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ORGANS TISSUES & CELLS VOLUME 13 / NO. 2 / JUNE 2010

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The Journal of European Transplant Coordinators Organization

IN CO-OPERATION WITH

Poste Italiane SpA - Sped. in a.p. D.L. 353/2003 (conv. in L. 27/02/2004 n. 46) art. 1, comma 1, DCB - Bologna

ISSN 1828 0595

ORGANS, ORGANS,TISSUES TISSUES&&CELLS, CELLS,(13), (13),107-118, X-XX, 2010 2010

THE ITALIAN “PROGRAMMA ALBA” Paolo M. Geraci1, Giampaolo Azzoni8, Massimo Abelli2, Elena Ticozzelli2, Teresa Rampino3, Vincenzo Sepe3, Marco Sacchi4, Maurizio Raimondi4, Antonio Braschi5a, Giorgio Iotti5b, Marco Maurelli5c, Maria Antonietta Bressan6, Antonio Dal Canton3, Marco Bosio7, Cristiano Martini9, Alessandro Nanni Costa10 Transplant Coordination Unit, Fondazione I.R.C.C.S. Policlinico “San Matteo”, Pavia, Italy Kidney Transplantation Unit, Fondazione I.R.C.C.S. Policlinico “San Matteo”, Pavia, Italy 3 Nephrology Dialysis Transplantation Unit, Fondazione I.R.C.C.S. Policlinico “San Matteo”, Pavia, Italy 4 AREU Lombardia, AAT 118 Pavia, Fondazione I.R.C.C.S. Policlinico “San Matteo”, Pavia, Italy 5a,b,c Intensive Care Unit 1a, 2b, 3c, Fondazione I.R.C.C.S. Policlinico “San Matteo”, Pavia, Italy 6 Accident & Emergency Unit, Fondazione I.R.C.C.S. Policlinico “San Matteo”, Pavia, Italy 7 Medical Directorate, Fondazione I.R.C.C.S. Policlinico “San Matteo”, Pavia, Italy 8 Department of Roman Law, History and Philosophy of Law, University of Pavia, Italy 9 Nord Italia Transplant program, Milan, Italy 10 CNT-Italian National Transplant Centre, Italian National Institute of Health, Rome, Italy 1 2

Keywords - Donation after circulatory death, DCD, non-heart-beating donation, NHBD, ECMO, organ procurement, kidney transplantation, bioethics Summary - A donation after cardiac/circulatory death (DCD), i.e. non-heart-beating donation (NHBD) programme named “Programma Alba” (Sunrise Programme) started in Pavia (Italy) in 2007. As in many countries, the main aim was to shorten the organ transplantation waiting lists. Initial targets were kidney and liver donations. Compared to other European countries and the US, the Italian DCD programme has taken more time to get established. Several reasons have apparently discouraged Italian physicians to set up such a transplantation programme, as unawareness of DCD organ viability, risk of diversion from heart beating donor programmes, ethical issues and the need to regulate medical requirements according to Italian legislation. Determination of death after irreversible cardiac arrest requires a 20-minute flat electrocardiogram, according to the law. This no-touch period is much longer than that established in legislations worldwide and organ viability after such a long no-touch period has been a major concern for many Italian transplant doctors over the years. Recent data allow up to 40-minutes warm ischemia time for preservation of organ viability. This has encouraged us to establish a DCD programme in Italy as well. Currently, three patients are out of dialysis with DCD kidneys.

This paper analyzes all issues of DCD in detail from death definition and ascertainment according to Italian legislation to financial, technical and human resources needed to begin and establish such a transplantation programme in an Italian hospital.

Introduction In the early years of organ transplantation, grafts were recovered from donors after cardiac death (DCD)1-3.

Mailing address: Paolo M. Geraci, MD, Consultant, Centro Coordinamento Donazioni e Trapianti, Area di Pavia, Fondazione I.R.C.C.S. Policlinico “San Matteo”, Viale Camillo Golgi 19, 27100 Pavia, Italy; e-mail: p.geraci@smatteo.pv.it

They were non-heart-beating donors (NHBDs). Donors were intensive care unit (ICU) based and suffered from head injuries or cerebrovascular accidents deemed irrecoverable. Organ recovery proceeded only after cardiorespiratory demise. The first kidney transplant from a heart-beating donor (HBD)4 was performed in Belgium in June 19635. In 1968, the Harvard criteria for brain death and related legal definition were introduced6 allowing transplant programmes based on organ recovery from HBDs, establishing donation after brain death (DBD).

107

These significantly reduced warm ischemia damage compared to DCD7.

The organ shortage Since 1970s, the indication for transplantation has progressively broadened, whereas organ donation has been advancing at a steadier pace. Over the years attempts to increase people´s motivation to donate their organs after death has been only partially repaid; in Italy, refusals to organ donation were 30.5% in 20098. Living donation (kidney and liver) has made a valuable contribution to enlarging the donor pool for kidney and liver transplantation programmes in some countries. In Italy, such plans are still progressing rather slowly. Expanded criteria for donors9-11 and use of marginal organs, including double kidney transplantation for marginal kidneys are currently of great interest.

However, these measures probably will never fill the gap between donation and graft demand.

In early 1980s, the failure to satisfy organ needs through DBD encouraged Kootstra’s group to improve and re-establish NHBD12,13 obtaining results comparable to DBD. It persuaded centres worldwide to actively re-start the practice of DCD14, i.e. NHBD. Definition and categories of donation after circulatory death and donors NHBD can be defined as “donation of organs and/or tissues from deceased patients with irreversible cessation of cardiac function”. The heart ceased beating, and this event could not, or would not be reversed15. In the US and Canada DCD corresponds to the European NHBD, whereas donation after brain death (DBD) is the equivalent of the European heart-beating donation (HBD) from brain dead donors. The term “asystolic donor” primarily appeared in the United Kingdom16 reports. Recently, Bernat et al based death determination on the cessation of circulatory and respiratory functions instead of cardiac function, using the acronym DCDD or DCD to refer to “organ donation after circulatory determination of death”, as an alternative to “organ donation after cardiac death”17.

Organs from DCDs are subjected to variable warm ischemia time (WIT), specifically when referred to the WIT acirculatory phase (WITap)18. In 1994, during the Maastricht first workshop on NHBD, four categories of NHBDs were proposed and accepted19. The Madrid group introduced the NHBD/DCD category V for sudden cardiac arrest in the ICU20 and the Italian group from Pavia recently proposed the NHBD/DCD category VI for ICU

108 P.M. Geraci et al.

deaths recognised during ECMO (Extra Corporeal Membrane Oxygenation) maintenance. ECMO was developed to support cardiorespiratory function for days or a few weeks in patients with severe heart or lung dysfunction pending heart21 and/or lung22 transplantation. ECMO is also used after failure of cardiopulmonary resuscitation23 and in prolonged in-hospital cardiac arrest24. Death can be declared for ECMO patients by the usual cardiac or neurological standards and organ preservation is already sustained by pre-existing extracorporeal circulation. An ECMO donor might be considered NHBD/DCD category VI (Table 1).

In such a cumbersome jungle of acronyms, we propose simplifying all donor groups, regardless of death ascertainment (brain or cardiac), into two categories: “deceased donor with absent or artificial organ perfusion” (DDAP) and “deceased donor with natural organ perfusion” (DDNP)25.

The first is NHBD mainly DCD, and the second HBD/ DBD. DDAP death can be “uncontrolled” as for categories I, II and V, “controlled” as for categories III and IV and “partially controlled” as for category VI. Worldwide DCD programmes The United States26, the United Kingdom27, Spain20, The Netherlands28, Switzerland29 Japan and other countries have long-standing DCD protocols. Japan only recently conformed to a law on brain death30 meaning that all transplants from deceased donors performed so far have been from DCD. At present, ten European countries have operating DCD programmes31. The German legislation stipulates that organs can only be taken from DBD, limiting DCD to category IV15. Belgium, The Netherlands along with UK “controlled” DCD and Spain “uncontrolled” DCD have the most effective European DCD programmes.

Why did it take so long to start a DCD programme in Italy?

Three main issues have delayed DCD organ recovery in Italy: education of healthcare professionals, ethics, and resource availability. After death tissue recovery from DCD was already a working routine.

Education of healthcare professionals

Awareness of DCD organ viability Healthcare professionals are familiar with DBD transplantation, but often are unaware that DCD supplies viable grafts for kidney, liver, pancreas and lung transplanta-

tion32. Although early reports suggested a poorer outcome for kidneys from DCD33, recent data demonstrated that long-term survival of DCD grafts is comparable to DBD transplants34,35. The success of DCD transplantation needs to be disseminated to physicians and nurses working in emergency departments, operating theatres and ICUs. In Spain, transplant coordinators have successfully organized DCD courses and workshops to educate local hospital personnel, including a nationwide annual course36,37. Italy could emulate this model, and hospitals or health districts might activate DCD educational programmes.

Italian legislation Laws on transplantation and death declaration do not exclude DCD organ recovery38-40. The Italian legislation provides for clinical diagnosis of death first and then for its ascertainment. Death ascertainment is always mandatory for brain dead patients. It is not requested for cardiac death without donation. In the case of DCD for organs or tissues, the Italian legislation death ascertainment consists of a 20-minute flat electrocardiogram (no-touch period) testifying the absence of heart activity39. The no-touch period means 20 minutes of WITap, i.e. without artificial perfusion, and it is specific to Italian legislation. It is common opinion that those 20-minute WITap tempered the enthusiasm of many Italian doctors for DCD. However, solid data have demonstrated that the graft is viable after 150-minute WIT including up to 40-minute WITap41.

Nevertheless, patients with severe brain injuries may survive for several days before brain death, with a deleterious effect on many organs. Following brain death, tissue injury from sympathetic and cytokines storm appears to play a major role in primary graft dysfunction.

Risk of diversion from DBD programmes Introduction of DCD in the US increased both DBD and DCD organ recovery. Eighty percent (16 districts) USA Donation Service Areas showed a 49.3% DCD increase, rising by 9.4% over traditional DBD transplants.

It is common opinion that in the long run DCD will increase the total number of organ donations42. European countries based on controlled DCD revealed a decrease of DBD activity. Spain showed a trend toward a decrease of specific organ transplantation such as heart. Whether it is controlled DCD success or DBD temporary failure needs to be analyzed43. European countries like Spain with DCD Maastricht categories I, II and IV showed a donor increase from 33.9 pmp in 2000 to 34.2 pmp in 2008 with stable DBD donations from 33.1 pmp in 2000 to 32.5 pmp in 2008. A reduction of DBD has been observed in European “controlled” DCD Maastricht category III31.

Ethics

Determination of death and timing of cardiac death It is likely that Italian physicians have been reluctant to pursue DCD organ transplantation because of ethical concerns.

In Italian ICUs treatment withdrawal for patients without a reasonable hope of recovery is widely practised whereas persistence is strongly discouraged in such cases. Maastricht category III is not excluded from “Programma Alba”, but it is not a current priority. It may also need a better definition to increase sharing among health operators. In Italy we do not have any bias to recommend life support withdrawal43,44. There are instead potential conflicts of interest for death determination and timing of cardiac death45. These are worldwide major ethical issues surrounding DCD. The Ethics Committee of the American College of Critical Care Medicine suggests that decisions concerning potential DCD (including determination of death) should be taken only by the intensivist or the emergency physicians caring for the patient46 and that cardiac death be diagnosed according to uniform criteria, irrespective of whether the patient will become an organ donor or not.

The issue of timing for cardiac death is not whether “spontaneous” circulation has ceased but when cessation is irreversible45,46 or permanent47. The Ethics Committee of the American College of Critical Care Medicine recommends observing the patient for a minimum of two minutes after asystole and up to a maximum of five minutes before death is declared45. The National Conference on Donation after Cardiac Death defines death when life-sustaining therapy is withdrawn, and spontaneous circulation does not return after two minutes of cessation of circulation42,48. The Society of Critical Care Medicine concluded that “at least two minutes of observation is required, and more than five minutes is not recommended” as also established by “The American Institute of Medicine”45,49.

Withdrawal of life support Italian legislation does not provide regulation for such an issue. As described, the Italian legislation provides for 20-minute flat electrocardiogram to declare the patient’s death. After such a long no-touch period there is no doubt over destruction of the whole brain and the inability to recover even in case of resumption of resuscitation aimed at organ preservation. It is common opinion among Italian bioethicists and physicians that donor’s will and recipient’s concern have equal rights raising a major conflict of interests between donor and recipient. If “The Ethics Committee of the American College of Critical Care Medicine” states that two to five minutes asystole allows whole brain death to be pronounced we might foresee potential organ damage after a 20-minute flat electrocardiogram. Some

The Italian “Programma Alba” 109

TABLE 1 - Maastricht modified DCD categories DCD Maastricht modified categories

Alternative categorization

I

Uncontrolled

II

Uncontrolled

III

Controlled

IV

Controlled

V1

Uncontrolled

VI2

Partially controlled

Potential donor status Death on hospital arrival Unsuccessful resuscitation attempt Awaiting cardiac arrest Cardiac arrest while brain death ICU sudden irreversible cardiac arrest Death in ECMO maintenance

Hospital Department

Action

Death ascertainment

Accident and Emergency

Organ viability evaluation

C

Accident and Emergency

Organ viability evaluation

C

Intensive Care Unit

Organ transplantation

C

Intensive Care Unit

Organ transplantation

C

Intensive Care Unit

Organ viability evaluation

C

Intensive Care Unit

Organ viability evaluation

C and B

DCD, donation after cardiac/circulatory death; 1 Madrid’s new category; 2 Pavia’s new category; ECMO, extracorporeal membrane oxygenation; C, cardiac standard death ascertainment; B, neurological standard death ascertainment: in this case the donor is a DBD/NHBD, i.e. DDAP.

Italian doctors have argued that DCD programmes should be carried out only after a new ad hoc law regulating all matters. This might be an additional factor that slowed the activation of DCD programmes in Italy.

Next of kin or legal representative’s consent for organ donation Italian legislation (Italian law 91/99) provides for a “opting out” donor’s choice (Art. 4) A temporary rule defined a type of “soft opting out” donor’s preference stating that: “donor’s consent expressed in life or as a secondary option, next of kin or legal representative’s absence of opposition to donate shortly after death declaration”. Italian law 91/99 (Art. 23) also states that written opposition by the next of kin has to be communicated within the time allowed to ascertain death (six hours, neurological standard; 20 minutes, cardiac standard)38. Breaking bad news should never include a request for organ donation. Particularly when the patient, a) is still alive, b) is brain dead or severely brain-injured with no apparent hope of survival. Success in obtaining consent appears to improve by separating the two events50,51. In case of irreversible cardiac arrest the two events need to be closer because of shortage of time for organ recovery. In this case the 20 minutes of no-touch period are valuable for verifying the consent, without which the procedure cannot progress.

Availability of resources

DCD organ acquisition requires many people and is demanding, needs commitment often resulting in a testing

110 P.M. Geraci et al.

high discard rate. There is no system in place to identify and manage potential DCDs without diverting resources (physician and nursing time, beds, operating theatres) away from other patients. It is important to create hospital or health district structures aimed at identifying and managing potential DCDs without significantly affecting emergency department or ICU resources. This would require establishing organ donor teams coordinating all aspects of organ and tissue procurement. In Italy such teams could be created in a small number of hospitals with long-term commitment to tissue and organ transplantation. In such a system, the attending ICU or emergency physician would not be involved once death has been declared and consent obtained. The system would require additional critical care room, operating theatre time and National Health System funding, so that participating hospitals would not be penalized. For kidney transplantation, any additional cost would probably be offset by savings on dialysis costs52. The Transplant Coordination Unit of the “Fondazione I.R.C.C.S. Policlinico San Matteo” (Pavia, Italy) has started to analyze costs and benefits of such a transplant structure with “Università Commerciale Bocconi” (Milan, Italy).

Design of the Pavia DCD “Programma Alba” After a local retrospective observational feasibility study we devised a local DCD protocol based on a model proposed by the “Centro Nazionale Trapianti” (Italian National Transplant Centre) already working in three pilot Italian hospitals: Treviso, Pisa and Cagliari53. The protocol was

also drawn up by an legal theorist from the University of Pavia specialized in bioethics issues. He worked out cultural, ethical and legal issues. The main aim was to introduce a strategy to add kidney donors to the traditional DBD, by recovering DCDs with a significant reduction of WITap organ injury. According to several authors54-56, it has been obtained by selecting ECMO perfusion to splanchnic under diaphragm organs in normothermic conditions57, “modified ECMO for DCD”. ECMO does not increase donor’s warm ischemia time, although currently data on organs under long-term artificial perfusion are not available.

is organ viability. However, it would be regrettable that a will for donation previously stated by pDCD cannot be accomplished because procedures for organ protection have been delayed. In the meantime it is mandatory to respect: a) the statute of living individual with all therapeutic rights; b) dignity and physical integrity rights in death. When organ donation consent is obtained and death is ascertained pDCD may turn into DCD. 4. Action timetable (Tables 2A and 2B)

a) On living pDCD: 1. CPR; 2. Early autopulse for external cardiac massage (ECM); 3. ECM stop for the 20-minute no-touch period; 4. Death ascertainment. In case pDCD

General principles They are: 1. Death ascertainment according to Italian legislation; 2. Donor’s consent; 3. Definition of potential donor; 4. Procedure timetable; 5. Recipient consent.

Table 2A - DCD timetable in case living organ donation consent or absence of opposition to organ donation is available A.

In the case of out-hospital critically ill patient in-hospital transport has to maintain equivalent level of patient care and monitoring. When in-hospital transportation is safe go to A1.

1. Death ascertainment according to Italian legislation

This must always begin just after the diagnosis of death: as reported before, a no-touch period of 20-minute flat electrocardiogram for cardiac death or six hours of clinical observation for brain death39. For category VI on ECMO maintenance, in order to diagnose clinical death during artificial circulation confirmatory evaluation of whole brain damage could be requested by demonstration of no blood brain perfusion. Death can be ascertained by neurological standards or cardiac standards when no electric cardiac activity is present. WITap in case of neurological standards is restricted to the acirculatory phase (ap) before starting CPR following initial cardiac arrest. WITap for cardiac standard is longer because in addition to the acirculatory phase before CPR, we need to count 20 more minutes of no-touch period.

A1. Blood tests to establish potential for organ donation A2. Alert operating theatre staff A3. Bladder catheterization A4. Nasogastric tube A5. Isolation of femoral vessels B.

B2. ECMO set-up B3. Operating theatre organ harvesting DCD, donation after cardiac/circulatory death; ECMO, extracorporeal membrane oxygenation

Table 2B - DCD timetable in case waiting for absence of opposition to organ donation A.

BEFORE DEATH ASCERTAINMENT

In case of out-hospital critically ill patient in-hospital transport has to maintain equivalent level of patient care and monitoring. When in-hospital transportation is safe go to A1.

3. Definition of potential DCD donor

A potential donor (pDCD) can be: a) a living critically ill patient during Advanced Cardiac Life Support (ACLS) with a bad prognosis; b) a patient waiting for death ascertainment by means of cardiac and respiratory criteria; c) a dead person where death has been ascertained by means of cardiac and respiratory criteria waiting for organ donation consent; d) a dead person after ascertainment by means of cardiac and respiratory criteria and consent, waiting for evaluation and clinical suitability for organ recovery. The waiting for donation consent [39] after death ascertainment can take some time. At this time the main concern

AFTER DEATH ASCERTAINMENT

B1. Cannulation of femoral vessels

2. Donor consent

Consent needs to be obtained shortly after the start of death ascertainment (Table 8A), and within 40 minutes WITap41 in order to preserve organ viability.

BEFORE DEATH ASCERTAINMENT

A1. Blood tests to establish potential for organ donation A2. Alert operating theatre staff A4. Bladder catheterization A5. Nasogastric tube B.

AFTER DEATH ASCERTAINMENT

B1. Isolation of femoral vessels B2. Cannulation of femoral vessels (only after consent) DCD, donation after cardiac/circulatory death

The Italian “Programma Alba” 111

TABLE 3 - Femoral vessel cannulation 1. One sided femoral vessel surgical isolation 2. Cannulation of one sided femoral artery and vein 3. Connection of femoral vessels to ECMO circuit tubing 4. Contralateral femoral artery isolation for placement of Fogarty balloon catheter 5. Aortic occlusion by Fogarty balloon catheter placed in supraceliac aorta. It should be visualized by chest X-ray to ensure target balloon positioning ECMO, extracorporeal membrane oxygenation

TABLE 4 - ECMO management A.

ECMO SET-UP

1. Priming solutions • 1/6 molar bicarbonate solution, 250 ml • 20 % mannitol solution, 250 ml 2. Connection one sided femoral artery and vein to ECMO circuit tubing 3. Normothermic perfusion • Ideal perfusion flow rate, 1.7 litre/ minute/ m2 body surface • Minimum perfusion flow rate, 1 litre/ minute/ m2 body surface B.

ECMO MAINTENANCE 30-minute interval blood tests

1. Blood gas analysis, pH 7.0-7.4, adjustment by 1 molar bicarbonate solution 2. Haematology 3. Liver and kidney blood tests C.

ECMO ANTICOAGULATION

1. Patient infusion of unfractionated heparin bolus 3 mg/ Kg body weight i.v. before connection to ECMO circuit tubing

D.

TABLE 5 - Warm ischemia time limits 1. WITap time up to 40 minutes, including 20-minute nontouch period and cardiac arrest time before starting initial CPR-ACLS 2. CPR-ACLS up to 110 minutes 3. Total WIT up to 150 minutes including up to 40-minute WITap 4. ECMO maintenance up to 6 hours WIT, warm ischemia time; WITap, acirculatory phase WIT; CPR, cardiopulmonary resuscitation; ACLS, advanced cardiac life support; ECMO, extracorporeal membrane oxygenation

c) After consent for organ donation: 1. Femoral vessel cannulation (Table 3). 2. A cardiopulmonary bypass (CPB) machine is connected to the donor and modified ECMO is initiated, i.e. perfusion to splanchnic under diaphragm organs in normothermic conditions (Table 4). This procedure excludes brain perfusion and does not retroactively negate the determination of the donor’s death17. CPB pump flow is a significant determinant of graft viability58 (Table 4). In case ECMO has to be stopped, the whole organ recovery procedure is cancelled. Modified ECMO maintenance should be continued up to a) organ macroscopic view in the operating theatre; b) following organ perfusion with the same cold preservation solution used through the ECMO cannulas. d) Time limits: are summarized in Table 5.

5. Recipient consent

Patients on a traditional transplantation waiting list must provide informed consent to receive a DCD organ. A second consent agreement is signed at the time of proposed DCD transplant. The acceptance of a DCD organ has no effect on waiting list position.

2. Patient infusion of unfractionated heparin bolus 1.5 mg/ Kg body weight i.v. at 90-minute interval

Enrolment criteria for potential donors

CRITERIA FOR ECMO DISCONTINUATION

Potential DCDs are patients under DCD categories II, IV, V VI. DCD category III has not been included in the “Programma Alba” as stated before. All DCD are uncontrolled categories, but category VI that is partially controlled. pDCD enrolment criteria are summarized in Table 6. The high discard rate makes this like a funnel system. The “Programma Alba” switches on as soon as emergency or ICU doctors identify a pDCD.

1. Perfusion flow rate < 1 litre/ minute/ m2 body surface 2. In case enrolment procedures take more than 6 ECMO hours ECMO, extracorporeal membrane oxygenation

expressed during life consent to organ donation surgical isolation of the femoral vessels for extracorporeal perfusion can be initiated. b) After death ascertainment: 1. CPR and ECM to preserve organ viability; 2. Surgical isolation of the femoral vessels for extracorporeal perfusion can be initiated also waiting for organ donation consent (Table 8B).

112 P.M. Geraci et al.

Procedures When the Transplant coordinator is alerted because a pDCD has been identified he calls together the Alba team

TABLE 6 - “Programma Alba” inclusion and exclusion criteria A.

TABLE 7 - “Programma Alba” who does what

INCLUSION CRITERIA

WHO

WHAT

A1. Lay witnessed cardiac arrest for accurate event time determination

Physician team leader (transplant coordinator)

• Staff coordination • Timetable definition • Achievement organ donation consent • Liaises with transplant allocation centre (CIR-NITp)

Nurse coordinator

• Teams up with transplant coordinator • Liaises with operating theatre staff • Liaises with transplant allocation centre (CIR-NITp)

Physician 1 (A&E, ICU)

Takes over pDCD care from emergency staff

Physician 2 (ICU)

Isolation and cannulation of femoral vessels

Nurses 1 and 2

Assist physicians 1 and 2 respectively

Cardiovascular perfusionist

Sets up and makes ECMO working

Operating theatre staff

Organ harvesting

A2. Cardiac arrest occurring not more than 15 minutes before healthcare professionals start CPR-ACLS A3. Patient refractory to ACLS A4. Age 15-65 years. From 61 to 65 year-old case-bycase evaluation A5. Body weight > 40 Kg A6. In-hospital transportation (see table 2A) ≤ 90 minutes A7. Absence of absolute contraindications to organ donation: • present or past medical history of cancer, drug abuse or other biological risk • present sepsis • chronic hemodialysis • criminal history or violent death • HIV, HBV, HCV positivity • massive haemorrhages • abdominal and femoral vessels affected by pathology or trauma that may limit ECMO running B.

EXCLUSION CRITERIA

B1. No lay witnessed cardiac arrest

A&E, Accident and Emergency; CIR-NITp = Centro Inter-regionale RiferimentoNord Italia Transplant; ICU, Intensive Care Unit; pDCD, potential donation after cardiac/circulatory death; ECMO, extracorporeal membrane oxygenation

B2. Cardiac arrest due to criminal event B3. Cardiac arrest occurred more than 15 minutes from health care professional support B4. Hemodynamic instability > 60 minutes or severe arterial hypotension with systolic blood pressure < 60 mmHg B5. Patient’s age < 15 or > 65 years B6. Body weight ≤ 40 Kg B7. In-hospital transportation (see table 2A) > 90 minutes B8. Absolute contraindication to organ donation (see A7.)

B9. Absence of living consent to organ donation and next of kin is not traceable CPR, cardiopulmonary resuscitation; ACLS, advanced cardiac life support; ECMO, extracorporeal membrane oxygenation

as described in Table 7. Further details are summarized in Tables 8A, 8B and 8C. However, a few points need to be clarified.

Category II donors: cardiac arrest occurs at an out-ofhospital site. Emergency physicians arrive at the scene and initiate CPR by a cardiocompressor like autopulse, which is continued while the individual is taken by ambulance

to the emergency room. On arrival, death is declared and ascertained as previously described. Category VI donors: when ICU ECMO maintenance is not effective death is declared and ascertained. When neurologic standards are used ECMO works as for maintenance. In case of cardiac standards a temporary stop is needed during the no-touch period. When pDCD is identified medical identification and procedures start as described for modified ECMO57,58.

Care and evaluation of kidney viability

Timetable before transplantation: 1) Donor’s abdominal ultrasound; 2) Kidney recovery and macroscopic evaluation; 3) Kidney biopsy for pathology; 4) Kidney perfusion by ad hoc machine is of great value for caring, hemodynamic evaluation and monitoring (e.g. RM3 Renal Preservation System, Water Medical System LLC, Rochester MN, USA)59.

Preliminary results “Programma Alba” started at the “Fondazione I.R.C.C.S. Policlinico San Matteo, Pavia, Italy” in September 2007.

The Italian “Programma Alba” 113

TABLE 8A - “Programma Alba” DCD Maastricht category II. From cardiac arrest to death ascertainment 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

Public emergency medical service (Italian 118) arrives at the place of cardiac arrest Time registration of cardiac arrest that is the beginning of warm ischemia ACLS, time registration Autopulse Public emergency doctor (Ped) makes preliminary evaluation for Alba enrolment Ped supposes irreversibility of cardiac arrest with poor prognosis Ped informs transplant coordinator (TC) TC checks Italian transplantation database (Sistema informativo trapianti, SIT) to verify possible living opposition to organ donation according to Italian law 91/99 In case of living opposition TC stops Alba procedures In case of living consent or absence of documentation to organ donation, TC pre-alerts Alba and operating theatre staff for organ recovery Ped continues ACLS during transportation to A&E (see criteria for in-hospital transportation in table 2A) At arrival to A&E: blood tests, bladder catheterization, nasogastric tube, liaise with Alba staff Clinical diagnosis of death ACLS discontinuation, but autopulse, bladder catheter and nasogastric tube are not removed Death ascertainment (20-minute no-touch period) TC approaches next of kin, family, or legal representative to inform on, a) death ascertainment; b) possibility of organ donation (see manuscript B3.)

After death ascertainment restarts autopulse

DCD, donation after cardiac/circulatory death; Alba, “Programma Alba”; ACLS, advanced cardiac life support; A&E, Accident and Emergency

TABLE 8B - “Programma Alba” DCD Maastricht category II. From death ascertainment to femoral vessel isolation A.

CONSENT ACHIEVEMENT OR CHECKING FOR NON OPPOSITION TO ORGAN DONATION

1.

2.

3.

4.

5.

6.

7.

8.

B.

Will for organ donation might be documented by the Italian transplantation database (Sistema informativo trapianti, SIT) or a personal identity document. Opposition or non opposition to organ donation might be known by next of kin or legal representative. For under age individuals (< 18 year-old) organ donation needs both parents’ determination ACLS for organ preservation TC takes family, social, drug, past and present medical history for Alba enrolment and to better identify the cause of death TC supervises blood sampling and check laboratory findings In case exclusion criteria should arise (see Table 6), TC stops all Alba procedures In case of enrolment TC keeps running Alba procedures When appropriate, TC liaises with on-call magistrate waiting for organ harvesting permit Femoral vessel surgical isolation, i.e. one sided femoral artery and vein, contralateral femoral artery

AWAITING NON OPPOSITION TO ORGAN DONATION

9. Next of kin is not traceable or takes time 10. ACLS continues for organ protection 11. TC keeps checking timetable for proper organ harvesting. From death ascertainment to ECMO must never take more than 110 minutes 12. Femoral vessel surgical isolation (better after consent achievement, just before femoral vessel cannulation), i.e. one sided femoral artery and vein, contralateral femoral artery 13. In case of opposition TC stops all Alba procedures 14. In case of non opposition go to Table 8C DCD, donation after cardiac/circulatory death; Alba, “Programma Alba”, ACLS, advanced cardiac life support; ECMO, extracorporeal membrane oxygenation

Since then five kidneys have been recovered from six DCDs, three from category II and three from category VI respectively. Five DCD kidneys have been transplanted.

Three from DCD category VI and two from category II respectively (Table 9). Many more than five have been pDCD alerts. Currently three out of five renal DCD transplants are out of dialysis (Table 9).

114 P.M. Geraci et al.

Conclusions Our short experience in DCD began in September 2008 to temporarily stop in 2009 because of an AN1H1 viral emergency. However the Lombardy Region granted the “Programma Alba” ad hoc financial, human and machinery (e.g. ECMO) resources for the years 2009 and 2010. Al-

TABLE 8C - “Programma Alba” DCD Maastricht category II. From femoral vessel isolation to organ recovery 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

Infusion by Alba nurse of unfractionated heparin i.v. bolus (3 mg/ Kg body weight) and pantoprazole 80 mg i.v. bolus Alba nurse takes blood samples according to transplant allocation centre (CIR-NITp) protocol and organizes sample transportation One-sided perfusion catheters are cannulated in femoral artery and vein Femoral perfusion catheters are connected to cardiopulmonary machine Fogarty balloon catheter is introduced via contralateral femoral artery and placed in supraceliac aorta to exclude thoracic organs from perfusion circuit Fogarty balloon is inflated with radioopaque contrast agent Chest X-ray confirms positioning of Fogarty balloon Perfusionist connect one sided femoral catheters to ECMO tubing circuit beginning normothermic ECMO perfusion Nurse coordinator alerts operating theatre staff TC informs transplant allocation centre (CIR-NITp) on Alba procedure status TC liaises with pathologist for organ sample analysis In case of abnormal laboratory findings transplant coordinator stops all DCD procedures In case of Alba enrolment the patient under ECMO perfusion is transported to the operating theatre Organ recovery

DCD, donation after cardiac/circulatory death; Alba, “Programma Alba”; ECMO, extracorporeal membrane oxygenation

TABLE 9 - Preliminary data from Italian DCD programme, “Programma Alba” DONOR NUMBER

DCD category / death ascertainment: cardiac (C) brain (B) Donor’s sex, male (M) female (F) / age, years Donor’s artificial perfusion, mode WITap, minutes Recovered kidneys, left (L) right (R) / yes (Y) not (N) Kidney preservation Kidney perfusion machine (PM), hours PM intravascular flow resistance, mmHg/mL/min Kidney biopsy, histology Cold ischemia time, hours Transplanted kidneys, yes (Y) not (N) Recipient’s age, years Recipient’s sex, male (M) female (F) Primary graft non function (PNF), yes (Y) not (N) Delayed graft function (DGF), yes (Y) not (N) / days Recipient’s dialysis after kidney transplantation, number of dialysis sessions Kidney survival, months Serum creatinine levels at last follow-up, mg/dl

0

1

2

3

4

5

VI / C

VI / C

II / C

II / C

VI / C

II / C

F / 44

M / 47

M / 57

M / 61

M / 52

M / 46

ECMO ptd

ECMO ptd

ACLS + ECMO ad

ACLS

ECMO ptd

ACLS

25

LY

25 RY

LY

25 RY

LY

39 RY

LY

40 RY

LY

RY

35 N

CS n/a

CS n/a

CS n/a

CS n/a

CS n/a

CS n/a

PM 6

PM 6

PM 11

PM 14

n/a n/a

n/a

n/a

n/a

n/a

n/a

n/a

0.7

0.7

0.30

0.25

n/a

ATN, AT n/a N

ATN, AT n/a N

ATN

ATN

ATN

ATN

ATN

ATN

ATN

ATN

n/a

16 Y

>18 N

14 Y

18 Y

8 N

8 N

19 Y

16 Y

n/a n/a

n/a n/a n/a

n/a n/a n/a

56 M Y

n/a n/a n/a

66 M N

47 M N

n/a n/a n/a

n/a n/a n/a

66 F N

43 F N

n/a n/a n/a

n/a

n/a

n/a

n/a

Y/19

Y/9

n/a

n/a

Y/7

N

n/a

n/a

n/a

n/a

n/a

9

3

n/a

n/a

2

0

n/a

n/a n/a

n/a n/a

n/a n/a

n/a n/a

192 1.8

< 11 n/a

n/a n/a

n/a n/a

112 1.3

112 1.4

n/a n/a

DCD, donation after cardiac/circulatory death; ECMO, extracorporeal membrane oxygenation; ptd, prior-to-death; ACLS, advanced cardiac life support; ad, after death; WITap, warm ischemia time acirculatory phase; n/a, not applicable; CS, organ perfusion by cold solution; PM, kidney perfusion machine; ATN, acute tubular necrosis; AT, arteriolar thrombosis; 1 renal venous thrombosis (explanted at day 10); 2 to date

The Italian “Programma Alba” 115

though our DCD programme is not fully established three patients are currently out of dialysis treatment and a few preliminary considerations need to be expressed: 1. Increased availability of ECMO devices in Italy has made the DCD programme feasible despite restrictions due to local legislation and some reluctance by medical professionals.

2. Death ascertainment by cardiac (20-minute notouch period) or brain (six hours) criteria has little weight on organ viability when compared to organ perfusion before retrieval: natural in DBD (DDNP) or artificial in DCD (DDAP).

3. Prehospital emergency services must be highly qualified to obtain Maastricht category I and II donors.

4. Category VI resulted by an advanced resuscitation programme on outhospital patients with early Emergency ECMO followed by ICU ECMO maintenance. Unfortunately these patients have little survival expectancy, but can be enrolled as DDAP within the “Programma Alba”.

5. More category VI donors will be recruited in Italy by patients undergoing ECMO as a bridge to lung or heart transplantation or as advanced treatment of severe respiratory or cardio-respiratory failure.

6. Non-beating heart prompts practitioners to diagnose death in any case. In Italy the current increase in wholebody ECMO facilities needs revaluation of such diagnosis.

Such an issue might request new ethics, legal and medical analysis at national level.

7. The Italian 20-minute no-touch period when the brain is definitely not perfused is an important ethical assurance compared to the “dead donor rule”.

8. After death ascertainment any medical intervention to restore brain circulation should be forbidden17. It might reassure all medical professionals fearing that ECMO organ preservation could interfere with otherwise inevitable progression to brain infarction retroactively reversing death determination.

9. The 20-minute no-touch period appears a useful time to obtain consent for organ donation, team coordination, make machinery ready to work, etc.

10. According to the literature, the physician team determining death must be separated from the procurement team. It prevents organ procurement considerations from influencing death determination60.

11. Full ethical care to any action or procedure to the patient should be guaranteed regardless whether he or she is enrolled for organ donation or not.

12. Donor evaluation is essential for the recipient’s safety. A perfusion machine after kidney retrieval is strongly recommended for caring, hemodynamic evaluation and monitoring.

13. Transplant waiting list recipients at centres where the

116 P.M. Geraci et al.

DCD programme is active have to be properly informed that they may receive organs from such donors. Recipients should sign their informed consent at the time of enrolment on the waiting list and before DCD transplantation.

14. At the time of enrolment in a traditional transplant waiting list, recipients’ agreement to receive DCD does not change their position within the transplant waiting list.

Text comments 1. From paragraph “Worldwide DCD programmes” and in all tables the acronym DCD should be considered as the new equivalent of NHBD. 2. Unless otherwise specified “C” of DCD is for cardiac or circulatory.

3. According to the paper context “D” in all acronyms can be for donation or donor.

4. Italian legislation “Death ascertainment” is the equivalent of anglo-american “Declaration of death”.

Acknowledgement We need to thank Prof. Amedeo G. Conte that suggested “Alba” (Sunrise) to name our DCD Organ Transplantation Programme.

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