Guidelines relating to solid organ transplants from non-heart beating donors Guidelines relating to solid organ transplants from non-heart beating donors

When Brigid McNamee's husband John died three people were given the chance of life. Brigid says "as our son Sean grows up he will be able to understand more about his father's gift, something he can be proud of." Reproduced courtesy of UK Transplant

Published by the British Transplantation Society Triangle House, Broomhill Road, London SW18 4HX Tel: 0870 833 2430 Fax: 0870 833 2434 Email: [email protected] Web: www.bts.org.uk

ISBN 0-9542221-7-2

Produced by Triangle Three Ltd British Transplantation Society

Contents

Process of writing 04

Introduction 05

Categorisation of non-heart beating donors 06

Donor selection criteria 07

Role of donor transplant co-ordinator prior to death of the donor 08 For category 3 and some category 4 donors For Category 1, 2, 5 and some category 4 donors 09

Consent 10

Diagnosis of death 11

Immediate post-mortem management for renal or renal and liver donors 12

Process of organ retrieval 14

Preservation of organs following non heart beating organ donation 16

Viability testing 17

Recipient selection, laboratory protocol 19

Initial immunosuppression and care 20

Graft outcome after non-heart beating organ retrieval 21 Outcome in renal transplantation 21 Outcome in pancreas transplantation 22 Outcome in liver transplantation 22 Outcome in lung transplantation 23

Informing recipient population 24

Staffing implications 25

Author's potential conflict of interests 27

References 28

Apendix A 31

Appendix B 33

Appendix C 34

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Process of writing

In the spring of 2002 the Council of the Other authorities that include: The British Transplantation Society agreed that Intensive Care Society, The Association of the Standards Committee (Chair: Dr C G Anaesthetists, The Academy of Medical Newstead, Consultant Renal Physician, Royal Colleges and Faculties in Leeds Teaching Hospitals Trust) should conjunction with the Department of prepare guidelines relating to this topic. Health are preparing guidance on the Dr Newstead wrote the first draft in management of the patient who has the conjunction with Mr S Willis (Transplant potential to become a non-heart beating Co ordinator, Leeds Teaching Hospitals organ donor. Trust) drawing extensively on protocols already in existence at Newcastle, Authors reviewed contributions made by Leicester, North and South Thames. others, in particular those published in the Subsequently revisions and original United States [1, 2]. contributions were made by: Mr D Talbot, (Consultant Hepatobiliary and Transplant The likelihood of early changes to British Surgeon, Freeman Hospital, Newcastle) Mr legislation covering this area also led to a N V Jamieson (Consultant Transplant reassessment of the document. This Surgeon Addenbrooke's Hospital change of strategy led to significant Cambridge), Miss L Robson Lead editing the subsequent draft was again 04 Transplant Co-ordinator Freeman Hospital, circulated to the above named colleagues Newcastle), Dr P Murphy and Dr D Bell for comment. (Neuro-ITU Leeds Teaching Hospitals Trust) After revision the draft was posted on the A preliminary draft was circulated at the BTS website for two months from July request of The Department of Health to a 2004 and the final version has taken into group of coroners attending a workshop account constructive comments received in late November 2002 to solicit from a number of contributors. comments. In the body of the document key points It was subsequently decided after are shown highlighted. discussion with a number of interested parties including The Council of the BTS that the BTS guidelines would be altered to cover the management of the process of donation after the diagnosis of death. It would in addition cover the areas of direct involvement of the "Transplant Team" both of the donor and evaluation of the patient who has the potential to become a donor. Excluded from this guidance therefore is the important contribution of other hospital staff for example those working in Accident and Emergency, Intensive Care as well as Coroners.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Introduction

The number of transplants performed in the United Kingdom has remained As well as the important health virtually static over the last ten years. benefit acquired by the recipient During this interval the number of following successful organ donors has decreased by transplantation organ donation can approximately 20%. provide benefits to the donor family. Organ donation is usually a positive The causes for the reduction in heart experience for bereaved families and beating cadaveric donors are may be the most comforting aspect of multifactorial. There has been a an otherwise tragic and sudden event. laudable decrease both in fatalities Non-heart beating donation in the from road traffic accidents in the situation where a patient cannot be United Kingdom as well as a diagnosed as dead using brainstem significant decrease in the number of criteria offers the family the choice to deaths from intracranial haemorrhage. donate organs which otherwise would Changes in neuro-intensive care not have been available. It also allows management may have contributed. healthcare professionals to carry out the wishes of the deceased when that 05 Renal and other solid organs as well as is known. tissue retrieval from non-heart beating donors is not a new concept. Before the introduction of legislation defining Renal and other solid organs as well as brain stem death in the 1970s all tissue retrieval from non-heart beating cadaveric kidneys were retrieved from donors is not a new concept non-heart beating donors. Organ donation is usually a positive In Maastricht (Netherlands), Japan experience for bereaved families and parts of the United States of America as well several units in the Non-heart beating donation in the United Kingdom, in particular; situation where a patient cannot be Addenbrooke's Hospital (Cambridge), diagnosed as dead using brainstem Guy's and St George's Hospitals criteria offers the family the choice to (London), Leicester General Hospital, donate organs which otherwise would and Freeman Hospital (Newcastle) not have been available. It also allows have longstanding programmes healthcare professionals to carry out retrieving organs (principally kidneys) the wishes of the deceased when that from non-heart beating donors. is known.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Categorisation of non-heart beating donors

These donors can be divided Category 3: awaiting cardiac into categories based arrest principally on work from the These are a group of patients for Maastricht group. This is whom death is inevitable but they important both for the do not fulfil brainstem dead criteria. logistics of retrieval and These patients are cared for in many outcome following areas within hospitals but most transplantation. commonly are identified in Neurosurgical Intensive Care Units, General Intensive Care Units, Coronary Care Units, Accident and Emergency Departments and Category 1: dead on arrival at Medical Wards. hospital For these individuals to be potential Category 4: cardiac arrest in a donors the moment of sudden brainstem dead cadaver 06 death needs to have been witnessed and the time that it occurred This is an individual in whom death documented as well as has been diagnosed by brainstem pre-admission resuscitation. criteria who then suffers an unexpected cardiac arrest. On some occasions these cases will be Category 2: unsuccessful awaiting the arrival of an organ resuscitation retrieval team. These are individuals in whom cardio-pulmonary resusitation is Category 5: unexpected commenced following collapse. cardiac arrest in patient in an These patients are usually in an ITU/ or critical care unit Accident and Emergency This has recently been suggested as Department, in which the interval of an addition to the other four resuscitation and the efficiency of categories [3] resuscitation has been well documented.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Donor selection criteria

To streamline the process it is helpful For lung donors for each retrieval team to adopt Guide selection criteria: selection criteria that are known to ITU Aged < 55 years and A&E as well as donor transplant P02 / Fi02 > 30Kpa co-ordinator staff. No gross abnormality on chest x-ray in past 24 hours. Unilateral changes do not preclude the For renal or renal and liver donors retrieval of one lung. Time for the cardiothoracic retrieval team to The arbitrary cut off point for be present at the withdrawal of treatment. something that changes gradually such as age is not logically defensible and referring staff encouraged to discuss all Contraindications potential donors with donor transplant Previous chest surgery (presence of a co-ordinators. chest drain does not preclude donation). Guide selection criteria: Asthma requiring systemic steroids. Smoking history, length of ventilation and positive gram stain of airway 07 1. Age<65 years (renal), age <70 years (liver) secretions are not absolute 2. Warm ischaemic time less than or equal to 20 minutes for the liver and less than or equal to contra-indications. 40 minutes for the kidneys. This time can be defined as starting when there is hypotension The Cardiothoracic retrieval team will below a systolic BP of 55 mmHg and is bring all the equipment they require measured up to the point of the cold perfusion of the organ. and transport to and from the hospital 3. No history of renal impairment. is organised by the Cardiothoracic 4. No uncontrolled hypertension or complicated Recipient Transplant Coordinator. The insulin dependent diabetes. team consists of 2 surgeons, a scrub 5. No uncontrolled systemic sepsis or malignancy nurse and a perfusionist. The team will using the same criteria as for potential donors not require any assistance with the who are declared death after brain stem testing. bronchoscopy procedure or the retrieval. The "Guidance on the Microbiological Safety of Human Organs, Tissues and To streamline the process it is helpful Cells used in Transplantation" issued for each retrieval team to adopt by the Advisory Committee on the selection criteria that are known to Microbiological Safety of Blood and Intensive Care Units and Accident and Tissues for Transplantation August Emergency as well as donor transplant 2000 will be followed [4]. co-ordinator staff.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Role of the donor transplant co-ordinator prior to death of the donor

For category 3 and some category 4 . A lack of objection for blood sampling for donors either immediate or later testing for When a Donor transplant co-ordinator attends virology and other infections, blood group the Intensive Care Unit it will be to assess the and HLA type. patients suitability for non-heart beating organ . The potential to administer ante mortum donation. The assessment will be initially from agents to maintain the function of an medical notes and ITU charts and will involve organ where that is either local policy or review of: in a particular case thought desirable. . The procedure following donation and the . Height, weight, ABO blood group, follow up by the Donor Transplant biochemistry co-ordinator. . Ventilation and Oxygenation . Haemodynamics, ECG, inotropic At this point lack of objection to organ and requirements, urine output, fluid balance tissue donation will be documented. . Medical History . Social History If the family retract lack of objection at any . Arterial blood gases (particularly for point the organ donation team will stand potential lung donors) down.

This information will be discussed with a The Donor Transplant co-ordinator will arrange 8 Consultant in Transplantation for their opinion the surgical team and operating theatre and regarding suitability for organ donation. ensure arrangements to transfer the patient to The potential for tissue donation should be theatre are in place. explored with competent authorities.

Although the method of treatment withdrawal For lung donation it is helpful to know is dictated by unit policy, the donor transplant whether the planned withdrawal of treatment co-ordinator must have knowledge of this includes extubation, as equipment for re- prior to the next of kin interview. intubation and bronchoscopy will be required once death has been certified. If the next of kin agree to consider organ donation a Donor transplant co-ordinator will discuss the following issues: Next of kin and family support will be offered according to the Critical Care Unit guidelines . What happens when death occurs and the and UK Transplant Donor Family Care Policy. need to go to theatre promptly following the certification of death. . Or the immediate cold preservation of A Donor transplant co-ordinator will review abdominal organs via in-situ perfusion the families understanding of the situation where this is agreed local practice. and discuss the process of retrieval, . Or circumstances where treatment ante-mortem blood sampling, testing of withdrawal and certification of death takes blood samples, ante-mortem treatments place in the operating theatre. designed to maintain the performance of . If the time between treatment withdrawal organs and the post-mortem cold and death is prolonged a point may be preservation where appropriate will be reached when organ donation is not discussed. possible. . Medical and social history including If the family retract lack of objection at any completion of UK Transplant's Donor point the organ donation team will stand assessment documentation and General down. Practitioner Questionnaire.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Role of the donor transplant co-ordinator prior to death of the donor

For Category 1, 2, 5 and some category 4 . Ensuring that families are aware that some donors kidneys may be found unsuitable for In this situation the co-ordinator as well as the transplantation post retrieval. surgical retrieval team are required to attend . The procedure following donation and the very promptly, most usually the Accident and follow up by the Donor transplant Emergency department and less often-other co-ordinator. departments in a hospital.

In this situation there is often very little time to At this point lack of objection to organ and acquire information. The co-ordinators tissue donation will be documented. assessment will be initially from Casualty staff and Paramedic records and medical history of If the family retract lack of objection at any particular relevance at this stage is previous point the organ donation team will stand malignancy, diabetes, hypertension and the down and the cannula used to administer the documentation relating to the failed cardio- cooling perfusate removed. pulmonary resuscitation. An estimate of the likely warm ischaemia time is extremely The Donor transplant co-ordinator will arrange important. the surgical team and operating theatre and will be responsible for the arrangements to The national donor register will be checked to transfer the patient to the operating theatre. see if the potential donor was registered. 9 The next of kin and other family members will This information will be discussed with a be offered support according to the Consultant in Transplantation for their opinion Department guidelines and the UK Transplant regarding suitability for organ donation. The Donor Family Care Policy. potential for tissue donation should be explored with competant authorities.

If next of kin or family are present a verbal lack of objection will be obtained prior to cannula insertion and perfusion. If family The Donor Co-ordinators prime purpose will members are not present cannulation can still be to gather information to allow clinicians to be initiated while efforts are made to locate assess suitability the for non-heart beating the next of kin. In this situation approval for organ donation. the in-situ cooling process will have to be obtained from the Coroners Office by prior Usually most critical is the potential donors agreement or on a case-by-case basis. It is past medical history as well as the anticipated that the Human Tissue Act will documentation relating to the failed clarify this area. cardio-pulmonary resuscitation. An accurate estimate of the likely warm ischaemia time is As soon as is practicable the co-ordinator will extremely important interview relatives. If they agree to consider organ donation a Donor transplant In the situation where approval of the in-situ co-ordinator will discuss: cooling process has been obtained from the Coroners office and other competent . Medical and social history, including authorities the team will initiate this. completion of UK Transplant's Donor assessment If the family retract lack of objection at any documentation and General Practitioner point the organ donation team will stand Questionnaire. down.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Consent

For in-situ organ perfusion Next of kin It is not clear at the present time that As a general guide, the legal next of kin of consent is required for in-situ organ the deceased person, as defined by the perfusion but it is certainly preferably Treasury Solicitor, are: commenced only after written consent being first obtained from next of kin. The 1) The legally married partner or close forthcoming Human Tissue Act it is blood relative; son, daughter, mother, anticipated will clarify this area from a father, grandchild, brother, sister. legal standpoint. The relatives are told that the purpose of the in-situ perfusion 2) A legally adopted child has the same technique is to cool the organs within the rights as if he or she had been born body so that it may be possible to remove into the adoptive family. them later and use them for transplantation. This will give the next of 3) A separated wife or husband has the kin more time to consider whether they same entitlement as existed before the wish to consent to organ donation. separation, even if there has been a 'Deed of Separation'. Entitlement Placing cannula for in situ-renal perfusion ceases, however, if there has been a in the situation where there are no 'Deed of Judicial Separation' as this has relatives available and the deceased's prior the same power as a Decree Absolute wishes are not known is possible and has of divorce. However, for the purposes of been practised in some areas in United this guidance, where spouses are 10 Kingdom for many years. In this situation separated, but not judicially, then consent for organ retrieval from the consent shall not be obtained from the deceased is discussed with relatives when spouse. A divorced spouse has no contacted as in the paragraph above. If entitlement. consent is not obtained the process is stood down. 4) Confusion may arise with any relationships involving 'step' As discussed above it is probable that the relationships, including in law forthcoming Human Tissue Bill will clarify relationships, common-law, or same the legal situation and if the final Bill were gender relationships and second-cousin similar to the draft legislation it is likely relationships. Such a person cannot be would encourage the expansion of this defined as 'legal next of kin'. The Draft opportunity to become an organ donor. Human tissue Bill in Part 2 section 24 (4) gives a new list of "qualifying For Organ retrieval relationships" [5]. Commencement of retrieval will only proceed when the following conditions ‘Whilst for the purposes of this policy have been met: certain persons, including common law spouses, are not regarded as next of kin, 1) Lack of objection is indicated by the wherever it is apparent that a close next of kin. relationship existed with the deceased, it is always advisable in these circumstances to 2) Where appropriate the Coroner, or consult with them. If there is the potential Deputy has given permission to for significant family dispute regarding proceed with organ retrieval. consent the procedure is often abandoned.

3) Where appropriate the Coroner's Placing cannula for in situ-renal perfusion Pathologist has given permission for in the situation where there are no organ retrieval and names the specific relatives available and the deceased's prior organs that can be removed. wishes are not known is possible and has been practised in some areas in United Kingdom for many years. In this situation consent for organ retrieval from relatives is discussed when they can be contacted. If lack of objection is not obtained the process is stood down.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Diagnosis of death

A fundamental principle of organ In the United States of America the donation is retrieval from a patient Committee on Non-Heart-Beating who has died. There is no statutory Transplantation II in their publication definition of death in English and Non-Heart-Beating Transplantation [1] Welsh Law. It is welcomed that the "found that the interval of five planned Human Tissue Bill [5] based minutes between the cessation of on the consultation document Human cardiopulmonary function and the Bodies Human Choices [6] is likely to declaration of death provided provide a definition. adequate assurance of the irreversible cessation of cardiopulmonary function, The Department of Health revised and satisfied the requirements of the code of practice published in 1998 Universal Determination of Death defined death as "the irreversible loss Act". of the capacity for consciousness combined with irreversible loss of the In hospital clinical practice in capacity to breathe". normothermic conditions and without the presence of agents that have been It seems logical that the key shown to offer a degree of cerebral 11 requirement is for the clinician protection there is rarely difficulty certifying death to be confident that establishing the diagnosis. an interval has elapsed without cardiac output that is long enough to ensure that hypoxic injury to the cerebral cortex and brain stem has occurred. It seems logical that the key This must be such that the patient has requirement is for the clinician suffered the irreversible loss of both certifying death to be confident that the capacity for consciousness and to an interval has elapsed without breathe. cardiac output that is long enough to ensure that hypoxic injury to the As is the case when the diagnosis of cerebral cortex and brain stem has death is made based on the absence occurred such that the patient has of brain stem reflexes the clinician suffered the irreversible loss of both making the diagnosis will not be part the capacity for consciousness and of the organ retrieval team. However to breathe the retrieving surgeon needs to be confident that a competent clinician An interval of a minimum of five has established the diagnosis. minutes is recommended.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Immediate post mortem management for renal or renal and liver donors

For Category 1, 2 and 5 donors perfusion. Some units utilise cooling Much the largest proportion of these devices require additional ports to be donors will be from within the inserted into the abdomen in addition Accident and Emergency departments. to perfusion cannula Referrals to the transplant team will be made after the attending medical In Spain and parts of the USA, but not team has pronounced death. It will be UK, cooling of the whole of the the responsibility of the attending abdominal viscera of the cadaver is medical team to explain to the practiced when after failed cardio- relatives that the patient has died. The pulmonary resuscitation large bore time and date of the pronouncement cannulae are inserted into major of death will be recorded in the arteries and veins in the groin and patient's notes. connected to an extracorporeal cooling and oxygenation circuit. In this External cardiac massage and situation this allows family members to ventilation with 100% oxygen can be contacted and informed of events then be re-established where this has and subsequently approach to 12 been agreed as the local protocol. consider organ donation. In Spain legislation also requires judicial Non heart beating donor kidneys may approval to proceed. be perfused and cooled in-situ using a double balloon, triple lumen intra- aortic catheter. The femoral artery and The Draft Human Tissue Bill which it is vein on one side is approached intended will replace The Human through a short groin incision and the Tissue Act of 1961 allows for persons double balloon perfusion catheter having control of the management of introduced into the aorta via a femoral the institution where the body is lying arteriotomy. 100 mls of blood are to take the minimum steps using the taken for viral serology, biochemistry, least invasive procedure necessary for tissue typing and toxicology. The preserving the body for use in balloons inflated and perfusion transplantation. This authority would commenced. Some units prefer to cease if it became established that instil radiographic contrast medium in consent for removal of a part for the balloons in order to check that the transplantation has not been, and will catheter is correctly positioned for not be, given. If this act is passed in selected perfusion of the renal arteries. this form it will at the least clarify the The system is vented by placing a foley legal situation. catheter into the femoral vein at the groin. The kidneys are perfused with a For some category five donors it may total of 10-20 litres of hyperosmolar be realistic to move to immediate citrate solution cooled to 4 C. Each organ retrieval and as for Category 3 litre of perfusate has 5000units of donors the logistics of this will depend heparin added. Some units additionally upon the availability of surgical staff use a bolus of 1.5 mega units of and operating theatres as well as the streptokinase which at the outset of need for relatives to be informed and register lack of objection.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Immediate post mortem management for renal or renal and liver donors

For Category 3 donors Category 1, 2 and 5 donors The timing of retrieval after the Referrals to the transplant team will be diagnosis of death due to cardiac made after the attending medical arrest is somewhat vexed. All team has pronounced death. It will be Transplant authorities have the responsibility of the attending recommended an interval to ensure medical team to explain to the brain stem death as well as cardiac relatives that the patient has died. standstill. In Pittsburgh an interval of There will be no interventions for a two minutes has been adopted. The period of five minutes. original Maastricht protocol had a ten External cardiac massage and minute interval however a period of ventilation with 100% oxygen can five minutes is now accepted in then be re-established. primary legislation in the Netherlands. Organs may be perfused and cooled in-situ This five minute period is in excess of the time the brain stem can survive in For Category 3 and 4 donors a situation of warm hypoxia and is the There will be no interventions for a 13 interval recommended by these period of five minutes guidelines. Usually after that interval rapid retrieval is initiated, if this needs be For Category 4 donors delayed in-situ organ cooling can be Interventions to optimise organ considered viability in these individuals, who are legally dead and awaiting retrieval, do For all donors not differ at first principle from Relatives need to be fully informed as continuing artificial support whilst early as is practicable and invited to awaiting that retrieval, particularly if register a lack of objection. Organ or 'lack of objection' for donation has tissue donation may be possible with been recorded. Resuscitation consent to some but not all of the manoeuvres, immediate transfer to the procedures. operating theatre and cannulation for cold perfusion could be accommodated without the need for any further legislation or guidelines. It would be mandatory however to keep the family informed and ensure their support for this course of action.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Process of organ retrieval

For abdominal organs If the surgeon is retrieving liver and If asystole does not occur within 2 pancreas this should be done in the hours the liver retrieval maybe usual way after aortic and portal abandoned, although kidney retrieval perfusion have been established. The maybe still possible after an interval of first bag of low viscosity kidney several hours. preservation solution and the first bag of UW solution for the portal vein Two approaches to achieve cold should contain heparin (20.000 IU). perfusion are used. Firstly to perform Care must be taken to avoid damage a femoral cut down and in situ to variants in the vasculature as these perfusion with a short while later aberrant vessels are more difficult to transfer to the operating theatre. The identify and easier to damage when second approach is to combine the pulse less. Probably this is best first cannulation with the laparotomy. The performed with in situ perfusion of latter approach is commonly used if the kidneys continuing while the liver livers and pancreas are retrieved, as and pancreas are mobilised. To reduce portal perfusion is then possible. With liver congestion it may be useful to 14 the femoral cut down approach the drain the IVC before aortic cannulation donor is moved to theatre and and some units utilise a fibrinolytic pre retrieval performed within two hours. flush. The conflict between the desirability of A standard abdominal incision is rapid surgical retrieving to minimise performed and the abdominal cavity ischaemia time and the need to keep cooled with ice slush as soon as to a minimum the manipulation of possible. For a kidney only retrieval pancreas for whole organ transplants these are removed and perfused. The proposes significant technical kidneys are partially prepared to assess challenges. the quality of perfusion and back table perfusion continued until the effluent The abdomen is closed and the form the renal vein is clear and the operator tabulates the procedure and kidneys appear uniformly perfused. the organs removed in the patients Some practitioners advocate the use notes for the Coroners pathologist. of streptokinase during the retrieval of organs from category one, two, three, For lungs four and five donors. In a small- If the withdrawal of treatment and randomised controlled study an cannulation and perfusion of the improvement in viability characteristic abdominal organs is to occur in the of procured kidneys was demonstrated Intensive Care Unit the following if a streptokinase pre-flush was used procedure for non heart-beating lung [7]. donation will be followed and is carried out simultaneously with the cannulation and perfusion of the abdominal organs.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Process of organ retrieval

1) The Cardiothoracic retrieval team There is more than one possible must be on site when treatment is approach to achieve cold perfusion withdrawn of abdominal organs. 2) Treatment is withdrawn 3) If asystole does not occur within 1 hour the lung retrieval will be Some practitioners advocate the use abandoned of streptokinase during the retrieval of 4) Asystole organs from category one, two, four 5) Death certified by local medical and five donors staff 6) Stand off time as per local protocol If the surgeon is retrieving liver and 7) Rigid bronchoscopy is performed pancreas this should be done in the 8) Size 16-Foley catheter is inserted usual way. Probably this is best first into the distal trachea performed with in situ perfusion of 9) Patient is reintubated with 6mm the kidneys continuing while the liver ET tube 10) The lungs are inflated, the ET tub and pancreas are mobilised. To reduce 15 is removed and the foley catheter liver congestion it may be useful to is placed in the larynx drain the IVC before aortic cannulation 11) The family can return once this and some units utilise a fibrinolytic pre and the cannulation and perfusion flush. of the abdominal organs are completed. The foley catheter is not visible. The conflict between the desirability 12) The patient is transferred to the of rapid surgical retrieving to minimise operating theatre ischaemia time and the need to keep 13) Time between asystole and cold to a minimum the manipulation of flush of the lungs in theatre pancreas for whole organ transplants should be less than 90 minutes proposes significant technical and ideally less than 60 minutes challenges 14) Sternotomy performed 15) Assessment of lungs 16) Pulmonary artery opened and clot The procedure for non heart-beating removed lung donation is carried out 17) Lungs are flushed simultaneously with the cannulation 18) Heart lung block is removed. If and perfusion of the abdominal there is no consent for heart valve donation the heart will be put organs. back into the body 19) Retrograde flush of the lungs on the back table and packed for transportation 20) Time from sternotomy to the end of the retrieval will be approximately 1 hour

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Preservation of organs following non heart beating organ donation

The Organ Preservation, graft survival in non-heart beating and Ischaemia/Reperfusion Discussion Forum heart-beating donors groups. They of the BTS will be producing guidelines for predicted a 20% reduction in the instance preservation in the future and so detailed of delayed graft function, and a 2-3% recommendations may well change. improvement in 10-year graft survival In the section of the British could be gained through machine Transplantation Society's website relating perfusion. Their analysis of cost/benefit of to this forum are collected recent key machine pulsatile perfusion was extended references to research in this area. from time of transplant to 10 year survival and concluded where delayed graft Two types of hypothermic preservation function has a higher incidence, such as in solutions are commonly used. kidneys retrieved from non-heart beating A normothermic haemoglobin based donors, the combined benefit of reduced solution is in development. delayed graft function and improvements in 10 year survival rates may well make The donor is initially perfused with large machine perfusion a cost effective option volumes of hypothermic flush. in the long term. The authors concluded EuroCollins, Marshalls or HTK solution can that more research is necessary to be used in this situation, as they are all determine whether machine perfusion can 16 relatively inexpensive. After retrieval the produce significant clinical and economic kidneys, which have already been benefit to organ preservation. damaged by warm ischaemia, should be flushed and stored either in University of As in heart beating organ retrieval the Wisconsin (UW) machine preservation, or standard solution used for liver and HTK solution. Some debate exists as to pancreas cold preservation is UW solution the merits of high viscosity solutions and though low viscosity solutions such as costs too have been raised as a concern, HTK have been proposed as being more however compared to the consequences appropriate. of transplanting a non-viable kidney the cost is justified. There is ongoing research activity to try to minimise the degree of ischaemic injury The potential contribution of machine [10, 11,12]. There is substantial research perfusion of kidneys retrieved from non- interest in the possibility that heart beating organ donors is not clear normothermic preservation may result in [8]. It does allow the possibility of less injury to livers [13]. This is particularly measuring a number of markers that may important in the setting of non-heart correlate with function. Whether the beating donation. process itself allows an extension of the acceptable cold ischaemia time or Kidneys which have already been improves initial function is not yet damaged by warm ischaemia should not established. A report on the value of be stored in Marshalls or EuroCollins machine perfusion in kidney solution transplantation, has been commissioned by the Department of Health [9]. This The potential contribution of machine concludes that the short-term cost/benefit perfusion of kidneys retrieved from of machine perfusion did not justify its non-heart beating organ donors is not use, but that there may be sufficient yet clear cost/benefit if long-term outcomes are considered - but the evidence base is There is substantial research interest in the incomplete. This meta-analysis modelled possibility that normothermic preservation the effects of machine perfusion on renal may result in less injury to livers.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Viability testing

A major limiting factor to the Risk factors for renal primary widespread adoption of a non-heart non-function beating organ donation and Donor factors: Age >60; Serum transplantation is the uncertainty Creatinine >150, Warm Ischaemic time regarding the function of the graft >45 minutes, Cold Ischaemic time >22 once transplanted. Delayed function, hours (ice storage). The efficacy of rejection and extended hospital stay cooling and rate of cooling have all are all a concern with non-heart been shown to be associated with beating organ donation but primary higher rates of primary non-function. non-function has more significant consequences. Primary non-function is Recipient factors: Sensitised or especially important for the recipient re-transplanted patients, early rejection of a life-sustaining organ such as a episodes and early expose to liver or lung. The need to minimise the nephrotoxic agents, including cold ischaemia time reduces the time cyclosporin and tacrolimus. available for viability testing. At present time though there is no The principal purpose of viability conclusive evidence as to the best testing is to reduce primary viability tests to use. There are 17 non-function. Non-heart beating advocators of visual inspection, donor kidneys are prone to acute perfusion characteristics on machine tubular necrosis. Viability testing perfusion and enzyme levels in the should therefore focus upon perfusate [14, 15]. Whatever method determining the severity of injury to is used by the centre careful audit is the tubules and supporting required to maintain good results and microcirculation. Evidence also if the primary non-function is greater suggests that the damage the kidneys than 5% the measures used for sustain is not necessarity bilateral, testing viability must be modified. therefore one could not assume that if one kidney presents as being viable Viability Criteria the other also falls into this category. (Newcastle 2001)

Flow > 23ml/100g GST < 200 IU/100g Temperature (°C) < 14 (surface temperature) (five time points) Wt increase (%) 10-25 % (relative contraindication) Index (ml/min/100g/mmHg) >0.4 (most important) Perfusion pressure (mmHg) <60 mmHg Perfusion fluid Belzer UW with 1000u heparin per litre Donor pre-treatment Heparin and Streptokinase

continued on page 18

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Viability testing

Additional points:

1) Younger donors with shorter warm ischemic times have better outcomes independent of the above variables. 2) Retrieval should be within ninety minutes of perfusion. 3) Cold ischemic time must not exceed 24 hours. 4) The position of the catheter balloons should be checked at retrieval.

Objective assessment of texture, colour, consistency and perfusion effluent on the back table are important parts of the assessment. 18 Primary non-function has significant adverse consequences. These are especially severe for the recipient of a life-sustaining organ such as a liver or lung

The principal purpose of viability testing is to reduce primary non-function

At present time though there is no conclusive evidence as to the best viability tests to use

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Recipient selection and laboratory protocol

Given the possibility of an inferior (initial) In order to try to minimize the duration of performance of kidneys retrieved from this interval it may be appropriate to non-heart beating donors some argue organize a "fast-track" method of that these organs should be reserved for handling recipients. Potential ways to candidates for whom the consequences of reduce the interval include pre-retrieval prolonged delayed graft function are not HLA typing, for organs where that is part especially serious or who do not benefit of the allocation algorithm. The selection particularly from a large nephron mass. of recipients who are unlikely to be sensitised to mismatched donor antigens For recipients of other organs in part and hence demonstrate a positive current because of the lack of other options the cross match (where that is performed) or allocation to any particular recipient is calling up potential recipients as reserves usually governed by local clinical where the first choice is at high risk of imperatives. prior donor specific sensitisation. These strategies will require access to efficient Kidneys (and other organs from non-heart and high quality HLA typing by the most beating donors) are currently in the UK accurate methods. allocated within the pool of potential recipients registered with the retrieving One algorithm and management protocol centre, in part to minimise the length of for allocation of kidneys that is similar to 19 cold ischaemia time. In the future it may the national scheme is included as be appropriate to allocate within a renal appendix A. Another approach is to sharing alliance waiting list. This will allocate one kidney from a donor by rules depend at least in part on local similar to the national allocation rules, but geographical considerations. Units at the other kidney by rules designed to present in general either allocate the favour candidates who have organs using the same criteria as organs demonstrated by spending by a long retrieved from heart beating donors or period on the waiting list that they are alter the allocation rules to favour less likely to receive a kidney from the candidates who are less likely to receive national pool [16]. An example of such a an offer via the national matching scheme is shown in appendix B. scheme. Units are likely to adopt strategies and Organs retrieved from non-heart beating allocation rules that are different to take donors are at risk of warm ischaemic into account local geography and injury during the interval from withdrawal established practice. of full support and cardiac arrest for category 3 donors and during Renal units in general either allocate the unsuccessful resuscitation attempts for kidneys using the same criteria as organs other categories of donors. Organs retrieved from heart beating donors or retrieved from heart beating donors do alter the allocation rules to favour not experience this initial warm ischaemic candidates who are less likely to receive injury. an offer via the national matching schemes. Cold ischaemic injury that occurs in the interval between retrieval and re- For recipients of livers and lungs in part implantation and is usually measured in because of the lack of other options the several hours is likely to be particularly allocation to any particular recipient is deleterious to the function of organs usually governed by local clinical retrieved from non-heart beating donors. imperatives.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Initial immunosuppression and care

Renal transplant recipients Systemic heparinisation is sometimes The Health Technology Appraisal employed particularly if there is no published in 2004 by The National immediate graft function or the donor Institute of Clinical Excellence on was category one, two, four or five. Immunosuppressive Therapy post Renal When the donor was from one of these Transplantation did not consider recipients categories protracted prophylactic of non-heart beating organs and in our antibiotic cover including for anaerobes view the recommendations should not be for three days post surgery is applied to this group. recommended.

It is not clear whether recipients of These organs are likely to have kidneys from non-heart beating donors experienced an increased length of warm experience a significant excess of ischaemia compared to organs retrieved rejection. It is certainly more difficult to from heart beating donors. The length of diagnose if there is delayed graft function. warm ischaemia influences the likelihood Weekly biopsy in the presence of delayed of delayed graft (and primary non) graft function is recommended. function. It is logical to try to minimise Histological appearances of the graft further nephrotoxic injury to the graft. To particularly of the blood vessels are often delay the introduction of nephrotoxic 20 atypical. Vascular changes that can mimic immunosuppression until the transplant is "vascular rejection" are not that functioning or to avoid nephrotoxic uncommon. immunosuppression is practiced my many centres. There are limited published results to guide practice. For recipients of other solid organs In a small-randomised trial of 29 patients The world wide experience in recipients of micro emulsion ciclosporin was compared liver, lung and pancreas transplants is still to tacrolimus in recipients of renal small. It is not yet clear if there are any transplants from non-heart beating complications that are peculiar to donors [17]. Unfortunately despite recipients of organs from this source. randomisation the degree of DR mismatch Neither is it clear what is the frequency of was uneven as was the proportion of complications compared to that seen in controlled and uncontrolled donors. There recipients of organs from heart beating were no clinically critical differences in donors. outcome. The majority of the recipients of non-heart beating kidneys reported in the Clearly primary non-function in recipients literature have received ciclosporin. The of liver or lung transplants is extremely optimal immunosuppressive strategy serious, as would be an increased remains to be established. incidence of certain other complications such as late hepatic artery thrombosis. Initial treatment with IL-2 receptor It is logical to try to minimise further blockers, prednisolone and nephrotoxic injury to the renal transplant. mycophenolate mofetil with the delayed introduction of a calcineurin inhibitor There is limited experience in recipients of when there is either graft function with a liver, lung and pancreas transplants. It is creatinine below an arbitrary level of say not clear if there are any complications 350 micromol/l or there is evidence of that are peculiar to recipients of organs rejection is practiced by some units. from this source.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Graft outcome after non-heart beating organ retrieval

Renal transplants Summarising the predicted outcome The outcome of 122 recipients of kidneys following kidney transplantation with from non-heart beating donors were kidneys retrieved from non-beating donors compared the same number of recipients is not straightforward. The series have of kidneys from heart beating donors with usually been reported from single centres up to 15 years follow up [18]. The rate of and involve relatively small numbers of delayed graft function was higher at 48 patients. The results may not be easily percent in the first compared to 24 reproduced in another service. Inevitably percent in the latter group. The rate of the series with the longest follow up are primary non-function was not significantly from grafts performed some while ago. different at 5.7 and 4.9 percent. Graft During the interval immunosuppressive survival counting recipient death as graft strategies have changed, the accuracy of failure was 74 and 76 percent at five years HLA matching and HLA specific antibody and 64 and 61 percent at 10 years. The screening improved and patient co- paper summarises the results of the morbidity better defined. Patients will largest comparable reports and table 1 is have been managed with a higher dose of principally adapted from this publication. dialysis, with improved correction of anaemia and hyperparathyroidism all of which may be expected to improve United Kingdom transplant have outcome. In contrast the average age of published a comparison of the outcome 21 patients starting dialysis's has increased of first cadaveric kidney only transplants significantly with inevitable effects on co- retrieved from non-heart beating and morbidity and predicted longevity. heart beating donors encompassing the

Table 1

Studies of Kidney Transplantation From Donors Without a Heartbeat

Reference No of First Year Duration Matched Graft Survival Transplantations of Program of Study Patients From Donors Without a Heartbeat

Time After Donors Donors Transplan- With a Without a tation Heartbeat Heartbeat yr yr Percent

Wijnen et al [19] 57 1980 12 Yes 5 55 54 Gonzalez Segura et al [20]† 52 1985 10 No 5 77 68 9 66 50 Pacholczyk et al [21] 76 1986 9 Yes 1 90 82 Balupuri et al [22] 47 1988 10 No 5 83 88 Sanchez-Fructuoso et al [23] 95 1989 10 No 5 84 83 Cho et al [24] 229 1994 2 No 1 86 83 Sanchez-Fructuosa et al [25] 188 1995 7 Yes 7 87 93 † The survival rates were estimated by Kaplan-Meier analysis. continue overleaf

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Graft outcome after non-heart beating organ retrieval

period 1994 to 2000 [26]. Although the At present the only donors that can be number of kidneys retrieved from non- used for liver transplantation are those heart beating donors is small at 172 that have minimal warm ischaemia and compared to 8046 in the other group the therefore are from the Maastricht data show an increased early graft loss in categories three and four. the non-heart beating group then parallel rates of graft was over the first year. One- year transplant survival was not In an ITU setting eight livers were significantly different at 82 versus 85 retrieved from non-heart beating donors percent where there was a non-heart where cardiac arrest occurred after a short beating versus heart beating donor. interval, 3 to 27 minutes after ceasing artificial ventilation. Patient and graft survival are 100 percent at a mean of 18 Pancreas transplants months follow up [28]. The results of 144 In one series of 18 simultaneous kidney recipients of livers from non-heart beating pancreas transplants performed between donors performed between 1993 and 1993 to 1999 when pancreata were 2001 were compared to the retrieved from category 3 non-heart contemporaneous 26856 liver transplants beating donors were compared in a single from heart beating organ donors centre study to 339 recipients of organs registered on the United Network of 22 for heart beating donors. There was a Organ Sharing database in the USA. One- higher rate of enteric conversion (32% year graft survival was 63.3% and 80.4% versus 13% p < 0.01) for recipients of (non-heart beating versus heart beating pancreas from non-heart beating versus donors p= 0.003). Three-year graft heart beating donors. No difference in survival was also poorer in recipients of patient (100% versus 95.4%) or pancreas organs from non-heart beating donors at (87.4% versus 86.5%) survival was seen 63.3% and 72.1% (p= 0.012). Recipients [27]. of a non-heart beating graft had a greater incidence of primary nonfunction (11.8% versus 6.4%, p= 0.008) and Non-heart beating donors may prove to retransplantation (13.9% versus 8.3%, be a particularly valuable source of cells p=0.04) compared to recipients of livers for isolated islet transplantation. from heart beating donors [29].

Liver transplants In a single centre study biliary complication occurred in five out of 15 The donor organ shortage of end-stage (33%) recipients of liver transplants from liver disease is a particular serious problem non-heart beating donors and in 19.2% given the lack of efficacy of any of recipients of livers from heart beating alternatives. However re-perfusion donors (n=221,p<0.01) [30]. It is of syndrome and primary non-function in the concern that half of these biliary transplant recipient is extremely serious complications were ischaemic and in the latter situation unless a cholangiopathies that are likely to lead to replacement graft can be found promptly secondary biliary cirrhosis and may require is invariably fatal. In addition the biliary regrafting. tree is especially at risk of ischaemic injury resulting in both early and late complications. Many groups are actively exploring this donor source at present and it may make a significant contribution to the donor pool in the future [31].

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Graft outcome after non-heart beating organ retrieval

Lung Transplantation Using similar technique that described Lung transplantation is a lifesaving above a Swedish group has recently therapy for selected patients with end described lung retrieval from a non-heart- stage lung disease, but its application is beating donor. The donor died after failed severely constrained by suitable donors. cardiopulmonary resuscitation following Within the UK only 20-30% of heart an acute myocardial infarction in a cardiac beating organ donors are suitable for lung intensive care unit. Three hours post death donation, this is in stark contrast to the and initial cooling the heart lung block retrieval rate for abdominal organs. was removed. The right lung was transplanted and has demonstrated good function at five months follow up [32]. The lung may be the ideal organ for non- heart beating organ donation because unlike other solid organs, the lung does As many retrieval units are in the process not rely on perfusion for parenchymal are developing non-heart beating cellular respiration to occur. Tissue levels protocols, the potential for lung donation of high-energy nucleotide phosphates should not be overlooked [33]. have been demonstrated to remain near normal up to four hours after the cessation of circulation provided the lungs Summarising the predicted outcome remain inflated with oxygen. following kidney transplantation with 23 kidneys retrieved from non-beating donors is not straightforward. It is The technique for the retrieval of lungs anticipated that the risks of primary non- from a non-heart beating organ donor function, delayed graft function are was developed in the animal model. Its increased and there is a reduced graft success relies upon rapid bilateral chest survival. cavity flushing or topical cooling to induce hypothermic conditions post cardiorespiratory arrest, the use of heparin In the UK there is an increased early renal and intravascular flush via a pulmonary graft loss in the non-heart beating group artery catheter. This technique has then parallel rates of graft was over the protected the function and morphology of first year. One-year transplant survival was cadaver lungs, which are then suitable for not significantly different at 82 versus 85 transplantation. percent where there was a non-heart beating versus heart beating donor.

The agonal period in humans is never as controlled as in a laboratory model and The experience of recipients of other solid organ viability is often compromised to a organs is presently small and it is difficult degree that is difficult to determine. Work to draw meaningful comparisons. is therefore continuing in to develop a ventilation and perfusion assessment technique for non-heart beating donor Given the shortage of solid organs for lungs, which could differentiate between transplantation the most appropriate those lungs with good and poor function comparison may be with the experience post-transplantation. of patients who do not receive an organ rather than with that seen after receiving an organ from a heart beating cadaveric Other work in the animal model has donor. demonstrated lungs from non-heart beating organ donors can provide adequate pulmonary function with careful manipulation of the recipient upon re-perfusion.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Informing the Recipient Population

As the shortfall between the number of Given that admission for such a procedure individuals placed on organ transplant is always an emergency and that often waiting lists and the number of cadaveric this occurs at unsocial hours to inform the organ donors grows there has been a patient group in good time about the progressive interest in attempting to potential for receiving an organ from a retrieve organs from so-called marginal or non-heart beating donor is good practice. extended donors. These are donors who To have a separate list of individuals for in the recent past would have been whom medical staff and the patient considered unsuitable for organ donation agrees that receiving a non-heart beating because of medical co-morbidity. The field kidney would be a good option is also is changing rapidly but there is good practice. In Appendix C is one such information allowing some predictions to patient information leaflet for potential be made about the likely difference in renal recipients that may be used as a outcome between an "ideal" cadaveric template to guide local practice. donor and less than ideal donors.

Many clinicians and patient groups feel By most criteria non-heart beating donors that the outcome following non-heart would be considered non-ideal. On beating donation is significantly poorer average deceased organ donors are less compared with the average cadaveric 24 ideal than a live donor where that is an brain dead donor and that the origin of option. Even among live donors there is the kidney transplant should be discussed clearly a graduation from what may be fully with the intended recipient. considered the perfect donor such as an Informing this discussion will be the identical twin, an option available only to "Maastrich" category of the donor. a very small number of people.

Where the organ is the only life sustaining Many clinicians and patient groups feel treatment then the patient's and medical that as the outcome following non-heart team's options are clearly greatly beating donation is on average poorer constrained. compared with that seen with the average deceased brain dead donor, the non heart beating origin of the kidney transplant should be discussed with the intended recipient. This is in the setting where there are other options for life sustaining therapy such as dialysis. These discussions are far from strait-forward, as for any individual there is a need to quantify the degree of "risk" associated with each course of action, in a situation where such quantification is almost impossible. Where the organ is the only life sustaining treatment then the patient's and medical team's options are clearly greatly constrained.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Staffing implications

Donor transplant co-ordinators Transplant surgical staff In order to facilitate non-heart beating On call surgical teams for organ retrieval organ donation Donor transplant co- from non-heart beating donors may need ordinator teams must ensure they can be to attend Accident and Emergency responsive to the needs of the Accident & departments at short notice in order to Emergency Department or Critical Care place perfusion cannula. Similar to the co- Unit. ordinators availability within 30 minutes travel in time to the main Accident and Emergency source may be necessary. In programs offering in-situ perfusion co- Again similar to the co-ordinators retrieval ordinators are often required to attend from patients on intensive care units may the Accident and Emergency departments demand long periods in attendance at the within 15-20 minutes of being contacted. hospital site during the agonal interval. For logistic reasons it may be sensible to declare an upper time limit for such a Strategies that are currently in place to wait. facilitate non-heart beating organ include; in-house Co-ordinators based in Accident & Emergency departments or specific The successful retrieval from a non-heart hospitals, as well as a second on Call beating donor may pose a significant Service for Non Heart Beating Organ logistic challenge if two kidneys, the liver 25 donation. and possibly other solid organs are retrieved in order to ensure adequate staff to implant recipients in a timely fashion. In some centres, two donor transplant co- ordinators attend a referral. One co- ordinator's responsibility is to support and Operating theatre personnel inform the family and staff within critical Rapid access to operating facilities is care unit and one to organise the mandatory to allow the prosecution of a logistical aspects of organ retrieval. successful non-heart beating donor program. This is true both for organ Intensive care departments retrieval and implantation. The retrieval from a cadaver without a heartbeat who The process of organ retrieval ought not is not ventilated is different to retrieval impinge on clinical care or significantly from a heart-beating donor. Support and affect staff numbers. The time devoted to education to operating theatre personnel staff development and education as well should be available, probably best as counselling is however significant and delivered by the transplant coordinators. consideration should be given to staff expansion of a nominated trained individual to carry out this role. This may well be an individual from an intensive care nursing or a transplant co-ordinator background.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Staffing implications

For laboratory It is much less easy to plan retrieval from non-heart beating donors in an active No single Histocompatibility and programme a back up retrieval team may Immunology staff member should attempt be required. to investigate an import/local donor and an asystolic donor at the same time. Experience has shown that the workload in this situation is just manageable but In a program offering in-situ organ time is fully committed and has to be perfusion following unexpected cardiac tightly managed. This is not appropriate to arrest there are considerable burdens the situation, which requires focused placed on the retrieval team who need effort for the production of high to attend a short notice. confidence and timely results. The primary person on-call should have a back up. Rapid access to operate facilities is mandatory to allow the prosecution of Inpatient ward areas a successful non-heart beating donor Kidneys retrieved from non-heart beating program. donor's have an increased likelihood of primary non and delayed graft function. 26 Recipients will be expected to have an No single Histocompatibility and increased need for dialysis support and Immunology staff member should attempt longer in patient stays that will have to to investigate an import/local heart be met from the acute transplant ward beating donor and a non-heart beating resources. donor at the same time. The primary person on-call should have a back up.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Author's potential conflicts of interest

Dr C G Newstead has received multiple Mr D Talbot: has received multiple honoria for lectures and teaching as well honorary for lectures and teaching. He as expenses for travel and has also received travel tickets and accommodation to attend scientific accommodation to attend various meetings principally from Fujisawa, meetings principally from Fujisawa, Novartis, Roche and Wyeth. He has Novartis, Roche and Wyeth. Research received Honoria for contributions to sponsorship has come from the Northern advisory boards for Roche and Wyeth, but Counties Kidney Research fund, the non-since appointed chair British Special trustees of the Newcastle Hospitals Transplantation Society Standards NHS Trust, Fujisawa, Roche and Novartis. Committee. Research and that of collaborators has been in part sponsored by the above named companies as well as Dr P Murphy none declared. the Yorkshire Kidney Research Fund, Medical Research Council, Ipsen International, Jensen-Cilag, Alpha Blood Miss L Robson none declared. Products, Baxter Healthcare and Biotrin International Mr S Willis none declared. 27 Dr D Bell none declared.

Mr N V Jamieson has received honoria for lectures and expenses for travel and accommodation to attend scientific meetings from Fujisawa, Novartis, Sangstat, Johnson and Johnson and Wyeth and has received Honoria for contributions to advisory boards for Wyeth.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

References

1) Non-Heart-beating Organ Transplantation. Transplantation 2003, 76, 1714-1719 Practice and Protocols. Pub Institute of Medicine National Academic Press, Washington DC ISBN 0-309-06641-7, 8) Matsuno N, Sakurai E, Tamaki I, full text version available at: Uchiyama M, Kozaki K, Kozaki M http://www.nap.edu/books/0309066417/html/ The effect of machine perfusion preservation verses cold storage on the function of kidneys from non-heart beating 2) Mandell MS, Taylor GJ, D'Alessandro A, donors McGaw LJ, Cohen E Transplantation 1994; 57(2): 293-294 Intraoperative Advisory Council on Donation After Cardiac Death of the United Network for Organ Sharing. Executive summary from 9) Wight J, Chilcott J, Holmes M, Brewer N the Intraoperative Advisory Council on The clinical and cost-effectiveness of Donation After Cardiac Death of the United pulsatile machine perfusion versus cold Network for Organ Sharing: practice storage of kidneys for transplantation guidelines retrieved from heart-beating and non-heart- Liver Transpl 2003; 9(10): 1120-1123 beating donors Health Technology Assessment 2003; 7: No 25 28 3) Sanchez-Fructuosa AI, Prats D, Torrente J et al Renal transplantation from non-heart 10) St Peter SD, Imber CJ, Lopez I, Hughes D, beating donors: a promising alternative to Friend PJ enlarge the donor pool Extended preservation of non-heart-beating J Am Soc Nephrol 2000; 11: 350-358 donor livers with normothermic machine perfusion Br J Surg 2002; 89(5): 609-616 4) Guidance on the Microbiological Safety of Human Organs, Tissues and Cells used in Transplantation. Available from: 11) St Peter SD, Imber CJ, Friend PJ www.doh.gov.uk/msbt Liver and kidney preservation by perfusion Lancet 2002; 359(9306): 604-613

5) Draft Human Tissue Bill www.dh.gov.uk/assetRoot/04/07/10/12/04071012. 12) Barros-Schelotto P, Net M, Valero R, Ruiz A, pdf Almenara R, Capdevila L, Sugranes G, Suarez-Crivaro F, Lopez-Boado MA, Pellegrino A, Deulofeu R, Miquel R, Taura P, 6) Human Bodies Human Choices The Law on Manyalich M, Garcia-Valdecasas JC Human Organs and Tissue in England and Reduced reperfusion injury by glycine in a Wales A consultation Report porcine liver transplantation model with www.dh.gov.uk/assetRoot/04/08/15/82/04081582. non-heart-beating donors pdf Transplant Proc 2002; 34(4): 1114-1117

7) Gok MA, Shenton BK, Buckley PE, Peaston R, 13) Reddy SP, Bhattacharjya S, Maniakin N, Cornell C, Soomro N, Jaques BC, Manas DM, Greenwood J, Guerreiro D, Hughes D, Imber Talbot D CJ, Pigott DW, Fuggle S, Taylor R, Friend PJ How to improve the quality of kidneys from Preservation of porcine non-heart-beating non-heart-beating donors: a randomised donor livers by sequential cold storage and controlled trial of thrombolysis in non-heart- warm perfusion beating donors Transplantation 2004; 77(9):1328-1332

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

14) Kievit JK, Nederstigt AP, Oomen AP, Janssen 21) Pacholczyk MJ, Lagiewska B, Szostek M et al MA, Schoot L, Kootstra G Transplantation of kidneys harvested from Release of alpha-glutathione S-transferase non-heart-beating donors: early and long (alpha GST) an pi-glutathione S-transferase term results (pi-GST) from ischaemic damaged kidneys Transpl Int 1996; 9(suppl 1): S81-S83 into the machine perfusate- relevance to viability assessment Trans Proc 1997; 29: 3591-3593. 22) Balpuri S, Buckley P, Snowden C et al The trouble with kidneys derived from the non heart-beating donor: a single centre 15) Balupuri S, Buckley P, Snowden C, 10-year experience Mohammed M, Sen B, Griffiths P, Hannon M, Transplantation 2000; 69: 842-946 Manas D, Kirby J, Talbot D The trouble with kidneys derived from the non-heart-beating donor: a single center 23) Sanchez-Fructuoso AI, Prats D, 10-year experience Torrente J et al Transplantation 2000; 69: 842-846 Renal transplantation from non-heart beating donors: a promising alternative to enlarge the donor pool 16) Dr C Dudley Personal communication on J Am Soc Nephrol 2000: 11: 350-358 behalf of Richard Bright Renal Unit, 29 Southmead Hospital, Bristol 24) Cho YW, Terasaki PI, Cecka JM, Gjertson DW Transplantation of kidneys from donors 17) Williams ST, Knight AL, White SA, whose hearts have stopped beating Doughman TM, Nicholson ML N Engl J Med 1998; 338: 221-225 Preliminary Analysis of a Randomised Trial Comparing Microemulsion Cyclosporin and Tacrolimus for Recipients of Renal 25) Sanchez-Fructuoso AI, de Miguel Marques Transplants From Non-Heart-Beating Donors M, Prats D, Barrientos A Transplant Proceedings 2000. 32; 196 Non-heart-beating donors: experience from the Hospital Clinico of Madrid J Nephrol 2003; 16(3): 387-392. 18) Weber M, Dindo, D, Demartines N, Ambühl PM, Clavein PA Kidney transplantation from donors without 26) UK Transplant, UK Transplant Activity Report a heartbeat 2001. ISSN 1477-8505: 23 N Engl J Med 2002; 347(4): 348-255

27) D'Alessandro AM, Odorico JS, Knechtle SJ, 19) Wijnen RMH, Booster MH, Stubenitski BM, Becker YT, Hoffmann RM, Kalayoglu M, de Boer J, Heineman E, Kootstra G Sollinger HW Outcome of transplantation of non-heart Simultaneous pancreas-kidney (SPK) beating donor kidneys transplantation from controlled non-heart- Lancet 1995; 345: 1067-1070 beating donors (NHBDs).Successful extrarenal transplantation from non-heart beating donors 20) Gonzalez Segura C, Castelao AM, Cell Transplant 2000; 9(6): 889-893 Torras J et al Long-term follow-up of transplanted non-heart-beating donor kidneys Transplant Proc 1995; 27: 2948-2950

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

28) Reich DJ, Munoz SJ, Rothstein KD, Nathan HM, Edwards JM, Hasz RD, Manzarbeitia CY Controlled non-heart-beating donor liver transplantation: a successful single center experience, with topic update Transplantation 2000; 70(8): 1159-1166

29) Abt PL, Desai NM, Crawford MD, Forman LM, Markmann JW, Olthoff KM, Markmann JF Survival following liver transplantation from non-heart-beating donors Ann Surg 2004; 239(1): 87-92

30) Abt P, Crawford M, Desai N, Markmann J, Olthoff K, Shaked A Liver transplantation from controlled non- heart beating donors: an increased incidence 30 of biliary complications Transplantation 2003; 75(10): 1659-1663

31) Muiesan P Can controlled non-heart-beating donors provide a solution to the organ shortage? Transplantation 2003; 75(10): 1627-1628

32) Steen S, Sjoberg T, Pierre L, Liao Q, Eriksson L, Algotsson L Transplantation of lungs from a non-heart beating donor Lancet 2001; 357(9259): 925-829

33) Egan, TM Non heart beating lung donors: yes or no Annals of Thoracic Surgery 2000; 70:1451 1452

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Appendix A Step 3 Sort order notified by UKT to transplant team on call Recipients listed at UKT for NHBD donors must: (note this may be prior to organ retrieval). 1) Have a well-documented clinical history 2) Have been screened for HLA specific sensitisation If top two candidates are registered as unsensitised. in accord with BTS guidelines (one sample every 3 months)

3) Must be either unsensitised or have a residual For top two potential recipients transplant team liaise reaction frequency of <10% with relevant renal medicine staff about current suitability for transplantation. Check made at this time 4) Adult patients registered on Local Centre waiting that no known sensitising events since last antibody list (non-heart beating donor kidneys are rarely screen. allocated to recipients outside of the retrieval centre).

5) Known to have indicated that willing to accept If one or more of top two candidates' medically non-heart beating donor kidney (to be actioned unsuitable move to candidate three and so on. after an interval to allow people to organize mail shot and replies to be collated) Decision made whether appropriate to call in Step 1 recipients prior to retrieval made. This will depend 31 Donor HLA typed on peripheral blood after consent upon how likely it is predicted that the retrieval may from relatives (virology testing, ABO group et cetera) be unsatisfactory. (4-4.5h) Otherwise call in candidates when organs retrieved.

Step 2 When patients contacted check made at this time that Matching run performed by UKT using the following no known sensitising events since last antibody screen. eligibility criteria and sort order (after appropriate implementation and testing): If one of or more of top two candidates does not meet criteria of no known sensitising event, serum 1) Adult patients registered on Local Centre waiting screen negative or if serum screen positive but and list known more than 0% residual PRA then a back up candidate is nominated from sort list in order up to a 2) Known to have indicated that willing to accept maximum of four total potential candidates for two non-heart beating donor kidney kidneys. 3) No donor relevant HLA antibodies known 4) 000 HLA A, B and DR mismatch grade For back up recipients transplant team liaise with 5) Minimum relevant renal medicine staff about up to date Recipient age donors age minus ten years (points suitability for transplantation. Check made at this time system to tie break) that no known sensitising events since last blood sample. 6) Usual matching rules for other mismatch grades (e.g., homozygotes first, HLA mismatch grade, points system to tie break) If one or more back up candidates unsuitable move to 7) Minimum next candidate and so on. Recipient age donors age minus five years 8) Recipients all ages

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Decision made whether appropriate to call in recipients prior to retrieval made. This will depend upon how likely it is predicted that the retrieval may be unsatisfactory. Otherwise call in candidates (and back ups) when organs retrieved

When patients contacted check made at this time that no known sensitising events since last blood sample.

Step 4 From results of step 3 perform crossmatches with selected recipients and back ups where nominated using according to locally agreed practices (2- 3h). Note crossmatch can take place prior to organ retrieval.

32 If historic peak or current positive cross match, recipients eliminated from consideration.

Step 5 Call in selected crossmatch negative recipients and repeat crossmatches with current sera (2-2.5h)

Or if decision made to call in prior to retrieval or prior to result of historic and current sera cross match known run cross match versus time of transplant sera when available. (2-2.5h)

Estimated total laboratory time ~ 8-10h

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Appendix B

All blood group compatible patients to be considered

Exclude patients whose recorded unacceptable antigens are shared by the donor.

Length of time on waiting list (latest listing excluding suspensions of > 6 months)

Days Points 1100-1500 5 1501-2000 10 1) Previous transplant? 2001-2400 15 a. Yes 0 2401-2774 20 b. No 5 >2775 25 33

4) Age Age Points < 40 10 41-60 5 > 60 0

5. Matchability score

Matchability score Points 9-10 10 7-8 8 5-6 5 3-4 3 1-2 0

The kidney is allocated to the recipient with the highest score. In the event of a tie subtract one point for each mismatched HLA antigen.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Appendix C Non-heart beating organ donation. When non- heart beating organ donation takes place the donor has been declared dead following the absence of Important Information for Patients Awaiting a breathing and a heartbeat. Kidney Transplant

Several Transplant Units in the United Kingdom are Non Heart Beating (NHB) Organ Donation developing a Non-heart beating Organ Donation programme. Although this will be a new development As you know the demand for kidney transplantation it is not a new idea. This method of organ donation in the UK is greater than the current supply of organs has been used successfully in North America, Japan, available. The Department of Health is implementing Europe and three centres within the UK for many several initiatives to improve this situation. years.

These include: Receiving any kidney transplant carries certain Making more direct appeals for people to carry . risks. These include those due to the actual operation, donor cards and use the organ donor register. the possibility of the transfer of infection from donor . Increasing the number of transplants from live to recipient and the anti-rejection medication. All donors. kidneys offered for transplantation also experience 34 some degree of damage. This is due to events prior to . Increasing the number of 'non-heart beating donation, the operation to remove the kidney, and the organ donation programmes'. length of time the kidney is stored before it can be transplanted. What is a Non Heart Beating Organ Donation programme? Special risks with non-heart beating organs. The They are three methods of kidney donation within the major difference between kidneys donated from non- United Kingdom. heart beating organ donors and other organ donors is the function of the kidney in the early days after the transplant. Usually these kidneys do not work straight Living-donor organ donation. In this situation a away. This delay in function can last for days or weeks blood relative or someone who is emotionally related after the transplant operation. The recipient is required to the recipient volunteers to be a kidney donor. to continue with dialysis for a while after transplantation. Unfortunately it is difficult to predict the speed of recovery of the kidney. Organ donation after brain death. This is often as a result of a head injury or stroke causing damage to the brain. If injury occurs to a vital area of the brain Rarely the kidney never regains function. This can called the 'brain stem'; that patient can never regain occur with any transplanted organ. The consequence consciousness or breath again and within hours their of this is the disappointment of having undergone an heart will stop beating. If tests conclude that death operation that has been unsuccessful and the has occurred consent for organ donation is discussed potential for your body to produce antibodies, which with the family. can make finding another transplant more difficult.

Guidelines relating to solid organ transplants from non-heart beating donors British Transplantation Society

Approximate Summary of Expected Results

Approximate Summary of Expected Results Percentage Percenta Percentage Percentage Never ge with Graft survival Graft Survival functioning delayed 1 year 5 year Function Live related 0 1 98 85

Organ 2 20 90 75 donation after brain death. Non-Heart 3 80 85 70 beating

As you can see the kidneys donated from non-heart beating organ donors have a small increased risk of If you would accept a kidney from a never functioning and a distinct increased risk of non-heart beating organ donor could you delayed function compared to kidneys donated from please return the enclosed authorisation slip, brain dead organ donors. The long-term results are which also asks for up to date contact details. similar. 35

If you do not return the authorisation slip we The purpose of this document is to provide you with will assume you do not want to be considered information so you can discuss with your relatives and for this type of transplant. the renal team whether you would consider having a non-heart beating Kidney transplant.

This development will not change your chances of receiving a kidney from the usual National Allocation System. But it will increase the chances of you receiving a kidney transplant sooner. This is because at present Kidneys donated from non-heart beating donors within the local region will only be used for patients on the local waiting list.

In order to keep the time between removing the kidney and transplantation to a minimum it is helpful if the Renal Transplant Unit are aware of those patients who would and those who would not accept a kidney from a non-heart beating organ donor.

Guidelines relating to solid organ transplants from non-heart beating donors Published by the British Transplantation Society Triangle House, Broomhill Road, London SW18 4HX Tel: 0870 833 2430 Fax: 0870 833 2434 Email: [email protected] Web: www.bts.org.uk

ISBN 0-9542221-7-2

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