Abstract
Objective: In 2002 the first lung transplant from non heart beating (NHB) donors took place in Madrid. The objective of this study was to analyse our Maastricht type I NHB lung donors retrieval program and to check out its profitability. Materials and methods: Based on the NHB lung donors retrieval program carried out at Hospital Clínico San Carlos (Madrid) in association with Hospital Puerta de Hierro (Madrid), all lung donors from the beginning of the program from June 2002 to December 2006 have been analysed. When faced with a case of sudden death, advanced life support manoeuvres are initiated before 15 min. If the patient meets a given set of criteria, code 0/9 is activated. Arrival time to the hospital cannot exceed 90 min. Femoral artery and vein are cannulated, extracorporeal circulation is started and lungs are preserved. After the relatives’ and judicial authorisation lungs are retrieved. Results: Out of a total of 322 occurrences of code 0/9, 43 lung retrievals and 25 implants were reported. A total of 95% of donors were male, with an average age of 41 years and 91% with blood group A or O. 2004 saw the highest number of retrievals (14). January, May and December showed the highest number of retrievals. Incidence of sudden deaths was higher from 7 to 10 a.m. and from 7 to 10 p.m. Twenty-three implants at Hospital Puerta de Hierro and three more at Hospital Marqués de Valdecilla (Santander) were reported. A considerable amount of preserved lungs, valid for transplant, were not retrieved because of a lack of an appropriate recipient at the time. Conclusions: A total of 58.1% of preserved lungs were implanted. The ratio of obtained lungs was 11.4% of actual donors and 7.7% of total occurrences. However, this percentage could have been higher if we take into account the number of valid lungs that were not transplanted because of the lack of recipients.
1 Introduction
Patients in brain death have represented, up to current date, the main lung donors source. However, only 15–20% of multiorganic donors can provide suitable lungs for transplant [1]. This low ratio, added to the increasing necessity of lung donors, has led to the search for alternative lung sources. In this context, non heart beating donors (NHBD) are described as a new source of grafts for transplant [2–6]. Lung is the only transplanted solid organ that does not require blood perfusion to allow cellular metabolism. Furthermore, lung viability after death has been proved [7]. The first international workshop in non heart beating donors was held in Maastricht in March 1995. The experience of several groups was shared, and technical, ethical and legal aspects about this type of donor were agreed upon [8]. A categorised Maastricht classification of NHBD was established (Table 1 ).
Maastricht classification for non heart beating donors.
In 1989 Hospital Clínico San Carlos (Madrid) began a kidney and liver retrieval program from Maastricht categories III and IV, and in 1995 categories I and II were included obtaining good results [9]. In June 2002 a lung preservation and retrieval program from NHBD was started. On the 25th of November 2002 the first successful bipulmonary transplant was performed; preservation and retrieval took place at Hospital Clínico San Carlos, and lungs were implanted at Hospital Puerta de Hierro (Madrid), following the collaboration between Thoracic Surgery and Transplants Coordination Services from both hospitals [10–14].
The objectives of this study are the following: to analyse our lung retrieval program from Maastricht category I NHBD (code 0/code 9), checking out its profitability, and obtaining objective data to re-evaluate and to improve the actual code 0/9 guidelines.
2 Materials and methods
Based on the NHB lung donors retrieval program carried out at Hospital Clínico San Carlos, all lung donors from the beginning of the program from the 1st of June 2002 to the 31st of December 2006 have been analysed. The following parameters have been taken into account: age, gender, blood group, cardiac arrest time, cardiopulmonary resuscitation (CPR) initiation time, arrival time at the hospital emergency unit, extracorporeal circulation start time, lung extraction begin time, elapsed time until the end of extraction, lungs validity, lungs destination, number and kind of transplants performed and the reasons for non implanting preserved lungs.
2.1 Retrieval guidelines for non heart beating donors
When faced with a case of sudden, neurological or traumatic death out of hospital, emergency systems of the Madrid area (SUMMA and SAMUR) get activated and the following events take place successively:
After 30 min of cardiopulmonary resuscitation, according to European Resuscitation Council (ERC), American Heart Association (AHA) and International Liaison Committee for Resuscitation (ILCOR) at the site of death, out-of-hospital emergency medical staff assesses cardiac arrest.
Time of cardiac arrest must be known. The suitability of the patient is established with standard selection criteria:
Start CPR manoeuvres within 15 min after cardiac arrest.
Age between 12 and 55 years.
Cause of death known or supposed, without thoracic or abdominal injuries with massive bleeding, or thoracic trauma.
Healthy appearance with no evidence of risk factors for AIDS.
Assistance and arrival time at Hospital Clínico San Carlos cannot exceed 90 min. During this time, potential donor must be under mechanical ventilation, external cardiac massage and fluid perfusion.
Activation of code 0/9 is done by notifying the transplant coordinator of Hospital Clínico San Carlos, who alerts the complete transplant team.
On arrival at emergency unit, the staff of the intensive care unit receive the patient and, when death is certified, the transplant coordinator evaluates the potential donor and determines whether the process continues or not.
The following steps take place at the emergency unit:
Legal permission for organ preservation is requested from the Judge on duty by fax.
Blood samples are taken to verify blood group, haemogramme, gasometry, biological chemistry, coagulation, CMV, HBV, HCV and HIV serology, proteinuria and pregnancy test.
A bolus of heparin (500 IU/kg) is administered.
A chest X-ray is taken.
After cardiac arrest the deadline for preservation manoeuvres establishment is fixed in 2 h. The donor is transferred to the operating room, where the femoral artery and vein are cannulised and 300 ml venous blood is removed to a sterile heparinised bag at 4 °C for its posterior use in pulmonary function evaluation. Extracorporeal circulation with oxygenation membrane and deep hypothermia (4 °C) is initiated. A Fogarty catheter is introduced via the contralateral femoral artery and placed supradiaphragmatically to improve abdominal organ preservation.
Mechanical ventilation is interrupted. Topical cooling of lungs is achieved by inserting two pleural drainage tubes (24F) through second intercostal space, median-clavicle line, in each haemithorax, and infusing Perfadex solution at 4 °C (about 4 l), resulting in complete collapse of lungs. The ideal temperature measured at oesophagus is lower than 20 °C, which means optimal cooled lungs for performing a transplant.
After family consent and Judge’s permission are obtained, preserved solution is removed from pleural cavities and mechanical ventilation is initiated with 100% FiO2 and PEEP 5.
A bronchoscopy is performed to rule out gastric aspiration and to evaluate the bronchial mucosa.
Lungs are offered to Hospital Puerta de Hierro or to the rest of national centres that perform lung transplant and accept this type of donor.
A median sternotomy is made, pleural cavities are opened and lungs are inspected. Pericardium is opened to clamp the aortic root and cava veins are ligated. A pursue-string in the pulmonary artery and another one in the left auricle are made.
To evaluate pulmonary function a cannula is introduced through the pulmonary artery pursue-string and it is connected to a Y circuit including cold Perfadex on one side and the donor’s venous blood on the other side. Antegrade Perfadex perfusion through the pulmonary artery is initiated, allowing blood evacuation of pulmonary circuit, until the effluent through left auricle is clear. This process is repeated retrogradely (through left auricle to pulmonary artery). The Perfadex perfusion is then stopped, a bolus of E1 prostaglandin (1 mg) is introduced in the pulmonary artery and the donor’s venous blood perfusion is initiated at the same time as Perfadex. When blood effluent through the left auricle is observed, it is blocked and the auricle pursue-string is closed. A blood sample from the left auricle is taken to make an arterial gas, and temperature is measured to correct the values.
If corrected PaO2 is higher than 300 mmHg, lungs are considered suitable for transplant.
Perfadex perfusion through pulmonary artery continues and one more litre perfusion through left auricle is performed. Lung retrieval is completed.
Transplant coordinator notifies the Judge on duty of the completion of retrieval, and the corpse is left to court arraignment.
3 Results
Preclinical phase was carried out from the 1st of June 2002 to the 25th of November 2002, and eight lung retrievals were performed. In three of them good results were obtained considering ischaemic times, pulmonary function and histology. As a consequence of these results, the lung implanting program from NHBD was initiated, carrying out the first successful transplant on the 25th of November 2002 at Hospital Puerta de Hierro, with the receipt being a 50-year-old woman in emergency situation.
From then and until the 31st of December 2006, there have been 322 code 0/9 warnings, out of which 67 (20.8%) were excluded for different reasons (heart beat recovery, wrong initial selection of possible donor …). Among the 255 remaining, 36 (14.1%) were lost for family denial, bad ischaemic times, previous tumours, and other factors. Therefore the real amount of actual multiorganic NHBD was 219 (from whom at least one organ was retrieved: kidney, cornea, bone, etc.). This means 68% of the total code 0/9 warnings. In 43 of the 219 donors (19.6%) lung preservation and posterior macroscopic and functional evaluation was performed, which means nearly 20% of actual multiorganic donors were potential NHB lung donors. Twenty-five of these lungs were implanted, that is, 58.1% of potential donors became actual NHB lung donors. Fifteen bipulmonary transplants, six right-unipulmonary and five left-unipulmonary were performed, adding up to 26 receipts; given that each of one donor’s lungs was implanted in two different receipts in two different cities (Fig. 1 ).
Summary of yield results.
Out of the 43 preserved and evaluated lungs, only two belonged to women, therefore 95.3% of the potential lung donors were men. However lungs from both women were implanted, this is, 100% of female donors became actual lung donors, as opposed to a 53.5% of male donors. The average age of donors was 41 years (with ages ranging from 14 to 54 years). The largest group was comprised of donors in the 41–50 years of age range (Fig. 2 ).
Donor’s age.
A total of 47% of preserved and evaluated lungs were blood group A, 44% group O, 7% group B and 2% were AB. In the case of implanted lungs, 52% were group A, 36% group O, 8% group B and 4% AB.
Regarding the yearly distribution, 2004 rated the highest number of retrievals (14). Seven implants were performed in 2004, another seven in 2006, and six in 2005.
During the months of January, May and December, the highest number of lungs (seven, five and five respectively) was evaluated. With regard to implants, the highest number occurred during the months of November and December (four and five) (Fig. 3 ).
Monthly implant distribution.
The observations highlighted a higher incidence of sudden deaths from 7 to 10 a.m. (12 incidences) and from 7 to 10 p.m. (nine incidences). The least number of incidences of sudden deaths (just one case) occurred in the timeslot comprising 10 p.m. to 1 a.m. (Fig. 4 ).
Time of code 0/9 warnings.
In 93% of the cases, the initiation of CPR manoeuvres began during the first 15 min after cardiac arrest (as mentioned in the previous guidelines). In three cases the manoeuvres began after a longer period, however two of them became actual lung donors.
Ninety-five percent of the cases arrived at emergency unit of Hospital Clínico San Carlos within 90 min of the beginning of CPR manoeuvres (as established in the guidelines). There were two cases arriving after that time (100 and 105 min) that were also suitable for transplant. However, the two cases arriving within the first 30 min were discarded for implant.
Extracorporeal circulation was initiated later than 2 h from cardiac arrest time in six cases; however, five of them became actual lung donors.
After the establishment of extracorporeal circulation, the average elapsed time from the granting of Judge’s permission and family consent to the beginning of lung retrieval manoeuvres was 1 h and 54 min (R: 30 min–3 h 35 min), lungs evaluation and retrieval average time from cannulation was 4 h and 19 min (R: 2 h 30 min–6 h 25 min).
A total amount of 26 lung transplants from 25 NHBD were performed, 23 of them at Hospital Puerta de Hierro (13 bipulmonary, six right-unipulmonary and four left-unipulmonary) and three more at Hospital Marqués de Valdecilla (Santander) (two bipulmonary and one left-unipulmonary) (Fig. 5 ).
Lung transplants from NHBD performed.
The reasons for non implanting preserved lungs (18 cases) were the following: two of them because of bad ischaemic times, two because of pulmonary contusion, two because of the presence of tumours, one case of pulmonary thrombo-embolism, another case of pulmonary artery stenosis, one case of sarcoidosis, and the rest of cases included bad macroscopic lung aspect, bad arterial gas results, gastric aspiration and pulmonary oedema. In two cases no receipts were found in a nation-wide search among hospitals that accept this type of donor (one of them blood group B and the other one blood group O).
The early results of the first 17 transplants were published last year, and they showed a tendency towards higher rate of primary lung dysfunction (53%), although easily solved, with a complete restoration in 170 h. The hospital length of stay was 34 days (R: 18–75). The hospital mortality rate was 18%, with the survival rates established in 82% at 3 months, 69% at 1 year and 58% at 3 years [14]. Grossly, these results do not differ from those obtained with encephalic donors, as seen in the comparison of 84 lung transplants from encephalic donors with 16 from NHBD (from January 2002 to September 2005), with no significant differences in terms of acute rejection, BOS and survival rates [15].
4 Discussion
Epidemiologic data of our donors (95% male, 48% between 41 and 50 years) are easily extrapolated to a population that is prone to suffer from sudden death by AMI, that is, middle age males. It has been speculated about the possibility of blood group A being a risk factor to suffer from cardiac arrest; maybe this fact added to the higher ratio of blood group A and O in the population, explains why 52% of donors belonged to blood group A and 36% belonged to blood group O.
It is a logical conclusion that summer months showed a smaller number of code 0/9 warnings because of the decrease of population in Madrid area during those months. However, it may be more difficult to explain why January, May and December were the months with a higher number of code 0/9 warnings. There are some studies correlating the colder temperatures with a higher risk of suffering from AMI [16]; this could be backed up by the fact that December and January were the months with the higher number of sudden deaths in our study. On the other hand some authors have studied the relationship between circadian rhythm and the probability of suffering an AMI [17,18] revealing the period of time from 6 to 12 a.m. as the one with more cardiac arrests, which agrees with our study, as the code 0/9 warnings were more frequent from 7 to 10 a.m. and from 7 to 10 p.m., adding up 48.8% of the total warnings.
We believe retrieval guidelines for NHBD should be reviewed regarding some of the time specifications, as more than 66% of potential donors in which CPR manoeuvres were initiated after 15 min became actual lung donors; the same occurred with 100% of potential donors that arrived to emergency unit after 90 min from the beginning of CPR manoeuvres, as also did 85% of potential donors in which extracorporeal circulation began later than 2 h since the initiation of CPR manoeuvres.
The yield of lungs obtained from NHBD was 11.4% of actual multiorganic donors and 7.7% of the total number of code 0/9 warnings. A total of 57.7% of transplants were bipulmonary (15 cases). If we take into account that out of the 11 unipulmonary transplants only in two cases both grafts belonged to the same donor, this means that in nine cases only one of the two lungs was used, and therefore, up to nine suitable lungs were wasted. This added to the two cases in which there were no receipts and a few other cases which failed because of no availability of the implanting team, brings us to a considerable amount of wasted suitable lungs.
Bearing this data in mind, and having confirmed that this program allows us to increase the donors’ source, which in turn allows us to increase the number of transplants, we believe the use of NHBD could be optimised with a few improvements of the process. Namely:
Minimise as much as possible the reaction time and shorten the transfer to Hospital Clínico San Carlos. In order to do so, the coordination between out-of-hospital emergency units and the rest of the actors involved in this programme, from the police to the medical staff of the hospital emergency unit, the surgeons and the transplant coordinators, is key.
Unify criteria amongst all centres where lung transplant is performed, so that grafts belonging to NHBD are considered suitable for transplant.
In cases of unipulmonary transplant, offer lungs that are not going to be implanted to other centres.
Carry out the whole process (retrieval and implant) by the same team and at the same centre. This would avoid cases in which evaluated lungs considered suitable for transplant are wasted because of the non availability of an implanting team. Hospital Clínico San Carlos is capable and willing to take this chance, although to current date, it seems unlikely that a consensus will be reached on this regard.
Appendix A Conference discussion
Dr S. Cassivi (Rochester, MN): Lung transplant remains a very important option for a growing number of patients with various end-stage lung diseases, who really have basically no other options for treatment. Nevertheless, the limited donor organ pool remains the largest factor limiting the more widespread availability of this important treatment option. So your paper is extremely interesting. As a first-response medical centre, you see the potential non heart beating donors first, and I want to commend you and your group in moving ahead with your non heart beating donor program. You have done a great job today in describing the mechanics and intricate functioning of how that program works. It is an important thing for us to understand how to make something like this happen.
My questions to you relate mostly, though, to the outcomes of those patients. As a lung transplant surgeon, I not only have to know how the lungs are taken out of the donor but how do they work in the recipient. I think it would be important for us to know this. I know you are in a difficult position because you are from the procurement centre and not the implantation centre. It would be important for us to know, (1) the in-hospital mortality of the recipients, (2) their length of hospitalisation post-transplant, (3) their 30-day mortality, and (4) their 1-year survival after the lung transplant receiving these non heart beating donor lungs. It would also be useful to compare these results with the results of the conventional brain dead donor lung transplants, and in doing so, potentially identify risk factors, such as the ischaemic time, the age, the donor pO2/FiO2 ratio, etcetera, that may correlate with poorer outcomes for the transplant recipient.
It would also be useful to know how the transplant recipient lists are managed. This is a separate topic, but in certain centres that do non heart beating donor lung transplant, they have a separate list that prioritises the use of these donor organs.
And finally, I would be interested to hear your comments on – and you mentioned this at the end – why bilateral lung transplants were not done in the nine patients in whom you didn’t use the contralateral lung.
I think it is important to try to increase the donor organ pool.
Dr Fernández: As I have said, and you have mentioned, we are not an implanting centre, we are just a retrieval centre, so we don’t have those data. But I have prepared two slides.
Last year, the results about the first 17 transplants from non heart beating donors were published. As you can see, there was a tendency to suffer from primary graft dysfunction, but it was easily solved. The hospital mortality rate was 18%, and the hospital length of stay was 34 days. These results, in another article published last year, didn’t differ from those results obtained from encephalic donors, as you can see.
Regarding your other questions, there is just one recipient list, but all patients must sign two different written consents for each kind of donor.
Finally, about the nine lungs that weren’t implanted, well, I think this is an important point. I mentioned it about future improvements. I think these lungs were not implanted because of the recipients’ characteristics, but I feel it is necessary to improve this point and to find centres performing implants from these kind of lung donors so we can use these lungs that are wasted for patients on the recipient list.
Dr D. Van Raemdonck (Leuven, Belgium): I would like to ask a short question. Have you been able to look at primary graft dysfunction and the correlation with the warm ischaemic time? You mentioned there is 53% rate of primary graft dysfunction. Was there a correlation with the ischaemic time?
Dr Fernández: We don’t have those data. We just know that this is easily solved.
Acknowledgements
The authors thank the out-of-hospital emergency systems of Madrid area (SUMMA and SAMUR) and the Transplants Coordination Service of Hospital Clínico San Carlos.
References
Author notes
Presented at the 16th European Conference on General Thoracic Surgery, Bologna, Italy, June 8–11, 2008.
