoid hemorrhage.86

In a case series, brain-dead cardiac donors with cardiac troponin I values > 3.1 ng/mL werefound to have diffuse subendocardial myocytolysis and coagulative necrosis, and five of eight ofthese hearts were diagnosed as having graft failure after transplantation.87 Interestingly,echocardiographic function and CK-MB values were not associated with cardiac troponin Ilevels in this study. In a larger study of 126 consecutive brain-dead donors, the OR for thedevelopment of acute graft failure after heart transplantation was 42.7 for donors with cardiactroponin I > 1.6 µg/L and 56.9 for donors with cardiac troponin T > 0.1 µg/L.88 In another studyassessing the predictive value of donor troponin T levels, donors with subarachnoid hemorrhage

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had slightly higher troponin T levels than those suffering from traumatic brain injury, and higherdonor troponin T levels were associated with more frequent requirement of epinephrine in thecorresponding heart transplant recipients within 24 hours of transplantation.89 Higher cardiacallograft rejection rates have also been associated with high donor troponin levels.90

Expanding the donor cardiac pool

The major factors contributing to the expansion of the cardiac donor pool include donor age andcoronary artery disease, structural abnormalities such as left ventricular hypertrophy, donor-recipient size mismatch, donor hepatitis B status and cold ischemia time.4

Donor age and cardiac structural abnormalities

Sweeney et al. have demonstrated 12-month survival rates of 75.9% in cardiac transplantrecipients who received hearts from high-risk donors. Donors at high risk included those withage greater than 40, systemic non-cardiac infection, ischemic time longer than 5 hours and therequirement for high doses of inotropes (> 10 µg/kg/min dopamine or > 5 µg/kg/minepinephrine).91

In a study comparing 296 recipients of hearts from donors less than or equal to 63 years of age to13 recipients of hearts from donors older than 63 years of age, a significantly higher incidence ofcardiac morbidity (myocardial infarction, malignant arrhythmias, coronary stenosis, transplantvasculopathy) and cytomegalovirus (CMV) infection was observed in the recipients of olderdonor hearts.92 However, no significant difference was seen between groups in mean left andright ventricle ejection fraction after one year, in early postoperative mortality or in cumulativesurvival.

In another series of 859 heart transplant recipients, 19 of whose hearts were from donors between60 and 65 years of age, early and late (94-month) mortality in the older donor group wassignificantly higher than that in the younger donor group (16% vs. 11.5% and 53% vs. 38.2%respectively).93

A solution to the problem of donor coronary artery disease is the use of “bench” CABG afterorgan procurement. In a small series of 10 cardiac recipients of donor hearts for which benchCABG was performed, eight recipients had long-term survival with a two-year graft patency of65%.94 The 2001 Crystal City Consensus Conference cardiac committee has recommended theuse of hearts with mild left ventricular hypertrophy (≤ 13 mm by echocardiography),particularily if cold ischemia time is short.4 However, the use of donor hearts with leftventricular hypertrophy of > 13 mm and EKG criteria for left ventricular hypertrophy (LVH) wasnot recommended. These and other recommendations for expanding the existing cardiac donorpool from the Crystal City Consensus Conference are outlined in table 1.

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Table 1. Crystal City modifications of existing heart donor criteria

Criteria Modifications

Age Donors > 55 may be used selectively, though co-existing LVH andlonger ischemic times may increase recipient mortality risks.

Size Despite an increased risk associated with small donors, a normal sizedadult male (> 70 kg) donor is suitable for most recipients.

Left ventricularhypertrophy (LVH)

Mild LVH (wall thickness ≤ 13 mm by echocardiography and no LVHby ECG criteria) does not preclude recovery, particularly with shorterischemic times.

Valvular lesions Certain lesions, such as mild or moderate mitral or tricuspidregurgitation, or a normally functioning bicuspid aortic valve, may beamenable to bench repair prior to transplantation.

Congenital lesions Certain lesions, such as secundum type ASD, may be amenable tobench repair.

Coronary angiography a. Male donor age 35–45 years or female donor age 35–50 years:Perform angiography if there is a history of cocaine use or ≥ 3 riskfactors for CAD.

b. Male donor age 46–55 years or female donor age 51–55 years:Angiography recommended.

c. Age > 55 years: Angiography strongly recommended.

CAD Donor hearts with mild coronary artery disease should be consideredfor recipients with relatively urgent need.

Rosengard BR et al. Am J Transplant 2002;2:701–11

Donor bacteremia and hepatitis B

Successful cardiac transplants have been performed from bacteremic donors.95 Consequently, thehearts from certain bacteremic donors without evidence of cardiac infection may be safelyconsidered for transplantation.

The effectiveness of transplanting hearts from donors serologically positive for hepatitis B virus(HBV) has been studied in endemic regions by Ko et al.96 In this series, hepatitis B surface-antigen-positive (HBsAg+) donor hearts were safely transplanted into anti-HBsAg+ recipients,HBV-naïve recipients and recipients with HBsAg-, anti-HbsAg-, anti-HBc+ and negative HBVDNA. HBV recurrences and new infections were successfully treated with lamivudine. (Onerecipient who was HbsAg-, anti-HbsAg-, anti-HBc+ and positive HBV DNA developed HBVhepatitis after transplantation.) Therefore, expanding the donor pool by utilizing hearts fromHBsAg+ donors is a reasonable option for recipients with or without previous HBV infection.

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In an analysis of heart transplantations from 1994 to 1997 using the UNOS database, 12% ofcardiac allograft recipients initially anti-HBc- converted to anti-HBc+ one year after beingtransplanted with a heart from an anti-HBc+ donor.97 In an analysis of the same data from theUNOS database, the one-year risk of an initially HCV-negative heart transplant recipientseroconverting to HCV positive when transplanted from an HCV-positive donor is 30%, with anassociated increase in one- and three-year mortality of 126% and 214% respectively.Consequently, the use of HCV-positive donor cardiac allograft is advocated in HCV-negativerecipients only in grave circumstances when there is little alternative to death.

Pulmonary Considerations

Pulmonary pathophysiology following brain death

The maintenance of adequate respiratory function to permit the successful procurement of thelungs appears to be the most challenging of all aspects of donor maintenance. Unfortunately,lungs are retrieved in less than 20% of brain-dead donors.98

Brain death is associated with both the syndrome of neurogenic pulmonary edema and theinduction of the inflammatory response.99 Neurogenic pulmonary edema is thought to beproduced through two potential mechanisms: hemodynamic stress failure or the directsympathetic stimulation of increased pulmonary capillary permeability. Brain death has alsobeen identified as inducing the inflammatory and immunological responses, including theupregulation of MHC I and II antigens and the induction of various cytokines such as interlukin6 (IL-6), which may damage the lung parenchyma.61,99–101 Evidence that neurogenic pulmonaryedema may be alleviated with glucocorticoids also suggests that an inflammatory componentexists in this process.102

Acute pulmonary allograft failure is usually associated with inadequate lung preservation,ischemia-reperfusion injury and cellular rejection.103 Pathological studies of lungs deemedunsuitable for donation have indicated that bronchopneumonia, diffuse alveolar damage anddiffuse lung consolidation are the three most common reasons for refusal of the organs.104 One-year survival for patients with primary lung allograft failure is 40%, compared with a 69% one-year survival for patients without graft failure.103,105 The syndrome of primary pulmonary graftfailure has pathological features of acute lung injury and occurs in 12% to 50% of transplantedpatients.106–108

Pulmonary infection and aspiration

Bronchial colonization or infection with bacteria is common in the ventilated organ donor. In aseries of 40 heart-lung transplants performed at Stanford, tracheal aspirate cultures demonstratedgram-positive bacteria in 80% of donors, gram-negative bacteria in 35% and yeast in 25%.109 Ina retrospective study of 115 cadaveric lung transplants, recipients with donor bronchoalveolarlavage (BAL) culture that was positive for either gram-positive or gram-negative bacteria hadlonger mean mechanical ventilation times and inferior six-month to four-year survival rates thanrecipients with a negative bacterial BAL culture.110 Recipients with BAL positive for fungi alonehad similar mechanical ventilation and survival outcomes as those with a negative BAL.

Bacterial pneumonia, usually caused by gram-negative organisms originating from the donor, isthe most common cause of recipient lung transplant infection. Lungs transplanted from CMV-

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seropositive donors into CMV-seronegative recipients result in up to a 90% rate of developmentof CMV infection in the recipient.111 This rate contrasts to an approximately 10% rate of CMVinfection in a CMV-seronegative recipient who receives an organ from a CMV-seronegativedonor.

The mechanism of organ donor death appears to influence the types of organisms found on BALof the procured lungs just prior to implantation. In a retrospective series of 123 lung donors, 57of whom died from major trauma and 66 of whom died of nontraumatic causes (typicallyintracerebral hemorrhage), significantly more of the traumatic donor group had undergone morethan 48 hours of ventilation prior to organ procurement; however, no significant difference wasnoted in the mean PaO2/FIO2 ratio just prior to donation or in the mean ischemic time of thedonor lungs.112 Although no difference was observed in the incidence of pathogenic bacteriaisolated by BAL, gram-negative enteric bacilli were isolated more often in the traumatic group(30%) than in the nontraumatic group (7%). Staphylococcus aureus (36%), followed by gram-negative enteric bacilli (30%), were the most commonly isolated organisms in the traumaticgroup compared to Hemophilus influenzae (34%) and Staphylococcus aureus (30%) in thenontraumatic group. Of importance is the fact that, for organs from traumatized donors who diedwithin 30 days of the trauma, five of the 16 recipients died as a result of gram-negative bacterialpneumonia in which the causative organisms were also identified in the corresponding donor’sBAL. The higher incidence of enteric gram-negative bacilli in the traumatized group washypothesized to be a result of possible gastric aspiration, the potentially less sterile site ofintubation in the field or the administration of broad-spectrum antibiotics and the resultingantibiotic pressure on the donor.

Given these findings, it is recommended that every potential lung organ donor undergobronchoscopy to isolate potential pathogens and better guide therapy in both the donor and therecipient.3,41 At present, no guidelines exist for the empiric use of antibiotics in donors with noevidence of bronchopneumonia. In a canine model of brain death and lung transplant, the use ofaerosolized and intravenous antibiotics combined (but not either alone) prevented pneumonia inlung recipients.116 General principles dictate that antibiotic use be limited and that the narrowestspectrum antibiotic necessary to treat isolated pathogens be used. 113

Chest x-ray

The limited role of the chest radiograph in the lung donor selection process has recently beendemonstrated in a study involving 84 potential lung donor radiographs reviewed by threethoracic surgeons and three respirologists. Observer agreement among the surgeons was slightand among the respirologists was only fair, indicating the significant variability present inradiograph interpretation even among transplant specialists.115,116

Therapeutic strategies

Therapeutic strategies to preserve pulmonary function include the judicious use of intravenousfluids and the careful consideration of cardiopulmonary interactions, including inhaled β-2agonists, dopamine, corticosteroids, mechanical ventilation strategies, surfactant and intravenousprostacyclin.

Fluid management. Fluid loading has been recommended to improve blood pressure in brain-dead donors.10,40 However, given the complexity of cardiopulmonary interactions, the strict

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reliance on CVP measurements to guide donor maintenance may be deleterious to the lungs. In astudy of 26 brain-dead donors, Ringer’s solution was infused to achieve a CVP of 8–10 mm Hgin 13 donors and CVP was maintained at 4–6 mm Hg in a second group of 13 donors. Asignificant increase in the alveolar arterial oxygen gradient occurred in those patients who werefluid loaded to achieve a CVP of 8–10 mm Hg.117 This increase may be a result of increasedpulmonary capillary permeability that accompanies raised ICP.

Pennefather demonstrated that there is a poor correlation between left-sided and right-sidedfilling pressures after brain death, with right ventricular pressures underestimating leftventricular pressures and putting patients at risk for elevated left-sided filling pressures andpulmonary edema.39 A similar disparity between right and left ventricular heart function has beenobserved in experimental canine models of brain death.118,119 After brain death in a canine model,a significant increase in right and left ventricular end-diastolic pressures and a decrease insystemic and pulmonary resistance and pulmonary impedance occurred. Right ventricularfunction decreased by 35%, which was significantly more than the 19% decrease in leftventricular function. It was postulated that the increase in blood flow to the pulmonaryvasculature as a result of decreased resistance and impedance causes significant pulmonaryoverflow injury and increases the extravascular lung water.

Current expert consensus recommends the use of the pulmonary artery catheter to optimize bothright- and left-sided filling pressures in the potential heart and lung donor.41 Pulmonary arterycatheterization and echocardiography may provide complementary information to assist in theappropriate management of the pulmonary and cardiac allograft donor.3,4

Inhaled β-2 agonists and dopamine. In ex vivo human donor lungs, terbutaline has been shownto stimulate alveolar fluid clearance.105 A similar improvement in oxygenation has beendemonstrated with the use of salmeterol in patients at risk for high altitude pulmonary edema.123

Moreover, a linear association has been noted between the rate of alveolar fluid clearance anddoses of dopamine ≤ 6 µg/kg/min.105 Although inhaled β-2 agonists show promise in thetreatment of certain forms of pulmonary edema, the lack of clinical studies in brain-dead organdonors precludes the recommendation of inhaled β-2 agonists as routine therapy in thiscircumstance.

Corticosteroids. Several publications have advocated the use of high-dose methylprednisolone todiminish the inflammatory response thought to be present in brain-dead donor lungs.4,25,51 Thisrecommendation is largely based on a single retrospective comparison of 118 consecutive lungdonors administered a non-uniform protocol of methylprednisolone (mean 14.5 mg/kg) versus 38donors not receiving methylprednisolone and demonstrating a significant improvement in donoroxygenation (in terms of arterial oxygen pressure or forced inspired oxygen) and lungprocurement rate in the methylprednisolone group.61 A recent analysis of the California DonorNetwork database comparing donor factors predicting the procurement of lungs with or withouthearts (88 donors) versus the procurement of hearts but no lungs (163 donors) demonstrated anindependent effect of using methylprednisolone (OR 3.0) in the donor.25

Corticosteroids have also been successfully utilized in treating non-infected patients with acuterespiratory distress syndrome (ARDS) during the later phase of the disease.121

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Mechanical ventilation. Contemporary methods of mechanical ventilation have been generallydriven by its use in ARDS.106,122 No randomized trials have been conducted to test the hypothesisabout whether one mode of ventilation is better than another in improving lung graft survival inorgan donors.

Recent reviews have advocated the use of pressure-controlled ventilation rather than volume-controlled modes of mechanical ventilation; however, these statements have not beensubstantiated with randomized controlled trials or well-designed cohort studies with brain-deadorgan donors.10,123 The use of pressure-controlled ventilation has, however, been compared to theuse of volume-controlled ventilation in a randomized trial of patients suffering from ARDS.124 Inthis study, the mode of mechanical ventilation was not independently associated with patientmortality. Hypothesized protective mechanisms of maintaining alveolar expansion include thecontinued stimulation of surfactant in addition to reduced hypoxic vasoconstriction, reducedendothelial edema, reduced microvascular plugging by blood elements and reduced mediator-induced lung injury and vasospasm.

Shearing forces that produce stress on alveoli, epithelial and endothelial damage, augmentationof the cytokine response, and capillary stress fractures resulting in hemorrhagic edema are allproposed mechanisms for the alveolar injury seen with mechanical-ventilator-induced lunginjury.125 Recruitment maneuvers in the form of high sustained PEEP or pressure-controlledventilation for short durations have been proposed as useful adjuncts to the lung protectiveventilatory strategies used to prevent alveolar stress and collapse in ARDS or acute lunginjury.126 Such strategies involve either the use of PEEP delivered up to 30 cm H20 and limitingmaximal plateau pressures at 45 cm H20 or, alternatively, the use of pressure-controlledventilation to a plateau pressure of 45 cm H20 (including up to 20 cm H2O of PEEP) for 15-minute intervals. A correlation between end-inspiratory and end-expiratory alveolar collapse wasdemonstrated in this study, indicating the advantage of alveolar expansion in both the inspiratoryand expiratory phase.127

Ventilating donors to achieve PaO2 of at least 60 mm Hg, using adequate doses of PEEP of ≥ 5cmH20 to minimize donor pulmonary atelectasis, and minimizing delivered tidal volumes

(irrespective of the mode of ventilation) aiming for a plateau pressure of ≤ 30 cm H20 tominimize donor lung injury appear to be reasonable targets given the available limited data inorgan donors.122

Surfactant. Animal models of surfactant have demonstrated the anti-inflammatory, antibacterial,and antiviral effects of surfactant.128 In the acutely injured lung, hyperoxia and plasma proteinsleaking into the alveoli have been shown to inhibit alveolar surfactant. In a rat model of lungtransplantation, a significant reduction in pulmonary compliance, functional residual capacityand decrease in surfactant composition were demonstrated immediately after pulmonary arteryflushing with modified Euro-Collins solution and persisted over six hours. These observationshave prompted other investigators to demonstrate the benefit of exogenous surfactant to improvethe pulmonary dysfunction resulting from the ischemia-reperfusion injury of donor lungs in aporcine lung transplant model.129 The use of surfactant in human lung donors has not beenrigorously investigated.

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Prostacyclin and inhaled nitric oxide. In a rat model of double lung transplantation, thevasodilatory effects of prostacyclin (35 µg/kg PGI2), given both intravenously and into thepulmonary flush solution, were compared with the effects of inhaled nitric oxide (targeting anexpiratory NO concentration of 20 ppm) for donor treatment. During 120 minutes of reperfusion,serial measurements of graft pulmonary vascular resistance (PVR) and alveolar arterial oxygendifference (AaDO2) were obtained. During reperfusion, the compliance was significantly reducedin NO in comparison with controls and PGI2. The PVR was significantly elevated and theAaDO2 was significantly reduced in the NO group compared with controls and PGI2.Histological analysis demonstrated significantly more interstitial edema in the NO group. Thedeterioration of graft function with NO, even in comparison to untreated grafts, was attributed tothe preferential vasodilation of the ventilated alveoli, with no effect on those alveoli that werecollapsed.

Due to prolonged ventilation and a supine position, microatelectasis is a common finding in thelungs of potential donors. In an experimental rat model, donor lungs developed microatelectasisdespite PEEP and a relatively short ventilatory period before organ procurement.130 Nitric oxideinhalation before and during organ perfusion then resulted in regional malperfusion in thoseareas where atelectasis was present.

Due to malperfusion, blood cells may not be cleared from the capillary bed, resulting inactivation of the inflammatory cascades during ischemia and reperfusion. In contrast,prostacyclin given intravenously reaches the entire vascular bed, independent of regionalventilation, thus allowing homogeneous distribution of the preservation solution. Sometransplant centers, such as the Barnes-Washington University Lung Transplant Group, administer500 µg of prostaglandin E-1 directly into the pulmonary artery prior to flushing with modifiedEuro-Collins solution and procuring the lung.131,132

Predictors of lung allograft dysfunction

In a recent cohort study of 225 consecutive lung transplants, independent predictors for thedevelopment of primary graft failure (incidence 11.8%) included recipient diagnosis of primarypulmonary hypertension (OR 4.52), donor African-American race (OR 5.56), donor femalegender (OR 4.11) and donor age < 21 years (OR 4.06) or > 45 years (OR 6.79).107 Of note wasthat neither smoking history nor the mode of donor death was associated with an increased riskof primary graft failure.

An analysis of the database from the California Transplant Donor Network demonstrated that thepresence of clear breath sounds in the donor (OR 2.1) and donor treatment withmethylprednisolone (OR 3.0) independently predicted successful lung procurement as opposedto heart but no lung procurement.25

Most studies evaluating the total lung graft ischemic time and its influence on acute and chronicrejection and recipient survival after lung transplantation have been small, single-center studiesand have failed to find an association between total lung graft ischemia time and recipientsurvival.133–136 However, one Australian study demonstrated a significant association withprolonged total lung ischemic time and recipient mortality.137

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An analysis of 5,052 lung transplants performed between 1987 and 1997 using the combinedUNOS and International Society for Heart and Lung Transplantation (ISHLT) Registry 138

showed that donor age < 11 years or > 50 years but not total lung graft ischemia time had asignificant worsening effect on recipient survival. However, when a multivariable model was fitto the data, a significant interaction was present between donor age and total cold ischemia time,and the interaction between older donor age and longer ischemia time was a significant predictorof one-year recipient mortality. This interaction was particularly true with donor ages of 45 andtotal lung ischemic time of more than 8 hours or with donor ages of 55 and total lung ischemictimes of more than 6 hours. However, recipients of lungs from 284 donors over 50 years old hadan encouraging one-year survival of 65.6%, which was 5–7% less than the 1997 cohort ofrecipients of lung transplants in the ISHLT registry.139 Similar results were demonstrated in amultivariable analysis of a cohort of 1,800 lung transplant recipients using the UNOS databasebetween 1993 and 1996, where age and cold ischemia time (within cold ischemic time limitspermitted for transplantation at the local centers) were not independently predictive of mortalityat a two-year follow-up.140

Expanding the lung donor pool

A detailed and recent review of lung transplant donor acceptability criteria has been published byOrens et al.6 The criteria for an ideal lung donor are outlined in table 2.

Table 2. Currently accepted “ideal” donor for lung transplantation

Age < 55

ABO compatibility

Clear chest radiograph

PaO2 > 300 on FIO2 = 1.0, PEEP 5 cm H2O

Tobacco history < 20 pack-years

Absence of chest trauma

No evidence of aspiration/sepsis

No prior cardiopulmonary surgery

Sputum gram stain shows absence of organisms

Absence of purulent secretions at bronchoscopy

Adapted from Orens JB et al. J Heart Lung Transplant 2003;22:1183-200

In an effort to improve donor lung selection, Ware et al. used physiological, microbiological andhistological methods to examine 29 pairs of rejected lungs from the California transplantregistry. Twelve of 29 (41%) pairs of rejected lungs would have been potentially suitable fortransplantation based on the level of pulmonary edema, intact alveolar fluid clearance andhistology.105 Based on these findings, the authors suggested that there is probably room forimproving the current criteria for donor selection.

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In a case series of 15 brain-dead patients, lung grafts that did not meet the usual criteria fortransplantation were found to have higher dynamic and static elastance measurements than donorlungs that met standard transplantation criteria.141

Donor oxygenation

Traditional oxygenation criteria used as a threshold in the acceptance of donor lungs include adonor PaO2 of more than 300 mm Hg on inspired oxygen fraction (FIO2) of 100% and PEEP of 5cm H2O.98,116 Aziz et al. have challenged donor PaO2 criteria by arguing that manypathophysiological factors in the organ donor influence the level of PaO2 independent ofindividual lung function.104 In this study, no difference in median duration of mechanicalventilation and one-year mortality was shown between recipients of lungs procured from donorswith a PaO2 of greater than 300 mm Hg and a pulmonary vein oxygen level (PvO2) of greaterthan 300 mm Hg and recipients of lungs harvested from donors with a PaO2 less than 300 mmHg and a PvO2 greater than 300 mm Hg.

In an occasional patient, parenchymal abnormalities may be isolated to one lung; despite poorglobal oxygenation, the contralateral lung has been successfully procured.142 Sundaresan et al.studied the outcomes of 133 consecutive lung transplants performed between 1991 and 1994.98

Eighty-nine donors were considered ideal according to the following criteria:

• age younger than 55 years

• smoking less than 20 pack-years

• arterial oxygen tension greater than 300 mm Hg using an inspired oxygen fraction of 100%

and a PEEP of 5 cm H2O

• chest radiograph negative for infiltrate or trauma including contusion or pneumothorax

Forty-four donors were considered to be marginal because of the failure to meet one or more ofthe above criteria. Recipients from the ideal versus the marginal group showed no significantdifference in median duration of postoperative mechanical ventilation and no significantdifference in alveolar-arterial oxygen gradient immediately after transplantation or at 24 hours.

Encouraging results have also been demonstrated in Australia.26 In a series of 219 potential lungdonors, 59 donors had a PaO2:FIO2 ratio of < 300 mm Hg on an FIO2 of 100% and PEEP 5, and18 of these 59 were clearly unsuitable donors. The remaining 41 potential lung donors weretreated with aggressive bronchial toilet using bronchoscopy, physiotherapy, increasing tidalvolume and increasing PEEP. After such therapy, 20 (34%) of the remaining 59 potential lungdonors improved their PaO2:FIO2 ratio to > 300 mm Hg on FIO2 100% and PEEP 5, and theselungs were subsequently transplanted. No difference in ICU length of stay or 30-day mortalitywas noted between recipients from ideal donors and from donors whose gas exchange wasinitially suboptimal. A subsequent multivariable model demonstrated that only cold ischemictime of the graft (and not donor PaO2/FIO2 ratio before explantation) was predictive of recipientPaO2:FIO2 ratio.

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Renal Considerations

Renal pathophysiology following brain death

A recent review of the effects of nonimmune tissue injury in renal transplantation outlined twoprincipal mechanisms through which nonimmune organ damage occurs after renaltransplantation; first by inciting the immune response and second by direct tissue injury.163

Nonimmune tissue damage is involved in part in the development of delayed graft function, inwhich brain death, prolonged ischemic time and immunologic factors play a role. Delayed graftfunction also predicts the development of adverse morbid events such as decreased graftsurvival, decreased recipient survival, increased rejection and increased allograft nephropathy.143

The 1997 Banff working classification of renal allograft pathology characterizes thehistopathologic features of renal allograft nephropathy as tubular atrophy, interstitial fibrosis andfibrous intimal thickening leading to a reduced glomerular filtration rate (GFR).144 Glomerularhyperemia and inflammation are characteristic histopathologic features of kidneys in brain-deaddonors.145 Donor brain death causes upregulaion of the inflammatory response in an antigen-independent manner. Early immune-mediated injury has been thought to result in primarynonfunction and failure of the renal allograft. However, the effects of nonimmunologic, antigen-independent damage to the kidney and other organs may be a trigger for subsequent renalalloresponsiveness.

In a rat model of brain death, animals bearing kidneys from brain-dead donors compared to thosefrom living donors and those from living controls anesthetized for six hours had significantlyincreased neutrophil, macrophage and T-cell infilatration on histological exam. The mRNA ofproinflammatory mediators detected in kidneys from brain-dead donor animals also increasedcompared to both control groups. An acceleration and amplification of the host immuneresponse, manifested by the augmented expression of chemokines (MCP-1, MIP-1, IL-8),cytokines (TNF-α, interferon-γ, IL-1β), adhesion molecules (E-selectin, ICAM-1) and majorhistocompatibility complex class II antigens, were also noted in the brain-dead donors.146 Thisexpression of P-selectin and the rapid infiltration of the cadaveric donor kidneys by neutrophilsmay trigger subsequent inflammatory changes that increase the incidence of delayed graftfunction and prime the kidneys for subsequent host immune mediated damage.

Cytokines are also thought to play a role in donor organ injury and subsequent worsening graftsurvival. Increased serum and urine interlukin 8 (IL-8) concentrations and increased urineinterlukin 6 (IL-6) concentrations in recipients 24 hours after kidney transplantation can predictthe severity of graft rejection.147

Serum IL-1β and macrophage inhibitory protein-1 in the kidneys of brain-dead rats compared toliving anesthetized controls were elevated within six hours of induction of brain death and onehour of revascularization. Moreover, by immunohistology, there was an increased number ofneutrophils and induction of P- and E-selectins, complement and cytokines up to five days afterrecipient engraftment.148 This supports the hypothesis that an initial nonimmune response inbrain-dead donor organs leads to later immune reactivity in the recipient and subsequent graftfailure.

24

Another rat model of brain death induction demonstrated an increase in immunologicalactivation of endothelial cells in the liver and kidney as evidenced by ICAM-1 expression,enabling leukocyte recruitment to the underlying organs.149 This may explain some of thedisparity in outcome between living and cadaveric donors.

A biochemical and pathological study of 20 brain-dead patients who were maintained on lifesupport for 0 to 48 days after brain death by administration of vasopressin and epinephrinedemonstrated a diuretic phase of prerenal failure on day 0 (day of brain death), which recoveredby day 1 and remained almost normal over a 14-day period. This phase was accompanied bymild hyponatremia and hypo-osmolarity with high urinary sodium output and osmolarity fordays 0 to 14. Of note was that the mean value for creatinine clearance was below the normalrange on day 0 but improved to within the normal range on days 1 to 14. Initial pathologicalchanges included glomerular hyperemia on day 0 with improvement thereafter and laterdevelopment of tubulointerstitial nephritis, arterial intimal proliferation and glomerularendothelial proliferation after a week. Mechanisms hypothesized for the protracted excesssodium excretion included (1) the diuretic phase of acute renal failure, (2) neurogenicimpairment of renal function through renal sympathetic nerve denervation resulting in anincrease in urine flow and sodium excretion, (3) the direct effects of high serum levels ofvasopressin and (4) the predominantly distal tubular pathology and interstitial fibrosis seen onpathological examination representative of tubulointerstitial nephritis.145 Most of the brain-deadpatients received vasopressin at an infusion rate of 1–2 units per hour (285 ± 45 µU/kg/min)with epinephrine to sustain a systolic blood pressure of more than 90 mm Hg. The serumantidiuretic hormone level in the patients receiving vasopressin was 10–40 pg/ml (normal range= 0.3–4.2 pg/ml). This delay of over one day to recover renal function may be responsible for theepidemiological observation that renal allografts procured from donors after 470 minutes fromthe neurological determination of death demonstrate significantly better primary graft functionthan those harvested from donors fewer than 470 minutes from the neurological determination ofdeath.23

Predictors of kidney allograft dysfunction

Post-transplantation renal function is associated with hemodynamic instability during and afterbrain death. Donor hemodynamic instability is correlated with post-transplant acute tubularnecrosis (ATN).18,150 Other factors that affect long-term kidney function are long duration of coldischemia times,151 donor age,152 recipient age, gender, extent of HLA match,153 duration of timeon dialysis prior to transplantation154 and immunosuppression protocol toxicity.155

Renal graft failure and ATN increase if donor systolic blood pressure is consistently less than80–90 mm Hg.8 Kidneys from hemodynamically stable donors have a lower rate of early graftnonfunction compared with those from hemodynamically unstable donors.156 Reduced graftsurvival may occur in organs retrieved from donors receiving high-dose dopamine, but this effectmay be limited to donors who are hypotensive at the time of organ retrieval. Mean donor arterialblood pressure below 80 mm Hg and high doses of dopamine (> 10 µg/kg/min) for donormaintenance are known risk factors of ATN after transplantation, as autoregulation of renalblood flow and glomerular filtration are declining below these levels.157 In a study of 77 pediatricorgan donors, 27 (35%) suffered at least one cardiac arrest, and 36 kidneys from 31 donorssuffered either ATN or primary nonfunction. The donors of these organs spent longer in the ICU

25

(60.6 vs 42 hours) and had a higher mean maximum serum sodium concentration (163.4 vs 158.5mmol/L) than those without these complications.19

As with other organs, prolonged cold ischemia time is associated with poor renal allograftfunction. In an analysis of the Collaborative Transplant Study database of kidney transplants, acold ischemic preservation time over 12 hours resulted in progressively worsening recipient graftsurvival, particularly if the cold ischemic time was greater than 48 hours.151 Interestingly,kidneys procured with a cold ischemic time of 0 to 6 hours had a worse graft survival time thankidneys procured between 25 and 36 hours because of a disregard for HLA matching in thekidneys with short ischemic times. The policy of certain centers was not to perform HLAmatching in organs with a cold ischemia time of 0–6 hours, as it was not thought to be importantfor long-term outcome in these otherwise healthy organs. Within the group of transplants withcold ischemic times of 0–6 hours, increasing HLA A, B, DR mismatching was associated with aprogressively worsening recipient graft survival.

Expanding the kidney donor pool

The pool of potential kidney donors may be expanded by considering potential donors over 60years of age, those with cerebrovascular accidents as an etiology of death, those with a serumcreatinine greater than 133 µmol/L (> 1.5 mg/dL) or a reduced creatinine clearance and thosewith a history of hypertension or type 1 or 2 diabetes mellitus.158–162 No uniformly accepteddefinition of the marginal donor exists in the literature; however, a proposal by Tullius et al.includes donor age > 65 years, creatinine clearance < 90 ml/min, serum creatinine > 133 µmol/L(1.5 mg/dl) during a stable phase of the donor, degree of glomerulosclerosis > 15 %, certainanatomic abnormalities such as more than one renal artery, etiology of donor death and coldischemic time to define marginal renal allografts.163

Technical and logistical considerations

Data from the National Transplant Database of the United Kingdom indicate that 9,014 kidneyswere procured in the United Kingdom and Ireland between 1992 and 1996. Of these, 1,726(19%) were identified by either the retrieval or recipient centers as having renovascular orparenchymal damage.164 Older donors had a significantly higher incidence of being damaged. Ofthe damaged kidneys, 1,630 (94%) were transplanted. Although there was significantly worseone- and three-year graft survival in recipients of kidneys from donors ≥ 40 years old, thepresence of kidney damage did not significantly affect graft survival.

26

Donor age, creatinine clearance, hypertension and etiology of death

Using a cohort of 29,068 kidney transplant recipients from the Organ Procurement andTransplantation Network, Port et al. used a Cox statistical model to define “expanded donorkidneys” as those with a relative risk of graft loss greater than 1.70, meaning a greater than 70%risk of graft failure.158 Donor characteristics that were independently associated withsignificantly increased risk for graft failure were older age (40 years or older), age younger than10 years, impaired renal function by creatinine > 133 µmol/L (> 1.5 mg/dL), history ofhypertension and cerebrovascular accident (CVA) as the cause of donor death. Cold ischemiatime was found to be predictive of poor graft survival only if it was greater than 24 hours.Interestingly, a history of diabetes mellitus was present in 2.9% of these donors but was notsignificantly associated with graft failure in the multivariable model, nor was the duration ofhypertension significant. Consistent with findings in populations undergoing lungtransplantation,107 black race (versus all other donor races) and female gender of the donor wereboth associated with an increased graft loss.159 Serum creatinine greater than 133 µmol/L (> 1.5mg/dL) was associated with a 10% higher risk of graft failure, as was a creatinine clearance < 60ml/min. Using a decision probability matrix based on this large database, all donors older than 60years and those aged 50–59 years with two or more additional risk factors (donor etiology ofdeath CVA, creatinine > 133 µmol/L, hypertension) produced a relative risk of graft failure ofgreater than 1.70 (table 3, next page). Forty-six percent of kidneys with a relative risk greaterthan 1.70 were discarded compared to a 4.5% discard rate for donors with a 1.00 relative risk.Ultimately, the one-year (three-year) kidney graft survival using a kidney from a donor with arisk status of < 1.70 was 90.6% (79.4%), from a donor with a risk status of 1.70–2.0 was 86.5%(71.1%) and from a donor with a risk status of > 2.5 was 84.5% (68.0%).

In another study comparing 63 kidney grafts from donors over 60 years of age transplanted intorecipients younger than 60 years of age compared to a control group where both donor andrecipients were less than 60 years of age, one- and five-year graft survival rates were 95% and83% in the control group compared to 94% and 81% favouring the older donor group, althoughthere was a significant difference in composite death-graft survival rates (favoring youngerdonors) when the increased death rates in the older donor group were included as a “competingrisk” in the analysis of graft failure.160

Donor diabetes mellitus

Using the University of Wisconsin transplant database, Becker et al.161 compared 42 recipients(30 of these being nondiabetic) of kidneys from diabetic donors to 1,971 recipients of kidneysfrom nondiabetic donors. Ironically, a significantly increased five-year patient and graft survivalwas noted in nondiabetic patients who received a kidney from a donor with type 2 diabetesmellitus compared to recipients of kidneys from nondiabetic donors. There was no significantdifference in the rates of graft rejection between groups. However, recipients of grafts fromdiabetic donors had a higher discharge creatinine level, an increased risk of proteinuria and morepost-transplant glucose intolerance compared to recipients of kidneys from nondiabetic donors.As expected, both patient and graft survival were decreased in recipients with pre-existingdiabetes.

27

Table 3. Relative risk of graft loss by four kidney donor characteristics

Relative Risk

Normal Creatinine High Creatinine

Age

(yr)

No HTN HTN No HTN HTN

Cause of death not CVA

0–9

10–39

40–49

50–59

60+

1.40a

1.00 (ref)

1.17a

1.41a

1.90a

1.59a

1.14a

1.33a

1.60a

2.16a

1.52a

1.09b

1.28a

1.53a

2.07a

—

1.24a

1.45a

1.74a

2.36a

Cause of death CVA

0–9

10–39

40–49

50–59

60+

1.60a

1.14a

1.34a

1.61a

2.17a

1.82a

1.30a

1.52a

1.83a

2.47

1.74a

1.24a

1.46a

1.75a

2.37a

1.98a

1.41a

1.66a

1.99a

2.69a

Modified from Port FK et al. Transplantation 2002;74:1281-6

Risk of graft loss relative to donors aged 10–39 years with a terminal serum creatinine < 133 µmol/L (< 1.5 mg/dL)but without HTN and CVA (reference population); other factors held constant. Adjusted for donor gender and raceand recipient age, gender, race, BMI, primary cause of end-stage renal disease, years on dialysis, HLA mismatches,year of transplantation and cold ischemic time. Bold numbers highlight RR > 1.70.

Terminal creatinine > 133 µmol/L (> 1.5 mg/dL)

ap < 0.0005

bp < 0.05

Donor hepatitis B and C status

In an analysis of kidney transplantations from 1994 to 1997 using the UNOS database, 15% ofrecipients initially anti-HBc- converted to anti-HBc+ one year after being transplanted with akidney from an anti-HBc+ donor.97 Moreover, recipients transplanted from donors positive toboth anti-HBc- and antibody to HCV had a 170% increase in the odds of one-year mortality.

If a donor is HBsAg- and anti-HBc+, it is recommended that IgM and IgG serology be obtainedfrom the donor and that kidneys from IgM+ donors not be used for transplantation because oftheir high potential for infecting the recipient.97 Organs from anti-HBc+ IgG+ donors are

28

recommended for anti-HBsAg- recipients in life-threatening situations or for anti-HBsAg+recipients with extenuating need such as vascular access failure for dialysis. Management of therecipients of these kidney allografts should include therapy with lamivudine and HBIG.

Using the data from the same UNOS database, the one-year risk of an initially HCV- kidneytransplant recipient developing HCV positivity when transplanted with an HCV+ donor is 39%.Consequently, the use of HCV+ kidney donors is not recommended in HCV- recipients.

Simultaneous double kidney transplant into a single recipient

A Spanish study of 181 kidney transplant recipients (21 simultaneous double kidney transplants)implemented a protocol whereby a kidney biopsy was always performed in donors who were 60years of age or older in order to analyse for the presence of glomerulosclerosis. Simultaneousdouble kidney transplant was performed for a single recipient when the donor age was 75 yearsor older or when a donor between 60 and 74 years of age had a glomerulosclerosis rate of morethan 15% (group I). A single kidney transplantation was performed for recipients when donorswere between 60 and 74 years of age with a glomerulosclerosis rate of less than 15% (group II)or when donors were younger than 60 years of age (group III). Kidneys with glomerulosclerosisrates greater than 50% were not used for transplantation. The primary nonfunction rate was lowin all three groups (5%, 5% and 4% respectively) and there was no significant difference in one-year recipient or graft survival rates (95%, 90% and 93% respectively).165

In a study from Germany, the authors developed a scoring system for the donor kidneys thatincorporated points for older donor age, worsening degree of glomerulosclerosis, donor stable-state serum creatinine and kidney weights (weight > 300 gram being optimal). Donors with 0–1points had two kidneys used for two separate transplants, donors with 2 points had both kidneysused for one simultaneous kidney transplant, and donors scoring more than 2 points were notused. Twenty-six recipients were studied, 22 of whom survived after an average of 18 months offollow-up. Two-year patient and graft survival was 92%, primary nonfunction occurred in 31%and acute rejection occurred in 14%.166

A comparison of dual kidney donors looked at 84 recipients of dual kidneys from donors ≥ 54years of age from the Dual Kidney Registry between 1993 and 1999 against 4,803 recipients ofsingle kidney transplants from the UNOS database transplanted between 1994 and 1997.167 Meanterminal creatinine clearance in the dual transplant donors was 70 ± 26 ml/min, and dualrecipients were more poorly HLA matched than single kidney recipients. Recipients of dualkidneys from donors ≥ 54 years of age versus single donor transplants from donors ≥ 54 years ofage had a significantly lower incidence of delayed graft function (19% versus 37%), significantlylower serum creatinines after two years (151 µmol/L versus 204 µmol/L) and improved one-yeargraft survival (90.8% versus 79.9%).

Survival and economic benefits of accepting marginal kidney donors

Ojo et al. reviewed the UNOS Scientific Renal Transplant Registry in conjunction with theUnited States Renal Data System.162 The survival of patients on the kidney transplant waiting listand receiving dialysis was compared to the survival of patients transplanted with a marginaldonor kidney and those transplanted with an ideal donor kidney. Marginal donor kidneys weredefined as those procured from donors > 55 years of age, donors with a > 10 year history ofhypertension, donors with a history of diabetes mellitus longer than 10 years duration, non-heart-

29

beating donors and donor organs with a cold preservation time > 36 hours. Five-year graft andpatient survival rates were 53% and 74% for recipients of marginal donor kidneys compared with67% and 80% for recipients of ideal donor kidneys. The adjusted annual death rate was 6.3% inthose waiting on dialysis compared to 4.7% and 3.3% for those receiving marginal and idealkidneys respectively. The average increase in life expectancy for recipients of marginal donorkidneys compared to those waiting for a kidney transplant was five years.

The economic cost of performing renal transplants using expanded donor criteria have beenassessed in an analysis using the UNOS Renal Transplant Registry linked with Medicare claims(Medicare was the primary payer data on 34,534 kidney transplants from 1991 to 1996).Expanded donors were defined as donors aged ≤ 5 or ≥ 55 years, non-heart-beating donors anddonors with a history of hypertension or diabetes. High-risk recipients were defined as thoseaged > 60 years or receiving a repeat transplant. The five-year present value of payments rangedfrom $121,698 for non-expanded donor/non-high-risk recipient to $165,716 for expandeddonor/high-risk recipient pairings.168 The break-even point with hemodialysis ranged from 4.4years for non-expanded donor/ non-high-risk recipient to 13 years for the expanded donor/high-risk recipient pairs.

Thus, the available literature supports both the survival and the economic benefits of acceptingmarginal kidney donors for transplantation.

30

Hepatic Considerations

Hepatic pathophysiology following brain death

As with other solid organs, the major factors compromising liver graft survival include factorsrelated to brain death as well as preservation-reperfusion injury. More specifically, the extent ofthe preservation-reperfusion injury depends directly on the duration of cold ischemia and notupon reperfusion.169 Cold preservation causes the sinusoidal lining cells (SLC) of the liver tobecome edematous, and with extended periods of cold ischemia the sinusoidal cells detach andthe hepatocyte microvilli become exposed to the sinusoidal lumen, resulting in cell death.

Leukocyte and lymphocyte aggregation and adherence to ischemic SLC also play major roles indonor liver injury. It is hypothesized that overexpression or conformational changes in adhesionmolecules such as intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesionmolecule 1 (VCAM-1) on the surface of SLC or endothelial cells respectively may mediate theattachment and subsequent injury caused by leukocytes.169 Platelet adherence to the abnormalsinusoids as well as Kupffer cell activation and procoagulant activity are also thought to mediatehepatocellular damage to the donor liver. Intermediate molecules in this process include reactiveoxygen intermediates and cytokines and possibly proteases, calcium, eicosanoids and plateletactivating factor. Collectively, it is postulated that these pathophysiological changes are directlyrelated to the development of primary dysfunction of the liver graft described below.

Risk factors for liver allograft dysfunction

Primary dysfunction (PDF) of the liver in the transplant recipient is the standard outcomemeasure for the success of a hepatic graft.

PDF is subdivided into primary nonfunction (PNF) and initial poor function (IPF). PNF isdefined as non-life-sustaining function of the liver after orthotopic liver transplant (OLT) leadingto death or retransplantation within seven days, and IPF is often defined as AST > 2000 IU/L andprothrombin time of more than 16 (or equivalent INR units) on postoperative days 2 to 7. Ingeneral, liver dysfunction beginning after the first week following liver transplantation is notattributable to pre-operative or intra-operative variables.

Historically, PNF occurs in 2-23% of liver transplant series.171 In a series of 323 consecutiveOLTs from Madison Wisconsin, the incidence of PDF was 22%, including a 16% incidence ofIPF and the balance of 6% as PNF.170 IPF was associated with significant mortality (21%), livergraft failure rate (34%) and retransplantation rate (15%) within the first three months oftransplantation. In a comparable long-term cohort study of 288 patients after the introduction ofthe University of Wisconsin (UW) preservation solution in Europe, PDF was identified in 21%of recipients with PNF and IPF rates of 7% and 14% respectively. In this European cohort, three-month and six-year liver graft failure rate in patients with IPF was 42% and 61% compared with9% and 28% in those with immediate function.171

Within the University of Wisconsin study, reduced-size livers, older donor age (> 49 years),moderate to severe fatty changes in the donor liver biopsy and prolonged preservation times(> 18 hrs) were associated with a higher risk of PDF in multivariable analysis.24 Based on these

31

findings, routine donor liver biopsies have been recommended in all liver donors in an effort todecrease the rate of IPF and PNF.

In an analysis of 649 OLTs performed in 11 centers in Spain from 1992 to 1993, extended coldischemia time > 12 hr (OR = 2.2) and arterial complications (OR = 5) were independentlyassociated with biliary complications. ABO incompatibility (relative risk [RR] = 3.2) and donorplasma sodium > 155 mmol/L (RR = 1.4) were independently associated with an increased rateof retransplantation before 30 days, and donor plasma sodium > 155 mmol/L (RR = 2.0) andABO incompatible grafts (RR = 3.3) were independently associated with death orretransplantation within 30 days.172 Other authors have demonstrated a similar detrimental effectof high sodium levels on liver graft outcomes.173 In a series of 168 liver transplants, a high donorserum sodium concentration, longer total ischemia time, large platelet transfusion during surgeryand prolonged recipient prothrombin time were independently associated with more severehepatic dysfunction after transplantation.174 High serum sodium levels in the donor may promotethe accumulation of idiogenic osmoles such as amino acids and methylamines within liver cellsas is seen with neurons and renal tubular cells. The subsequent transplantation of these livers inrecipients with relatively normal sodium levels may promote intracellular water accumulationthrough osmosis, possibly leading to cell lysis and death manifested as PNF or IPF. The benefitof correcting donor serum sodium to levels below 155 mmol/L has been described by Totsuka etal. in a prospective study of 181 consecutive OLTs.175 The frequency of liver graft loss wasfound to be significantly higher in the patients with uncorrected sodium (33%) compared to thefrequency of graft loss in a normal sodium (12.7 %) or corrected sodium (11.1%).

The influence of donor nutrition on graft survival has been studied in several small animalmodels but not in human studies. In a rabbit and porcine model, Boudjema et al. demonstratedthat animals receiving livers from donors that received enteral nutrition prior to transplantationhad better survival than animals receiving livers from fasting donors.176 Similarily, a significantimprovement in SLC viability has been demonstrated in rats receiving liver grafts from donorrats receiving enteral feeding plus intraperitoneal glucose prior to liver procurement. Uchida etal. demonstrated an improvement in liver graft survival with livers procured from rats who weregiven only water or water containing glucose for four days compared to fed rats.177 In a porcinemodel of liver transplantation, donor pigs provided with parenteral nutrition in the form of 20%glucose had reduced preservation-reperfusion injury compared to donor pigs that were providedwith an enteral diet. The only human series of liver transplants that included donor nutritionalstatus failed to identify an independent effect of donor nutrition on postoperative liver graftfunction.174

In summary, the sinusoidal lining cells of the liver appear to be particularly vulnerable to injuryresulting from both donor brain death and preservation-reperfusion. Older donor age in adulttransplantation and very young age in pediatric transplantation, moderate to severe steatosis onliver biopsy, prolonged cold ischemia time (in excess of 12–18 hours), ABO incompatibility, anddonor hypernatremia (sodium > 155 mmol/L) appear to be the most robust predictors of PNF andIPF related to the donor (table 4). Other factors that may be associated with liver allograftdysfunction include (1) donor gender, race, etiology of brain death and ICU length of stay, (2)perioperative warm ischemia time, extent of platelet transfusions and technical complicationsand (3) recipient age, medical status, renal insufficiency, retransplantation and vasopressor use. Itis reasonable to consider preventing or treating causes of hypernatremia in the organ donor,

32

targeting a serum sodium of < 155 mmol/L. The latter would include the limitation of excessivedoses of osmotic diuretic agents, adequate fluid resuscitation, and the rapid diagnosis andmanagement of DI.

Table 4. Potential risk factors associated with liver graft dysfunction

Donor Perioperative Recipient

Age > 50

Gender (female donor in male recipient)

Race (black donor in white recipient)

Weight

Cause of brain death

ICU length of stay > 5 days

Use of vasopressors

Cold preservation time > 12 hours

High serum sodium > 155 mmol/L

Steatosis > 30%

Partial liver grafts

Warm ischemia time

Technial complications

Blood product use including platelets

Retransplantation

Age

Medical status

Renal insufficiency

Adapted from Busuttil R, Tanaka K. Liver Transpl 2003;9:651–6.

Expanding the liver donor pool

The American Society of Transplant Surgeons and the American Society of Transplantation havereviewed the issues related to optimizing the use of cadaveric donors, and their recommendationsabout liver transplantation have recently been published.3,5

A liver may be transected to the right of the middle hepatic vein, resulting in the creation of twoequally sized adult grafts, or it may be prepared for an extended right lobe graft for an adultrecipient and a left lateral segment graft for a pediatric recipient by transection along the plane ofthe falciform ligament.178,179 Splitting of the liver graft may be performed ex vivo or in situbefore aortic cross-clamping.180 In general, results obtained from splitting for adult/child pairshave been more favourable than results from splitting for two adults.5

In the largest adult/child pair series of in vivo liver grafts, Ghobrial et al. did not demonstrate asignificant difference in patient survival at a median of 14.5 months between recipients whoreceived a split-liver graft (76%) and those who received a whole organ OLT.181 Similar resultshave been reported using ex vivo splitting for adult/child pairs of recipients by the King’sCollege Hospital Liver Transplant Programme.183 In this series, 22 donor livers weretransplanted into 41 patients. After a median follow-up of 12 months, patient and graft survival

33

rates were 90% and 88% respectively. In a review of the European Split Liver Registry between1988 and 1993, comparable patient and graft survival rates were demonstrated between split livergrafts and whole liver grafts.183

Based on these and other studies (table 5), the Crystal City committee overseeing livertransplantation recommends the use of split-liver transplantation for adult/child recipient pairs insuitable liver donors, defined as follows:180,181,184–192

• age > 10 yrs, < 45 yrs

• hemodynamically stable enough to be a heart donor

• intensive care unit duration < 5 days

• liver function tests < 5 times upper limit of normal

• serum sodium < 170 mmol/L

34

Table 5. Split-liver transplantation

Center Author Year n RecipientSurvival

GraftSurvival

ComplicationRate

Adult/adult pair

Hamburg

Villejuif

Bergamo

Genoa

Hamburg

Broerin

Azoulay

Colledan

Andorno

Gundlach

2001

1996

2001

2001

2001

12

44

8

10

4

93%

79%

87%

100%

100%

85%

78%

63%

80%

100%

N/A

37%

75%

N/A

N/A

Adult/child pair

Hamburg

Los Angeles

London

Los Angeles

Hamburg

Hannover

Milano

Rogiers

Goss

Rela

Ghobrial

Broering

Nashan

Maggi

1996

1997

1998

2000

2001

2001

2001

14

28

41

102

49

78

29

93%

92%

90%

80%

82%

80%

88%

85%

86%

88%

78%

76%

N/A

66%

N/A

19%

39%

N/A

28%

N/A

23%

Adapted from Emond JC et al. Liver Transpl 2002;8:863-72

Donor liver age

An early review of the UNOS data from 1987 to 1990 suggested that there was a significantlyworse one-year recipient survival with liver allografts from donors aged 45–55 years comparedto those from donors aged 15–45 years. However, this survival difference was less than 10%.193

Several studies have demonstrated that recipients of liver allografts from donors who are olderthan 50 years of age have similar outcomes to those who receive their liver from younger donorsas long as no additional risk factors are present.194–197

Donor hepatitis B and C

The incidence of anti-HBc+ in the donor population varies by geography and has beendemonstrated to be as high as 15% at an urban transplant center in the United States and 27% inSpanish donors over 60 years of age.198,199 Antibody against hepatitis B core antigen (anti-HBc+)

35

in the donor predicts risk of transmission of hepatitis B virus (HBV) and hepatitis B reactivationin the recipient after transplantation.200 A decrease in the risk of HBV reactivation is evident inrecipients who are anti-HBc+ and have antibodies against hepatitis B surface antigen (anti-HBsAg+). Conversely, an increase in the risk of HBV reactivation in evident in recipients whoare anti-HBc- and anti-HBsAg-. The detection of HBsAg+ in the donor implies that the donor isat risk for transmitting hepatitis B virus; this organ may be considered for recipients who areanti-HBsAg+ or critically ill. Donors with isolated anti-HBsAg+ (with HBsAg- and anti-HBc-),usually obtained from immunization or previous HBV infection, have no active viral replicationand are unlikely to transmit hepatitis B to the recipient.199,201 Alternatively, donors who areHBsAg- (with anti-HBsAg+ and anti-HBc+) demonstrate immunity to the hepatitis B virus;however, after transplantation into an immunosuppressed host, transmission of the infection tothe liver transplant recipient has been demonstrated, with rates between 8% and 100%.202–207 Inthis circumstance, liver biopsy of the donor organ may be necessary to assess for evidence ofactive hepatitis; some authors recommend routine biopsies in anti-HBc+ donors.200

The liver donor of perhaps most concern is the donor who is anti-HBc+ (with HBsAg- and anti-HBsAg-), reflecting an insufficient period for the development of anti-HBsAg+ and an activelyinfectious state. Prieto et al. have demonstrated that such donors infect recipient livers at a rate of50% compared to a rate of 2% in recipient livers from donors who are anti-HBc-.199 Otherinvestigators have demonstrated good one-year graft survival of 85–88.6% in recipients of anti-HBc+ liver grafts if these recipients received HBIG and lamivudine therapy.198,208 Yu et al.reviewed 15 recipients of liver allografts from anti-HBc+ donors, six of whom were HBsAg+and nine of whom were HBsAg- before transplantation.209 All the recipients were administeredlamivudine 100 or 150 mg/day after transplantation, and recipients who were HBsAg+ alsoreceived HBIG prophylaxis. One of two recipients who was HBsAg+ and received a liver biopsyhad detectable hepatic HBV DNA. None of the recipients who were HBsAg- acquired anti-HBcor HBsAg+, and none of the seven patients who underwent a liver biopsy had hepatic HBV DNAisolated.

Recipient anti-HBc status is important in predicting the development of HBV aftertransplantation, as small series of patients have demonstrated a 0–13% frequency of reactivationin recipients of anti-HBc+ livers who were also anti-HBc+ compared to 33–100% frequency ofreactivation in recipients who were anti-HBc- prior to transplantation.201 The frequency of HBVreactivation from anti-HBc+ donors to anti-HBsAg+ recipients is uncertain because of limitedclinical series addressing this topic, but ranges from 0–33%.201,202 Most authors have suggestedthat routine prophylaxis with lamivudine and HBIG is not necessary for recipients who are anti-HBc+ and or anti-AbsAg+; however, one author recommends routine prophylaxis for allrecipients of anti-HBc+ livers.210 A summary of the management of recipients of anti-HBc+ liverdonors is outlined in table 6.199,211,212

Anti-HBc+ livers should initially be offered to HBsAg+ recipients, as limited data suggest thattransplantation of these livers in patients with HBV cirrhosis or fulminant HBV infection doesnot affect mortality.213 Failing this match, anti-HBc+ livers should then be offered to anti-HBC+and anti-HBsAg+ recipients, with close serological and virological monitoring of HBV DNA,HBsAg, anti-HBc and anti-HBsAg.200 If neither of these recipient types are available, then theanti-HBc+ organ should be offered to an anti-HBsAg- recipient with the understanding that there

36

is a high probability of HBV reactivation and that recipients should be placed on prophylactictherapy with lamivudine and HBIG.

Table 6. Risk of HBV and management of anti-HBc+ liver recipients

Anti-HBc / anti-HBsAg Status

Donor Recipient

Risk of HBVReactivation

Proposed Management Alternatives

+/+ or +/-

-/+

HBV DNA+

IgM anti-HBc+

HBsAg+

-/-

+/-

+/+

any type

any type

any type

any type

high

0% - 13%

low

very low

high

high

high

lam/lam plus HBIG

lam vs. no prophylaxis plus surveillance

lam vs. no prophylaxis plus surveillance

no prophylaxis

lam/lam plus HBIG

lam/lam plus HBIG

lam plus HBIG

Munoz SJ. Liver Transplantation 2002;8:S82-7

Abbreviations: lam = lamivudine; IgM = immunoglobulin M

Antibodies to hepatitis C virus are isolated in approximately 5% of all organ donors. Thepresence of the antibody indicates infection, and all organ donors with a positive HCV PCR willtransmit HCV to the recipient.214 Transplantation of HCV+ donors to HCV- recipients should beperformed only in exceptional circumstances. Transplantation of a liver from an HBC- donor toan HBV+ recipient does not significantly increase the recipient’s mortality.215 According to theUNOS database for 1994 to 1997, 2,923 HCV+ patients underwent OLT; 96 (3%) of thesereceived an HCV+ allograft, and 2,827 (97%) received an HCV- allograft.216

In summary, adult/child split-liver donation, older donors without significant steatosis orprolonged cold ischemic time, and anti-HBsAg+ or anti-HBc+ donor livers in combination withlamivudine and HBIG therapy should be considered for transplantation in an effort to expand theliver donor organ pool. Liver allografts from donors who are HCV+ should be used only inrecipients who are HCV+.

37

Infection Considerations

Donor bacteremia

Isolated cases of solid organ infection in the donor being transmitted to the recipient have beendocument, with potentially devastating consequences including graft infection, sepsis and poorinitial graft function in a liver recipient.217–221 However, with careful attention to the use ofprophylactic antibiotics such as vancomycin, ceftazidime and cefotaxime in the recipientimmediately after transplantation and until donor blood culture results were obtained, twoauthors have demonstrated no transmission of bacterial infection in 124 recipients of solidorgans.95,114

In a study of 569 liver and heart donors, 29 (5%) of donors were subsequently found to bebacteremic at the time of organ procurement.95 The recipients of all of the organs from thesedonors were routinely treated with vancomycin and either ceftazidime or cefotaxime until thethird day after transplantation, followed by norfloxacin until discharge as well as standardco-trimoxazole prophylaxis. Gram-positive bacteria were isolated in 76% of the bacteremicpatients and gram-negative bacteria were isolated in 24%. None of the recipients becamebacteremic with organisms that had been isolated from their respective donors, and there was nodifference in 60-day patient or graft survival

In an analysis of all organ donors cared for by the New England Organ Bank between 1990 and1996, 95 (5.1%) of 1,775 organ donors were identified as bacteremic.114 No evidence of bacterialtransmission could be identified in 212 recipients. There was no difference in 30-day graft andpatient survival for recipients of organs from bacteremic compared to non-bacteremic donors.

Other authors have described the successful transplantation of organs from donors declared braindead from meningitis caused by Neisseria meningitidis, Streptococcus pneumoniae andEscherichia coli without transmission to the recipient.222

Prophylactic antibiotics and screening

Little or no literature exists on the use of prophylactic antibiotic therapy in the organ donor.General principles of antibiotic use in other critically ill patients suggest that minimizing the useof empiric antibiotics and narrowing the spectrum of coverage to target specifically isolatedbacteria or fungi would be reasonable.

Recently, standards for the handling of donor organs have been published by the CanadianStandards Association. These standards state that the degree to which risk of infectiouscomplications should be accepted in the recipient is to some extent governed by the urgency ofthe transplant as well as the availability of the donor organ.

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Hematological Considerations

There are no rigorous studies that assess the role of red blood cell transfusions in the brain-deaddonor. Both the Crystal City Consensus Conference Report and Van Bakel et al. haverecommended maintaining a hemoglobin level ≥ 10 g/L or a hematocrit greater than 30%.4,8 Incontrast, current critical care practice advocates the use of red blood cell transfusions in non-bleeding patients only at a hemoglobin level < 70 g/L.223

In a randomized trial of allogeneic red blood cell transfusions in critically ill patients, treatmentprotocols included a restrictive strategy of transfusing at a hemoglobin threshold of 70 g/L (andmaintaining hemoglobin between 70 and 90 g/L) versus a liberal strategy of receiving red bloodcells at 100 g/L (and maintaining hemoglobin between 100 and 120 g/L).224 Overall mortalityrates were not different between groups but there was a trend toward worsening survival in thosewith acute coronary syndromes not transfused liberally. However, the endpoints of transfusionstudies in the ICU are patient survival, not organ preservation.

Donor Malignancy

Brain-dead patients with certain types of skin and central nervous system (CNS) cancers shouldbe considered for potential organ donation.

In a cohort study of 14,705 cadaveric donors within the UNOS registry, 257 donors from whom650 organs were procured.225 Three-hundred ninety-five of the 650 organs were obtained fromdonors suffering from non-melanoma skin and CNS cancers. During a mean follow-up of 45months, no recipients of these organs developed a donor-associated tumour (by histology), and71.5% of all the non-skin and non-CNS cancer donors had a cancer-free interval of greater thanfive years.

In another analysis of 42,340 cadaveric donors within the UNOS registry from 1992 to 1999, 397had a past history of CNS tumour.226 No significant difference in recipient survival wasidentified between patients receiving organs from CNS tumour donors and patients receivingorgans from donors without CNS tumors. Moreover, of the 39 patients reporting malignancies inthe post-transplant period, none had tumours that were associated with the donor tumour.

Nonetheless, previous authors have described isolated cases of the transmission ofmedulloblastoma, glioblastoma and high grade glial neoplasms from donors to transplantrecipients, particularly if the donors had undergone previous intracranial surgery orventriculoperitoneal shunting.227–232 With this in mind, Detry et al. estimated the risk of CNStumour transmission to be between 0% and 3% based on retrospective studies.233

Based on these findings, it has been recommended that donors with CNS tumorrs are acceptableas long as the recipient’s risk of dying on the waiting list is much higher than 3%. However, bothDetry and Kauffman have cautioned against the use of organs from donors with previousintracranial manipulation.226,233

An outline of acceptable and marginal organs from donors with previous malignancy is providedin table 7 (next page). This outline is adapted from the 2001 Crystal City Report and theconsensus report of the Pulmonary Council of the International Society for Heart and LungTransplantation.3,6

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Logistics and Organization of Transplant Programs

UNOS demonstrated that implementing a critical pathway of structured organ donormanagement (compared to a similar period one year prior to the critical pathway) resulted in anoverall increase of 10.3% in the number of organs recovered per 100 donors, an 11.3% increasein the number of organs transplanted per 100 donors and an overall increase of 19.4% fortransplanted hearts. This critical pathway is the current protocol recommended by the UNOS.234

However, the benefit of this strategy appears to have more of an impact on the procurement ofheart, lung and pancreas; there was no significant increase in the number of kidneys or liverstransplanted per 100 donors when comparing the critical pathway group to the historical controlgroup.

Table 7. Summary of literature for donors with a history of malignancy

Acceptable Not acceptable

Low-grade skin cancer (basal cell and squamous cell)

Carcinoma in situ of organs such as the uterine cervix

Primary tumours of central nervous system

• lowest risk

• benign meningiomas

• pituitary adenomas

• acoustic schwannomas

• craniopharyngiomas

• astrocytoma grade I

• epidermoid cysts, colloid cysts

• low-grade oligodendrogliomas

• gangliogliomas, gangliocytomas

• pineocytomas, ependymomas

• well-differentiated teratomas

• papillomas

• hemangioblastomas

If previous treatment with presumedcure, consider organs as marginal,including:

• renal cell cancer

• lung cancer

• melanoma

• choriocarcinoma

• breast cancer

• colon cancer

40

If there are risk factors for metastases, consider organs asmarginal, including:

• moderate risk

• astrocytoma grade II

• gliomatosis ceribri

• highest risk

• anaplastic astrocytoma grade III

• glioblastoma multiforme

• medulloblastoma

• anaplastic oligodendroglioma

• pineoblastomas

• chordomas

• malignant ependymomas

• primary cerebral lymphoma

• high grade histology

• glioblastoma and medulloblastoma

• previous craniotomy

• ventricular shunts

• tumor radiation

• recurrence in the brain, or a long interval fromprimary therapy

Adapted from Orens JB et al. J Heart Lung Transplant 2003;22:1183-200,

and Rosengard BR et al. Am J Transplant 2002;2:701-11

41

Conclusion

There has been significant progress in the understanding of the pathophysiology of brain deathand its effects on donor and recipient organ function over the last 20 years. Much of thisinformation has come from animal experimentation and case series of brain-dead donors. Severalcohort studies have provided valuable information about donor characteristics that decreaserecipient graft survival and increase recipient mortality. The databases used in these studies havealso been very helpful in modelling the statistical risk of allograft failure when predefinedmarginal donors have been used for transplantation.

Both evolving clinical experience and the analysis of institutional and national donor-recipientdatabases has demonstrated that previously “untransplantable” organs can be safely andeffectively transplanted with good graft survival. Analysis of the datasets indicates that olderdonor age and longer cold ischemic time are consistent predictors of poor graft survivalirrespective of the organ (heart, lung, kidney or liver). Despite these challenges with marginaldonors, it is hoped that further scientific research into better donor management, better organpreservation techniques and improved predictive models for matching marginal donors withrecipients will permit the expansion of the Canadian donor pool in the future.

A summary of routine investigations and management strategies for the multi-organ donor isprovided in table 8. Although many of these recommendations have a sound physiologicalfoundation, very few therapeutic recommendations have been tested within the context ofrandomized clinical trials. Rather, specific recommendations for therapies to improve themaintenance of donor function and graft survival have generally come from expert panels oftransplant physicians and surgeons. As the demand for donor organs increases and the number ofdonors remains stable, future emphasis should be placed on testing various therapeutichypotheses within the context of well-designed randomized trials and cohort studies.

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Table 8. Summary of donor investigation and management

Investigations and Monitoring Therapy

Cardiovascular Investigation

• EKG

• troponin

• echocardiogram: consider ifmale donor age > 45 years orfemale donor age > 50 years

• dobutamine stressechocardiography: 5, 10, 15, 20µg/kg/min at 3-minute intervals

• angiography

Monitoring

• central venous line

• arterial line

• pulse oximetry

• pulmonary artery catheter ifhemodynamically unstable orevidence of cardiac dysfunctionor pulmonary edema

For autonomic storm: esmolol (Brevibloc) loadingdose of 1.5 mg/kg over 30 seconds followed by aninfusion of 50–300 µg/kg/min. Titrate to achieveSBP ≤ 160 mm Hg and HR ≤ 80 / min

Maintain SBP ≥ 90 mm Hg or MAP ≥ 60 mm Hg

Maintain CVP 6–8 mm Hg and PCWP 8–12 mm Hgfor potential lung donors

Maintain CVP 8–10 mm Hg and PCWP 8–12 mmHg if both thoracic and abdominal organs areconsidered

Maintain CVP 10–12 and PCWP 8–12 mm Hg ifonly abdominal organs are to be considered

Cardiac index ≥ 2.4 L/min/m2

SVRI 800–1,200 dyn/sec/cm2

Optimize stroke work index using

• vasopressin up to 40 mU/kg/hr

• norepinephrine 0–20 µg/min

• dopamine or dobutamine ≤ 10 µg/kg/min

• acetylcysteine 0.6–1.0 gram IV within 24 hoursof coronary angiography and repeat within 24after angiography

Pulmonary Chest x-ray

Bronchoscopy to evaluate airway foranatomical abnormalities

Bronchoscopy and bronchoalveolarlavage for microbiological tests

MonitoringArterial blood gasses

Plateau pressure monitoring

Frequent endotracheal suctioning

Chest physiotherapy

Bronchoscopy for bronchial toilet

Mechanical ventilation

• PaO2 > 100 mm Hg, FIO2 ≤ 50%

• maintain arterial pH 7.35–7.45

• volume-controlled or pressure-controlledventilation varying tidal volumes to maintainplateau pressures ≤ 30 cm H2O

• PEEP ≥ 5 cm H20

• recruitment maneuvers of PEEP 10–20 cm H20and pressure-controlled ventilation of 35–45cm H20 for duration of 15 minutes every 4hours

Salbutimol 2.5 mg nebulized q4h forbronchodilatation and pulmonary edema

(continued next page)

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Table 8. Summary of donor investigation and management (cont’d)

Renal/Metabolic Investigations:

• electrolytes, urea, creatinine,Ca++, Mg++, PO4=

• terminal creatinine clearancemeasurement (Cockcroft-Gaultequation)

Monitoring:

• urine output hourly

Vasopressin, norepinephrine to maintain a MAP ≥80 mm Hg if donor only considered for kidneys

Crystalloids or colloids to maintain urine output ≥ 1mL/kg/hr

Maintain K+ > 4.0 mmol/L

Maintain Na+ < 150 mmol/L

Maintain physiological levels of Ca++, Mg++,PO4=

Maintain pH 7.35 to 7.45 with bicarbonate ifnecessary

Liver Bilirubin, AST, ALT, alkalinephosphatase, INR, PTT, glucose

Liver biopsy when hepatic steatosissuspected or with marginal donors

Maintain MAP ≥ 90 mm Hg

Maintain serum Na+ < 155 mmol/L

Glucose as D5W, D5/0.9% saline or D5/0.45%saline

Hematological CBC, INR, PTT

ABO screening

Cytotoxic screen

Red blood cells to maintain Hb > 70 g/dL foruncomplicated patients and Hb > 100 g/dL formarginal cardiac donors

Fresh frozen plasma to correct coagulopathy

HormonalResuscitation

Vasopressin 0–40 mU/kg/hr IV or DDAVP 2 unitsIV q 6–8 hrs for DI

Insulin Toronto 0–20 U/hr to maintain physiologicalglucose levels

Methylprednisolone 15 mg/kg IV q24h

T3 bolus 4 µg followed by a continuous infusion of 3µg/hr

Infection Blood cultures

Bronchoscopy and bronchoalveolarlavage for culture and sensitivity

CMV

Hepatitis B, anti-HBc, anti-HBsAg,HbsAg, hepatitis C

HIV, human T-cell lymphotropicvirus type 1 (HTLV-1)

Toxoplasma gondi, Epstein-Barrvirus (EBV), syphilis,mycobacterium tuberculosis

Vancomycin 1 gm IV q12h + ceftazidime 1 gram IVq8h

44

Abbreviations

ADH antidiuretic hormone (vasopressin)ARDS acute respiratory distress syndromeATN acute tubular necrosisAVP arginine vasopressin (vasopressin)CABG coronary artery bypass graftingCMV cytomegalovirusCNS central nervous systemCVA cerebrovascular accidentCVP central venous pressureDDAVP 1-desamino-8-D-arginine vasopressinDI diabetes insipidusGFR glomerular filtration rateHBV hepatitis B virusHBC hepatits C virusICP intracranial pressureICU intensive care unitIPF initial poor function (liver)ISHLT International Society for Heart and Lung TransplantationMAP mean arterial pressureOLT orthotopic liver transplantPDF primary dysfunction (liver)PGI2 prostacyclinPNF primary nonfunction (liver)SBP systolic blood pressureSLC sinusoidal lining cellsSVR systemic vascular resistanceT3 triiodothyronineT4 levothyroxineTSH thyroid stimulating hormoneUNOS United Network for Organ Sharing

Note: Drugs converted to units/kg/hr utilize a reference weight of 60 kg unless otherwisespecified.

45

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