Francisco Del Río

Victims of Cardiac Arrest Occurring Outside the Hospital: A Source of Transplantable Kidneys

Context Waiting lists for kidney transplants are long. Contribution This study from Madrid, Spain, compared transplantation outcomes of 584 recipients of kidneys from heart-beating donors and 320 recipients of kidneys from nonheart-beating donors who died of cardiac arrest that occurred outside the hospital. One-year (about 90%) and 5-year (about 85%) graft survival rates were similar for transplantations from nonheart-beating donors and those from heart-beating donors who were younger than 60 years of age. Cautions This retrospective study is from a center with a well-developed nonheart-beating donor transplantation program. Implications People who die of cardiac arrest that occurs outside the hospital can be a viable source for kidney transplantations. The Editors The waiting list and waiting time for transplantations will inevitably become longer as the demand for kidneys continues to exceed the supply. The kidney waiting list of the United Network for Organ Sharing currently increases at a rate of 20% per year, and the list will be 100000 to 150000 patients long by the year 2010 (1). The overall annual mortality rate for wait-listed patients for kidney transplants is estimated to be 6.3% (2). While obtaining more organs from brain-dead donors with heartbeats is necessary, additional sources of organs are also needed, which has prompted the use of the nonheart-beating donor. Nonheart-beating donors are categorized into 5 types (Appendix Table) (3). Type I and type II are considered uncontrolled donors because cardiac arrest events in these patients occur outside the hospital and, thus, the transplant team is unaware of them. In type III and type IV nonheart-beating donors, cardiac arrest is managed, or controlled, in the hospital, and the transplant team can prepare for the procurement process. In type V nonheart-beating donors, this aspect can vary. Several reports have discussed the use of nonheart-beating donors (424), and the incidence of this type of donation is increasing. However, most patients described in these studies have in-hospital cardiac arrest, and few references have been made to donors whose deaths occur outside the hospital. Appendix Table. Description of the NonHeart-Beating Donor Types (Maastricht System) In 1989, our institution (Hospital Clnico San Carlos, Madrid, Spain) began a nonheart-beating donor procurement and transplant program. Our hospital is currently the largest procurement center for this type of transplantation in Spain, supplying 46% of the nonheart-beating donor kidneys transplanted in Spain in 1997 (3, 25). Most of our donors are adults who die suddenly outside the hospital and are transferred to the hospital for the sole purpose of donation (Maastricht type I donors) (26). We aimed to compare the graft survival of kidneys from uncontrolled nonheart-beating donors (Maastricht donors type I and II) and kidneys from heart-beating donors. Methods Donor Program In 1989, our hospital started a program to obtain organs from nonheart-beating donors (3). In 1996, we signed a formal agreement with the Madrid emergency facilities (SAMUR, 061, SERCAM) and established a standard protocol for obtaining organs from persons who die suddenly outside the hospital of irreversible cardiac arrest (type I Maastricht donor category) and are transported to our center for organ donation. Before 1996, most of these persons were directly transported to the morgue, but after 1996, patients were transferred to our hospital after unsuccessful cardiovascular pulmonary resuscitation (CPR). This protocol does not affect any CPR maneuver. All measures and times specified in the established CPR procedures are undertaken, and we evaluate the patient as a potential donor only when the cardiac arrest is considered irreversible (when an effective heartbeat cannot be recovered after a stipulated period [usually 30 minutes] or when the lesions provoking the cardiac arrest are incompatible with life). The following conditions should also be met when considering a potential donor: known cause of death, ruling out violence; known time of cardiac arrest; no bleeding injuries to the thorax or abdomen to avoid blood leaks in subsequent cardiopulmonary bypass during procurement; external cardiac massage and mechanical ventilation performed within 15 minutes of the cardiac arrest; no external signs of possible intravenous drug abuse suggesting a risk for HIV, hepatitis C, or hepatitis B infection; and donor age less than 60 years. When an individual has been classified as a potential donor, the emergency team continues with cardiac massage, mechanical ventilation, and intravenous fluid perfusion to maintain adequate hemodynamic conditions during transport to our hospital. Upon arrival, the transplant coordination team checks for the conventional prerequisites for donation (for example, no infections; negative results on serologic tests for HIV and hepatitis B and C; and no tumors) and then transfers the cadaver to the operating room. In type I and type II nonheart-beating donors, the femoral vein and artery are cannulated via an incision in the right side of the groin and are connected to a cardiopulmonary bypass machine with external oxygenation and hypothermia. The maximum time of warm ischemia (from the start of cardiac arrest until bypass) should not exceed 120 minutes. Maximum pump cold perfusion time is 240 minutes. While the organ is being perfused, the transplant coordination team fulfills the legal requirements for donation. The first step is to locate the family of the deceased person and obtain consent for organ extraction. Organ retrieval is performed according to the Maastricht protocol, which requires a diagnosis of death by physicians independent of those of the procurement team and a procurement protocol approved by the local medical ethics committee according to the current organ procurement legislation. Since 1999, Spain has had a law (Real Decreto 2070/1999) that allows organ donation after cardiac arrest. Under this law, the donor can undergo cardiopulmonary bypass until the necessary consent is obtained for organ extraction. In the past year, only 7% of families declined consent for organ extraction. Study Design and Sample From January 1989 to December 2004, our center transplanted 342 kidneys from nonheart-beating donors. According to the modified Maastricht donor classification scheme (3), these graft donors are classified as follows: 273 (79.8%) type I donors (dead on arrival), 47 (13.7%) type II donors (unsuccessful resuscitation in the emergency department), 6 (1.8%) type III donors (cardiac arrest in intensive care), 4 (1.2%) type IV donors (cardiac arrest during or after a diagnosis of brain death), and 12 (3.5%) type V donors (unexpected cardiac arrest in intensive care). In our retrospective study of procedures at our center, we compared data from 320 recipients of kidneys from uncontrolled, nonheart-beating donors (type I or type II Maastricht donor category) with those from 584 recipients of kidneys from adult cadaveric heart-beating donors between January 1989 and December 2004. We divided the heart-beating donor transplants into 2 groups according to donor age: younger than 60 years of age (n= 458) and 60 years of age or older (n= 126). Figure 1 shows data on the transplantations performed per year. We excluded transplantations from types III, IV, and V nonheart-beating donors and those from heart-beating donors other than adult cadaveric donors (en bloc pediatric renal transplantations or double renal transplantations from older donors). Figure 1. Kidney transplantations at the Hospital Clnico San Carlos, Madrid, Spain, January 1989December 2004. Other transplantations are those involving other than single adult cadaveric heart-beating donors (en bloc pediatric renal transplantations or double renal transplantations from donors 60 years of age) and those involving types III, IV, and V nonheart-beating donors. Treatment and Outcome Measures We treated transplant recipients with quadruple sequential therapy (antithymocyte globulin for 7 days, azathioprine, prednisone from the time of transplantation, and cyclosporine from day 5) from January 1989 to July 1996. From July 1996 to March 2001, the immunosuppression regimen used was triple therapy with cyclosporine or tacrolimus (plus prednisone and mycophenolate). After March 2001, recipients of kidneys from nonheart-beating donors and from heart-beating donors 60 years of age or older received daclizumab and a half-dosage of tacrolimus (0.1 mg/kg of body weight per day to achieve trough levels between 5 ng/mL and 8 ng/mL) during the first 2 weeks to avoid delayed graft function, whereas recipients of kidneys from heart-beating donors younger than 60 years of age did not receive daclizumab and were treated with full-dosage tacrolimus (0.2 mg/kg per day to achieve trough levels between 8 ng/mL and 12 ng/mL). The dosages of mycophenolate and steroids were similar for the 3 groups. Hyperimmunized patients (preformed reactive antibodies 50%) were treated with the monoclonal antibody muromonab-CD3 or antithymocyte globulin. We defined delayed graft function as the need for dialysis during the immediate post-transplantation period. Patients who showed delayed graft function underwent a biopsy every 7 days until renal function started to improve. We graded acute rejection according to the Banff 97 classification (27). We treated grade I rejection (interstitial infiltration and tubulitis) with high doses of pulse steroids. We treated grade II (intimal arteritis) or grade III (transmural arteritis) rejection with either muromonab-CD3 or antithymocyte globulin. Our policy is to discharge patients when graft function starts to improve. Subsequent ambulatory patient management does not vary according to donor type. The end point of the study was graft loss, defined as nephrectomy, retransplantation, or permanent return to dialysis. We followed pa

Increasing the donor pool using en bloc pediatric kidneys for transplant.

Objectives. En bloc pediatric kidney transplants (EBPKT) are still a subject of controversy. The aim of this study was to determine whether acceptable long-term graft survival and function can be achieved in EBPKT compared with the transplant of single, cadaveric, adult donor kidneys. Methods. A retrospective review was conducted of 66 recipients of en bloc kidneys from cadaveric pediatric donors and 434 patients who underwent transplantation with a single kidney from an adult donor between January 1990 and May 2002 at the authors’ hospital. The recipients were well-matched demographically. Both transplant groups were analyzed for short- and long-term performance in terms of transplant outcome and quality of graft function. Results. Overall death-censored actuarial graft survival rates at 1 and 5 years were 89.2% and 84.6% in the adult kidney transplants (AKT) and 83.3% and 81.1% in EBPKT, respectively (P =0.56). In the EBPKT group, graft function was improved over that observed in AKT. Vascular thrombosis was the most common cause of graft loss in EBPKT. Acute rejection occurred more frequently in AKT and Cox’s regression analysis indicated that undergoing an AKT was a predictive factor for acute vascular rejection (adjusted risk ratio, 3.8; 95% confidence interval, 1.4–10.2; P =0.001). Conclusions. Overall graft survival was similar in both groups, vascular complications were the main cause of graft loss in EBPKT, and the EBPKT showed excellent long-term graft function and a low incidence of acute rejection.

Uncontrolled donation after circulatory death: European practices and recommendations for the development and optimization of an effective programme

The shortage of organs remains one of the biggest challenges in transplantation. To address this, we are increasingly turning to donation after circulatory death (DCD) donors and now in some countries to uncontrolled DCD donors. We consolidate the knowledge on uncontrolled DCD in Europe and provide recommendations and guidance for the development and optimization of effective uncontrolled DCD programmes.

Trasplante de pulmón con donantes no controlados a corazón parado. Factores pronósticos dependientes del donante y evolución inmediata postrasplante

INTRODUCTION Uncontrolled donation after cardiac death (DACD) has become an alternative to lung transplantation with encephalic-death donation. The main objective of this study is to describe the incidence of clinically relevant events in the period of thirty days after lung transplant with uncontrolled DACD and the influence of factors depending on the donor and donation process as well. PATIENTS AND METHODS Historical cohort study of 33 lung transplant receivers at Hospital Puerta de Hierro and Hospital Marqués de Valdecilla with 32 DACD from Hospital Clínico San Carlos from 2002 to 2008. We studied surgical and medical complications, primary graft dysfunction, acute rejection, pneumonia and mortality. We made an evaluation of the donor characteristics and donation procedure times (minutes). RESULTS Median age of recipients was 50.5 years (interquartile range, 38.5-58). There were 28 males and 5 females. Cumulative incidence of events in the first month was: pneumonia 10 (31.3%); primary graft dysfunction 15 (46.9%); rejection 12 (37.5%); mortality 4 (12.1%); medical complications 25 (78.1%); and surgical complications 18 (56.3%). Median time of cardiac arrest was higher in those who presented pneumonia (15 vs. 7.5; p = 0.027). Median time of cold ischemia was higher in those who presented surgical complications and mortality (436 vs. 343.5; p = 0.04; 505 vs. 410; p = 0.033, respectively), and median of total ischemia times were longer in the recipients who died (828 vs. 695; p = 0.036). CONCLUSIONS Uncontrolled DACD are a valid alternative for expanding the donor pool in order to mitigate the current shortage of lungs that are valid for transplantation. The incidence of complications is comparable with published data in the literature.

Preclinical experience in transplant with lung obtained from non heart beating donors

describe LTx outcomes. Results: Since 1990 743 LTx donor referrals to The Alfred were reviewed and 73 reported a history of asthma(HoA). From 12/73 referrals where the donor died of asthma (mean age 21, mean p02 505mmHg), 2 double LTx(DLTx) were performed. Of remaining 61 referrals, 25 became lung donors (mean age 28.5 12, mean p02 486 84mmHg) all having a HoA (17 treated) but died from other causes. From these donors, 33 LTx were performed;16 DLTx and 17 single LTx(SLTx). For all 35 LTx recipients from these donors (mean age 49.5 12.3, 19 female) median ICU and hospital stay were 8.1days (range 2-72) and 26.5 days (range 2-72) respectively. Comparing LTx outcomes from donors with treated asthma versus those not on treatment there was a significant difference in last p02 of donors (457 74mmHg vs 531 80mmHg, p 0.05), however no significant difference in % predicted 6 months post op FEV1 (70 19 vs 66 25), ICU and hospital stay. 5 recipients died within 30 days (3 early graft failure) 6 died later (2 due to BOS). 30 day, 1 year, and 5 year survival rates were 86%, 76%, and 70% respectively, no different to our overall LTx outcomes. 26 asthmatic donors with pO2 300mmHg, who died of other causes, were not utilised for LTx. Reasons for this were often complex but a history of asthma alone may have precluded their use in the early years of our program. Conclusion: We have insufficient data to comment on the use of donors who have died of severe asthma. However we have seen an increase in asthmatic donor referrals (3 in 1990-91 up to 16 in 2001-02) and with appropriate selection/utilisation, these lung donors have increased the donor pool with excellent long-term outcomes.

Validation of a new proposal to avoid donor resuscitation in controlled donation after circulatory death with normothermic regional perfusion

AIM The use of abdominal normothermic regional perfusion (nRP) and premortem interventions in controlled donation after circulatory death (cDCD) may represent a significant advance to increase the number and quality of grafts recovered in cDCD. The main limitation for the widespread acceptance of nRP in cDCD is the concerns of restoring circulation to the brain once death has been declared should the thoracic aorta not be adequately blocked. METHODS We describe and validate a specific methodology to ensure an appropriate blocking of the thoracic aorta in a multicenter study using this technique. RESULTS A total of 78 procedures with premortem cannulation and abdominal nRP were performed in four different hospitals. No case of heart or brain resuscitation was observed after nRP CONCLUSION: The use of premortem interventions before nRP and the aortic occlusion balloon may increase the number of grafts recovered in cDCD. Our proposed methodology avoids the ethical problem of resuscitation by guaranteeing that circulation to the heart and brain is not restored after nRP.

Characterization of human fibroblastic reticular cells as potential immunotherapeutic tools

Fibroblastic reticular cells (FRCs) are essential players during adaptive immune responses not only as a structural support for the encounter of antigen-presenting cells and naive T lymphocytes but also as a source of modulatory signals. However, little is known about this cell population in humans. To address the phenotypical and functional analysis of human FRCs here we established splenic (SP) and mesenteric lymph node (LN) CD45-CD31-CD90+podoplanin+ myofibroblastic cell cultures. They shared the phenotypical characteristics distinctive of FRCs, including the expression of immunomodulatory factors and peripheral tissue antigens. Nevertheless, human FRCs also showed particular features, some differing from mouse FRCs, like the lack of nitric oxide synthase (NOS2) expression after interferon (IFN)γstimulation. Interestingly, SP-FRCs expressed higher levels of interleukin (IL)-6, BMP4, CCL2, CXCL12 and Notch molecules, and strongly adapted their functional profile to lipopolysaccharide (LPS), polyinosinic:polycytidylic acid (Poly I:C) and IFNγ stimulation. In contrast, we found higher expression of transforming growth factor (TGF)β and Activin A in LN-FRCs that barely responded via Toll-Like Receptor (TLR)3 and constitutively expressed retinaldehyde dehydrogenase 1 enzyme, absent in SP-FRCs. This study reveals human FRCs can be valuable models to increase our knowledge about the physiology of human secondary lymphoid organs in health and disease and to explore the therapeutic options of FRCs.

European Vignettes in Donation After Circulatory Death

Donation after circulatory death (DCD) is increasing in Europe, yet there is widespread variability in practice. Insight into actual practice is difficult to acquire simply by analyzing protocols and laws from each individual country. For this reason, the 3 DCD vignettes in this article have been constructed to outline routine and standard DCD practice in the United Kingdom, the Netherlands, and Spain. These imagined vignettes reflect a “typical” case, based on the authors’ extensive experience with DCD but are not real patient cases. They are a resource aimed at stimulating discussion regarding European organ donation practice and provide a knowledge bank for those wanting to establish a DCD program in their country. It is our hope that by providing these vignettes, the wider organ donation and transplant community, as well as philosophers and the public, will have a better understanding of what DCD really is and what it really isn’t.

Mechanical CPR devices in donors after cardiac death

Denmark) blood gas analyzer is fast and reliable. The ABL-90 is light and portable and data can be automatically sent to the patient data management system or even the physician’s PDA. A study was carried out in order to investigate the feasibility of the unit in amobile emergency care unit. Materials and methods: The response towards g-forces and vibration had to be assessed before implementing the unit in the MECU. A dummy with the same dimensions and weight as the ABL-90 was constructed. An accelerometer was placed on top of the dummy, measuring g-forces during several regular ambulance runs. Furthermore, the shock response spectrum of the unit was calculated.Uponestablishing theextentof g-forces exertedandcalculating the shock response spectrum, further testing was carried out. Results: Although g-forces exerted were rather low (1.5–1.95g in all directions), initial findings demonstrated that the ABL-90was unstable. An inlet of the apparatus proved to be responsible for discontinuation within the calibration system. A re-designed cradle with added cushioning and a new inlet, designed to minimize the risk of a discontinued connection between the inlet and solution pack, enabled the ABL-90 to function. Conclusions: This study has shown that a slightly modified ABL-90 works in a MECU. As the apparatus has the potential for transmitting prehospital results to intra hospital patient datamanagement systems, this finding opens up for improved diagnostic and treatment possibilities, both prehospitally and in preparing emergency departments for patients before their arrival at the departments.