CLINICAL
AND
TRANSLATIONAL RESEARCH
Donation After Circulatory Determination of Death: The University of Michigan Experience With Extracorporeal Support Alvaro Rojas-Pen˜a, MD,1,2 Lauren E. Sall, BS,1 Mark T. Gravel, RN,1 Elaine G. Cooley, RN,1 Shawn J. Pelletier, MD,1 Robert H. Bartlett, MD,1 and Jeffrey D. Punch1 Background. Extracorporeal support (ECS) during organ procurement from donors after circulatory determination of death (DCDD) could increase the number of donor organs and decrease posttransplant complications. This study reports the experience of a large transplant center with controlled DCDD. Methods. A retrospective review of all potential controlled-DCDD cases between October 1, 2000 and July 31, 2013 was performed. We focused on methods, ethical and practical issues, and recipient outcome data of organs procured and transplanted in our institution using ECS-assisted DCDD (E-DCDD). Results. ECS was used for organ procurement in 37 controlled DCDD. The number of organs procured per donor was 2.59, and the number of organs transplanted per donor was 1.68. Delayed graft function occurred in 31% of renal grafts. In three donors (8%), organ donation was not completed because of surgeon judgment. Forty-eight renal grafts (65.8%), thirteen livers (61.9%), and one pancreas (50%) were successfully transplanted. Conclusions. ECS can be routinely implemented in controlled DCDD. In our experience, the organs provided per donor was 2.59. Widely applied, EDCDD could result in more donor organs, especially when applied to DCDD in uncontrolled conditions. Keywords: Extracorporeal support, Donation after circulatory determination of death, Organ procurement, Organ preconditioning, Delayed graft function. (Transplantation 2014;98: 328Y334)
he availability of donor organs is the limiting factor in solid organ transplantation. UNOS database reported that as of July 2013, over 119,000 patients await organs in the United States (1). The IOM 2006 report on organ donation identified organ retrieval after cardiac death as the number one research priority to improve organ donation (2). Organ procurement after cardiac death (donation after circulatory determination of deathVDCDD) is practiced in some centers, but problems associated with immediate organ failure limit this technique. In 2013, the American Thoracic Society The authors declare no funding or conflicts of interest. 1 Department of Surgery, University of Michigan, Ann Arbor, MI. 2 Address correspondence to: Alvaro Rojas-Pen˜a, M.D., University of Michigan ECLS Laboratory, 1150 W. Medical Center Drive, B560 MSRBII, Ann Arbor, MI 48109. E-mail: [email protected] A.R.-P., S.J.P., R.H.B., and J.D.P. participated in designing and performing the research, writing and editing the article, analyzing the data, and contributed analytic tools. L.B.S. contributed analytic tools and participated in analyzing the data. M.T.G. and E.G.C. participated in designing and performing the research, analyzing the data, and contributed analytic tools. Received 6 September 2013. Revision requested 3 October 2013. Accepted 14 January 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/983-328 DOI: 10.1097/TP.0000000000000070
published an official statement related to DCDD ethics and health policy encouraging the use of these donors (3). Procuring organs from DCDD is usually done through a process known as ‘‘rapid recovery’’ (RR). DCDD accounts for only 6% to 8% of organs used in the United States, and is almost exclusive to renal grafts (4), because the recipient can be supported with alternative renal replacement therapy during the period of non-function which is associated with the extent of warm ischemia (WI). After declaration of death, it is standard clinical practice to wait at least 5 min before beginning any organ procurement process (5). When RR-DCDD is instituted after the 5-min period of asystole, the organs are typically retrieved within 30 to 45 min. When the ischemic organs are removed for transplantation, reperfusion injury takes place in the recipient and graft function may not occur for days, weeks, or not at all. The rate of primary non-function (PNF) is 26% when cold storage alone is used, 1% to 5% when pulsatile machine perfusion is used, and the rate of delayed graft function (DGF) is 25% to 60% (6Y11). Livers are procured infrequently in DCDD because of posttransplantation immediate failure and the increased incidence of biliary complications associated to ischemic injury to the biliary tree (12). At the University of Michigan (UM), we have a large transplant program and a large extracorporeal support (ECS) program. In 2000, we combined these programs to use ECS as
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1.68 1 13 ORPD, organs recovered per donor; OTPD, organs transplanted per donor
48 2.59 2 21 73
Pancreas Kidneys
Livers
Pancreas
ORPD
Kidneys
Livers
Organs Transplanted (n) Organs Recovered (n)
B: Organs Recovered and Transplanted at UM from 37 E-DCDDs
22 37
TBI, traumatic brain injury; MVA, motor vehicle/motorcycle accident; CVA, cerebrovascular accident; HABI, hypoxic-anoxic brain injury
38.7 15
Mean Female Male Final No. E-DCDD
OTPD
TBI=2/MVA=13/CVA=11/HABI=11 30Y143.6 79.5
Range Range
Mean
Weight, kg Age, yr Gender A: Demographics of UM E-DCDDs
Kidney Transplants A total of 73 renal grafts were procured from the 37 E-DCDD, and 48 renal grafts were transplanted (65.8%). From these, 29 were carried out at UM and 19 in other centers. Mean cold storage and pump times were 17.4 hr and 10.2 hr, consistent with local OPO protocols, and mean vascular anastomosis time was 33 min. Twenty-five retrieved kidneys were not transplanted (34.2%). The reasons were as follows: four with positive serology, six resulting from ECS technical reasons, three with unacceptable anatomy, and 12 for other reasons including (high RRI during cold perfusion, no recipient, or other logistic issue). Of the 29 renal grafts transplanted at UM, the incidence of DGF, defined as the need of hemodialysis within the first 7 days posttransplantation, was 31%, and one kidney had PNF (3.5%). Three-year survival rates are presented in Figure 1. During this time period, eight kidneys were procured by RR technique when E-DCD was not available or when the donor could not be cannulated for ECS (one case). The rate of DGF was 64% and PNF 12.5%. These groups are not comparable, and the information is provided to describe the complication rates with RR in our institution.
TABLE 1.
E-DCDD Settings The average ECS duration was 86T5 min, and blood flow was 47T5.3 mL/kg/min (È3.5 L/min). ECS restored the metabolic and respiratory acidosis reflected in improved oxygen delivery and saturation until organ procurement. Arterial blood gases from the initiation of ECS until its termination are shown in Table 2A; eight complications occurred during E-DCDD (21.6%) are shown in Table 2B. In three donors (8%), livers were not taken because the organs did not appear to be well perfused at the time of laparotomy. This was early in our experience and we did not want to subject the recipients to a potential unsuccessful transplant. In the others, organs were procured and successfully transplanted despite technical complications.
Demographics of E-DCDD (A) and summary of organs recovered and transplanted from E-DCDDs at UM (B)
RESULTS
9Y65
Cause of Death
a method of in situ conditioning of abdominal organs in circumstances of controlled DCDD (Maastricht category III) (13), when the family requests organ donation. This resulted in successful procurement and transplantation of kidneys, livers, and pancreas. We reported our initial experience in 2005 with 20 ECS-assisted DCDD (14). This report updates our experience with ECS as a method of in situ conditioning and procurement of controlled DCDD. We call this technique E-DCDD.
During this period, there were 50 potential E-DCDD identified at UM. E-DCDD procurement was completed in 37 donors. The demographic characteristics, cause of death, age, and primary diagnosis are summarized in Table 1A. Seven of the E-DCDD were children. All organs procured and transplanted from the 37 E-DCDD at our institution are summarized in Table 1B. The number of organs procured per donor (OPPD) was 2.59, and the number of organs transplanted per donor (OTPD) was 1.68. ECS was not used in 13 potential E-DCDD (11 had prolonged agonal period and did not arrest within the expected time [G60 min before 2006, and G90 min thereafter], and two had other complications).
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TABLE 2.
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Arterial blood gases before and after extracorporeal support (A) and EDCDD complications at UM (B)
A: Arterial Blood Gases Before and After ECS Variable pH SvO2, % PaO2 PaCO2, mm Hg SaO2, % K+, mmol/L
Initiation of ECS
Termination of ECS
7.099T0.024 45.5T3.6 304.8T39.2 55.5T8.4 84.4T3.5 6.1T0.8
7.288T0.027 67.0T3.2 373.3T41.3 34.5T2.4 90.4T3.4 4.9T0.5
SvO2, mixed venous oxygen saturation; PaO2, partial pressure of oxygen; PaCO2, partial pressure of carbon dioxide; SaO2, arterial blood saturation B: E-DCDD Complications (8/37) Type of Complication
n
Percentage
Management/Outcome
ECS flow G45 mL/kg/min
4
10.8%
Cannulation (vascular access not possible)
2
5.4%
Severe bleeding Aortic balloon migration
1 1
2.7% 2.7%
Converted to RR=3 DCDD ECS continued=1 DCDD Converted to RR=1 DCDD Organs not recovered=1 DCDD Organs not recovered Organs not recovered
Liver Transplants Twenty-one E-DCDD livers were procured and 13 were transplanted (61.9%). Eight (38.1%) were not transplanted because of technical complications (4) and surgeon judgment (4). Recipient MELD score was 15 to 17. One- and twoyear graft-survival rates were 85.7% and 71.4%, respectively. Both biliary strictures and PNF were reported in one patient each (14.3%). Pancreas Transplantation Two pancreatic grafts were recovered, and one was transplanted.
DISCUSSION DCDD donation in the United States only accounts for 6% to 8% of the donor pool (1). Almost all of these are controlled DCDD, and RR is used in the majority of the cases (kidneys being the majority, followed by livers). RR-DCDD
FIGURE 1.
kidneys have a higher DGF rates than kidneys from DNDD, although most are functional at 1 year. Normothermic ECS establishes organ perfusion after cardiac arrest (CA) and treats WI of the agonal period immediately the donor rather than later in the recipient (15Y17). ECS restores perfusion and metabolic parameters to normal (Table 2A). One explanation is that, as in any shock resuscitation, warm blood perfusion includes both the cause of ischemia/reperfusion injury (neutrophils) and the treatment of ischemic-reperfusion injury (energy nutrition, free radical scavengers). Another explanation is that normothermic oxygen delivery to tissue can allow for constant regeneration of ATP and NAD, maintaining normal nucleotide metabolism, and most importantly preventing the accumulation of potentially toxic metabolites.(18, 19) The number of organs recovered per donor was 2.59 (Table 3). Aside from the scientific advantages described above, practical advantages of E-DCDD are that (1) withdrawal of
Renal graft survival of DCDD kidneys transplanted at UM.
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TABLE 3. Issue
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Organ recovery in DCDD: comparison of procurement technique RR-DCDD
E-DCDD
Organs donated Kidneys/selective livers All, except heart Goal Deep cooling/decrease metabolism Restore warm circulation and oxygenation/normal metabolism Time to organ procurement Urgent Elective Cold storage Routine/pump perfusion Pump perfusion not necessary Organ assessment During pump perfusion or at transplantation At recovery, during pump perfusion or at transplantation Limitations Rapid cooling and operative room time Cannulation and ECS management Post Tx function 40%Y60% DGF 8%Y30% DGF
support is carried out in the ICU rather than in the operating room, and (2) organ retrieval is semi-elective rather than emergent. E-DCDD is the preferred method of organ recovery in controlled DCDD in our institution. Our ECS technique is essentially the use of a standard VA-ECS. Cannulas placed in the femoral vessels are large enough to provide more than 45 mL/kg/min of flow. The temperature is maintained at 37-C throughout. Anticoagulation with systemic heparin maintains the activated clotting time greater than 300 sec. In our initial experience, we assumed that the brain was totally dead (documented by examination) after the agonal period plus 5 min of no circulation, and we maintained CA with a large dose of 1 to 2 g lidocaine. Later, we instituted the use of a thoracic aortic balloon cannula during perfusion to prevent both coronary artery flow and any residual brain blood flow. E-DCDD support can be carried out in any hospital with cardiac surgery capability. The practical and ethical issues with E-DCDD are often more challenging than the scientific issues. There is common agreement that there should be a distinct separation between the treatment team (withdrawing support and declaring death) and the transplant team (procure and transplant organs). There is also consensus that any intervention should not be done that actively hastens CA in the donor, the heparinization of the premortem donor being the most relevant (3, 20). In E-DCDD, good communication between the treatment team and transplant team is required, and both should communicate with the family at the same time (3). When the family requests organ donation, we place catheters for E-DCDD and flush them with heparinized solution before withdrawing care, and obviously before actual CA. Our hospital institutional review board (IRB) agreed with this approach. Our IRB and legal experts believe that there is no legal issue, only local interpretation of consensus policies. This hospital policy has never been challenged. However, if this is a potential limitation to E-DCD, our laboratory studies have shown that anticoagulation, cannulation, and perfusion can all be done 5 min or more after declaration of death with successful ECS. We have studied many of the details of E-DCDD in the laboratory, using a porcine model of apneic CA (21, 22). We have learned that heparin given 5 min after CA is as effective as heparin given before; that the perfusion temperatures can be allowed to gradually drop from 37-C to room temperature, obviating the need for a heat exchanger and water bath in the circuit (23); that kidneys and livers can be successfully resuscitated by ECS after more than 30 min of warm ischemic time; and that lungs can be successfully resuscitated by ECS (relying on bronchial flow
from the distal aorta) and lung function can be evaluated despite the fact that there is no pulmonary circulation (24). We are currently investigating the use of thrombolytic drugs and other measures to extend the tolerable warm ischemic time to more than 60 min. Our IRB agreed that placement of cannulas before death fulfilled the wishes of the family that organ donation should be optimized. However, cannulas can be placed after death by percutaneous puncture with ultrasound guidance if desired. The initial protocol included the use of phenobarbital during perfusion because some reviewers worried that some brain stem activity might be restored, even after 5 min of no circulation. We discontinued phenobarbital after instituting aortic occlusion. In addition to removing any concern regarding brain function, another reason for aortic occlusion is to prevent perfusion of the upper body after death, which can be misleading to the family. All monitors were removed at the bedside to spare the family the agony of watching pressure and ECG tracing deteriorate over many minutes. This is the policy for any elective withdrawal of treatment at UM ICUs. Monitors at the nursing station document absence of circulation and cardiac rhythm, and death is declared by examination at the bedside. A group from Wake Forest University School of Medicine have reported recovery and transplantation of 19 E-DCDD kidneys with a similar technique with 21% DGF (25, 26). Three large transplant centers in Spain (La Corun˜a, Madrid, and Barcelona) have been studying E-DCDD and RRDCDD for several years in animals and patients. The group from La Corun˜a has reported renal grafts from uncontrolled DCDD with higher rates of DGF (84%) and PNF (16%) when manual CPR and in situ cooling is used, compared to CPR+ abdominal counterpulsation without cooling (26% and 10%, respectively) (9). The liver experience of this group suggested that uncontrolled DCDD grafts require some type of support and preconditioning aiming to minimize WI time to reduce the high rate of biliary complications (41.7%), and to obtain 2-year graft survival rates, comparable to livers from controlled DCDD (27, 28). The group from Madrid has been using normothermic ECS for uncontrolled DCDD since 2005. They recently reported experience with 20 livers recovered with ECS and compared the results to 40 DNDD livers. The incidence of PNF was 10% (2.5% DNDD), and cholangiopathy was 5% (0% DNDD) with equivalent graft and patient survival at 1 year between both groups (29). The group from Barcelona have widely studied E-DCDD in porcine models and identified the benefits of normothermic
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preconditioning of hepatic grafts before total body cooling after 40 min of WI, and suggested that hypothermic preservation conditions endothelial and Kupffer cell injury leading to graft failure (30Y32). The same group, most recently reported their clinical experience (33, 34). Fondevila et al. reported the 12-year uncontrolled E-DCDD Barcelona liver program. Thirty-four liver transplants (9%) from 400 potential donors were performed, a very low applicability. One-year recipient and graft survivals were 82% and 70%, respectively (median follow-up 24 months). The authors suggested that with better preservation technology and expanded transplant criteria, livers from these donors will be used more frequently (35). The National University Hospital in Taipei, Taiwan, reported using ECS for 31 DCDD renal grafts using 4-C perfusion for 60T5 min, with 42% DGF rates (36). Several other centers have reported using cold femoral perfusion RRDCDD (37). A review of all of these studies shows that DGF
FIGURE 2.
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rates are higher when colder perfusion is used. All of this information raises the question of possible deleterious effects of immediate cold perfusion on early kidney function. This experience in controlled DCDD, and our laboratory experience with porcine models indicating that organs can be recovered by ECS after a warm ischemic period greater than 30 min, has prompted us to evaluate ECS in uncontrolled DCDD (15). We are currently establishing the protocol for instituting ECS in the emergency room in patients who arrive in CA or in whom cardiac resuscitation attempts have failed. The use of E-DCDD in uncontrolled CA (emergent DCDD) would have an even greater impact on the number of organs available for transplantation.
CONCLUSION ECS is an effective method to restore abdominal organ function after cardiac death. The results of kidney, liver, and
UM E-DCDD protocol (A) and schematic of the UM E-DCDD circuit (B).
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pancreas transplantation after E-DCDD are equal to those from brain-dead donors and better than RR-DCDD. Any medical center that is equipped to do cardiac surgery can implement the ECS technique in controlled-DCDD situations. If this technique were widely used, it could significantly increase the number and quality of abdominal organs for transplantation. The technique of E-DCDD developed here in controlled conditions could result in a major increase in donor organs if applied to the much larger group of potential uncontrolled DCDD.
MATERIALS AND METHODS A single-center retrospective review of E-DCDD cases from October 1, 2000 to July 31, 2013 includes controlled DCDD abdominal graft donors in which the kidneys, livers or pancreas, or both, were procured after declaration of death by CA after planned withdrawal of mechanical or pharmaceutical life support. Recipient outcome data for all patients who received renal grafts from DCDD procured at UM were gathered from the Scientific Registry of Transplant Recipients database. This study was approved by the UM Health System IRB.
E-DCDD Case Selection We considered donors less than 65 years old for abdominal organ recovery using the following criteria: Those who had severe, acute irreversible brain injury but did not meet criteria for brain stem death. Patients in the ICU on mechanical ventilation and other supportive care. Care was going to be withdrawn because of futility with the understanding of the family. The family wished to donate organs. There were no contraindications to transplantation of donated organs. When patients met all these criteria, a sample was taken for tissue typing and documentation of adequate abdominal organ function. Figure 2A summarizes the UM-DCDD protocol, and Figure 2B shows the ECS circuit schematic used in E-DCDD.
ECS Circuit The ECS circuit consists of a blood pump, membrane lung, heat exchanger, and access cannulas. The circuit was prepared by the ECS team and was essentially the same circuit used for emergency cardiac support during CPR. The pump was a roller or centrifugal pump and membrane lung was a microporous Affinity NT oxygenator (Medtronic, Inc. Minneapolis, MN). The circuit was primed with 0.75 to 1 L Normosol-R solution (Hospira Inc., Lake Forest, IL), 50 mEq of HCO3, 50 g Albumin (Human) (Flexbumin; Baxter, Westlake Village, CA), 20,000 U heparin sodium (AAP Pharmaceuticals, Schaumburg, IL), and 50 g mannitol (Hospira). Before withdrawal of life support, the right femoral and vein were cannulated percutaneously. Large cannulas were placed over a guidewire into these vessels before withdrawal of support. For adult patients, these cannulas were 18 to 23 Fr for venous drainage, typically 21 Fr, and 15 to 19 Fr for arterial reinfusion, typically 19 Fr. After placement, the cannulas were loaded with a heparinized saline solution to prevent clotting during the time from withdrawal of care to cessation of spontaneous circulation (agonal period).
Withdrawal of Life Support and Donation All of these patients were on mechanical ventilation, and although all had potential for spontaneous breathing, no evidence of cortical brain function was observed. All were on intravenous support and most were on vasoactive drugs to sustain cardiac function and blood pressure. When support was withdrawn, the patient was extubated with no supplemental oxygen. Intravenous fluids and medications were stopped, and the bedside monitors turned off. During the agonal period, the family may be at the bedside. When there was no spontaneous respiration, no palpable pulse, and no apparent circulation, the absence of cardiac activity was determined by stethoscope and death declared. Typically, the agonal period lasted 5 to 30 min; if the agonal period
333
lasted less than 90 min, E-DCDD was not started because of the potential for organ damage during a prolonged period of poor perfusion.
ECS Management After declaration of death, a 5-min waiting period was instituted, assuring no return of breathing or circulation. ECS was then turned on in venoarterial (VA) fashion at normothermiaV37-C. As described in our initial publication, in our early experience we perfused the entire body, giving 2 g lidocaine to prevent return of cardiac rhythm. We did not have any sign of brain stem recovery, but changed the protocol to balloon aortic occlusion to prevent brain and coronary perfusion. When an aortic occlusion catheter was not used, 1 to 2 g lidocaine was infused preventing return of cardiac activity. Perfusion was maintained at greater than or equal to 45 mL/kg/min. The family could return if they wished for final goodbyes. The patient was then taken electively to the operating room.
Organ Recovery In the operating room, the abdomen was prepared in standard fashion. A midline incision was made and the abdominal organs evaluated. The aorta was cross-clamped at the diaphragm. ECS continued while the abdominal organs were dissected. The effectiveness of abdominal organ resuscitation was judged by gross appearance for liver, kidney, and pancreas, and urine output for kidneys. If the organs were considered suitable for transplantation, the vessels were completely dissected and prepared for in situ flush. In 2003, the Michigan Organ Procurement Organization (Gift of Life) standardized their protocol for in situ organ flushing with cold heparinized Custodiol (h-HTK). The ex situ flush is performed while the donor perfusate (blood) is exchanged for 2 to 8 L h-HTK during ECS, and then organs are removed and placed in iced cold storage.
Cold Machine Perfusion All E-DCDD renal grafts at the UM were machine perfused with the Organ Perfusion System using Kidney Perfusion Solution (KPS-1) before transplantation. All transplanted grafts had renal resistive indexes less than 0.50 mm Hg/mL/min (Fig. 2).
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TRANSLATIONAL RESEARCH
Donation After Circulatory Determination of Death: The University of Michigan Experience With Extracorporeal Support Alvaro Rojas-Pen˜a, MD,1,2 Lauren E. Sall, BS,1 Mark T. Gravel, RN,1 Elaine G. Cooley, RN,1 Shawn J. Pelletier, MD,1 Robert H. Bartlett, MD,1 and Jeffrey D. Punch1 Background. Extracorporeal support (ECS) during organ procurement from donors after circulatory determination of death (DCDD) could increase the number of donor organs and decrease posttransplant complications. This study reports the experience of a large transplant center with controlled DCDD. Methods. A retrospective review of all potential controlled-DCDD cases between October 1, 2000 and July 31, 2013 was performed. We focused on methods, ethical and practical issues, and recipient outcome data of organs procured and transplanted in our institution using ECS-assisted DCDD (E-DCDD). Results. ECS was used for organ procurement in 37 controlled DCDD. The number of organs procured per donor was 2.59, and the number of organs transplanted per donor was 1.68. Delayed graft function occurred in 31% of renal grafts. In three donors (8%), organ donation was not completed because of surgeon judgment. Forty-eight renal grafts (65.8%), thirteen livers (61.9%), and one pancreas (50%) were successfully transplanted. Conclusions. ECS can be routinely implemented in controlled DCDD. In our experience, the organs provided per donor was 2.59. Widely applied, EDCDD could result in more donor organs, especially when applied to DCDD in uncontrolled conditions. Keywords: Extracorporeal support, Donation after circulatory determination of death, Organ procurement, Organ preconditioning, Delayed graft function. (Transplantation 2014;98: 328Y334)
he availability of donor organs is the limiting factor in solid organ transplantation. UNOS database reported that as of July 2013, over 119,000 patients await organs in the United States (1). The IOM 2006 report on organ donation identified organ retrieval after cardiac death as the number one research priority to improve organ donation (2). Organ procurement after cardiac death (donation after circulatory determination of deathVDCDD) is practiced in some centers, but problems associated with immediate organ failure limit this technique. In 2013, the American Thoracic Society The authors declare no funding or conflicts of interest. 1 Department of Surgery, University of Michigan, Ann Arbor, MI. 2 Address correspondence to: Alvaro Rojas-Pen˜a, M.D., University of Michigan ECLS Laboratory, 1150 W. Medical Center Drive, B560 MSRBII, Ann Arbor, MI 48109. E-mail: [email protected] A.R.-P., S.J.P., R.H.B., and J.D.P. participated in designing and performing the research, writing and editing the article, analyzing the data, and contributed analytic tools. L.B.S. contributed analytic tools and participated in analyzing the data. M.T.G. and E.G.C. participated in designing and performing the research, analyzing the data, and contributed analytic tools. Received 6 September 2013. Revision requested 3 October 2013. Accepted 14 January 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/983-328 DOI: 10.1097/TP.0000000000000070
published an official statement related to DCDD ethics and health policy encouraging the use of these donors (3). Procuring organs from DCDD is usually done through a process known as ‘‘rapid recovery’’ (RR). DCDD accounts for only 6% to 8% of organs used in the United States, and is almost exclusive to renal grafts (4), because the recipient can be supported with alternative renal replacement therapy during the period of non-function which is associated with the extent of warm ischemia (WI). After declaration of death, it is standard clinical practice to wait at least 5 min before beginning any organ procurement process (5). When RR-DCDD is instituted after the 5-min period of asystole, the organs are typically retrieved within 30 to 45 min. When the ischemic organs are removed for transplantation, reperfusion injury takes place in the recipient and graft function may not occur for days, weeks, or not at all. The rate of primary non-function (PNF) is 26% when cold storage alone is used, 1% to 5% when pulsatile machine perfusion is used, and the rate of delayed graft function (DGF) is 25% to 60% (6Y11). Livers are procured infrequently in DCDD because of posttransplantation immediate failure and the increased incidence of biliary complications associated to ischemic injury to the biliary tree (12). At the University of Michigan (UM), we have a large transplant program and a large extracorporeal support (ECS) program. In 2000, we combined these programs to use ECS as
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1.68 1 13 ORPD, organs recovered per donor; OTPD, organs transplanted per donor
48 2.59 2 21 73
Pancreas Kidneys
Livers
Pancreas
ORPD
Kidneys
Livers
Organs Transplanted (n) Organs Recovered (n)
B: Organs Recovered and Transplanted at UM from 37 E-DCDDs
22 37
TBI, traumatic brain injury; MVA, motor vehicle/motorcycle accident; CVA, cerebrovascular accident; HABI, hypoxic-anoxic brain injury
38.7 15
Mean Female Male Final No. E-DCDD
OTPD
TBI=2/MVA=13/CVA=11/HABI=11 30Y143.6 79.5
Range Range
Mean
Weight, kg Age, yr Gender A: Demographics of UM E-DCDDs
Kidney Transplants A total of 73 renal grafts were procured from the 37 E-DCDD, and 48 renal grafts were transplanted (65.8%). From these, 29 were carried out at UM and 19 in other centers. Mean cold storage and pump times were 17.4 hr and 10.2 hr, consistent with local OPO protocols, and mean vascular anastomosis time was 33 min. Twenty-five retrieved kidneys were not transplanted (34.2%). The reasons were as follows: four with positive serology, six resulting from ECS technical reasons, three with unacceptable anatomy, and 12 for other reasons including (high RRI during cold perfusion, no recipient, or other logistic issue). Of the 29 renal grafts transplanted at UM, the incidence of DGF, defined as the need of hemodialysis within the first 7 days posttransplantation, was 31%, and one kidney had PNF (3.5%). Three-year survival rates are presented in Figure 1. During this time period, eight kidneys were procured by RR technique when E-DCD was not available or when the donor could not be cannulated for ECS (one case). The rate of DGF was 64% and PNF 12.5%. These groups are not comparable, and the information is provided to describe the complication rates with RR in our institution.
TABLE 1.
E-DCDD Settings The average ECS duration was 86T5 min, and blood flow was 47T5.3 mL/kg/min (È3.5 L/min). ECS restored the metabolic and respiratory acidosis reflected in improved oxygen delivery and saturation until organ procurement. Arterial blood gases from the initiation of ECS until its termination are shown in Table 2A; eight complications occurred during E-DCDD (21.6%) are shown in Table 2B. In three donors (8%), livers were not taken because the organs did not appear to be well perfused at the time of laparotomy. This was early in our experience and we did not want to subject the recipients to a potential unsuccessful transplant. In the others, organs were procured and successfully transplanted despite technical complications.
Demographics of E-DCDD (A) and summary of organs recovered and transplanted from E-DCDDs at UM (B)
RESULTS
9Y65
Cause of Death
a method of in situ conditioning of abdominal organs in circumstances of controlled DCDD (Maastricht category III) (13), when the family requests organ donation. This resulted in successful procurement and transplantation of kidneys, livers, and pancreas. We reported our initial experience in 2005 with 20 ECS-assisted DCDD (14). This report updates our experience with ECS as a method of in situ conditioning and procurement of controlled DCDD. We call this technique E-DCDD.
During this period, there were 50 potential E-DCDD identified at UM. E-DCDD procurement was completed in 37 donors. The demographic characteristics, cause of death, age, and primary diagnosis are summarized in Table 1A. Seven of the E-DCDD were children. All organs procured and transplanted from the 37 E-DCDD at our institution are summarized in Table 1B. The number of organs procured per donor (OPPD) was 2.59, and the number of organs transplanted per donor (OTPD) was 1.68. ECS was not used in 13 potential E-DCDD (11 had prolonged agonal period and did not arrest within the expected time [G60 min before 2006, and G90 min thereafter], and two had other complications).
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TABLE 2.
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Arterial blood gases before and after extracorporeal support (A) and EDCDD complications at UM (B)
A: Arterial Blood Gases Before and After ECS Variable pH SvO2, % PaO2 PaCO2, mm Hg SaO2, % K+, mmol/L
Initiation of ECS
Termination of ECS
7.099T0.024 45.5T3.6 304.8T39.2 55.5T8.4 84.4T3.5 6.1T0.8
7.288T0.027 67.0T3.2 373.3T41.3 34.5T2.4 90.4T3.4 4.9T0.5
SvO2, mixed venous oxygen saturation; PaO2, partial pressure of oxygen; PaCO2, partial pressure of carbon dioxide; SaO2, arterial blood saturation B: E-DCDD Complications (8/37) Type of Complication
n
Percentage
Management/Outcome
ECS flow G45 mL/kg/min
4
10.8%
Cannulation (vascular access not possible)
2
5.4%
Severe bleeding Aortic balloon migration
1 1
2.7% 2.7%
Converted to RR=3 DCDD ECS continued=1 DCDD Converted to RR=1 DCDD Organs not recovered=1 DCDD Organs not recovered Organs not recovered
Liver Transplants Twenty-one E-DCDD livers were procured and 13 were transplanted (61.9%). Eight (38.1%) were not transplanted because of technical complications (4) and surgeon judgment (4). Recipient MELD score was 15 to 17. One- and twoyear graft-survival rates were 85.7% and 71.4%, respectively. Both biliary strictures and PNF were reported in one patient each (14.3%). Pancreas Transplantation Two pancreatic grafts were recovered, and one was transplanted.
DISCUSSION DCDD donation in the United States only accounts for 6% to 8% of the donor pool (1). Almost all of these are controlled DCDD, and RR is used in the majority of the cases (kidneys being the majority, followed by livers). RR-DCDD
FIGURE 1.
kidneys have a higher DGF rates than kidneys from DNDD, although most are functional at 1 year. Normothermic ECS establishes organ perfusion after cardiac arrest (CA) and treats WI of the agonal period immediately the donor rather than later in the recipient (15Y17). ECS restores perfusion and metabolic parameters to normal (Table 2A). One explanation is that, as in any shock resuscitation, warm blood perfusion includes both the cause of ischemia/reperfusion injury (neutrophils) and the treatment of ischemic-reperfusion injury (energy nutrition, free radical scavengers). Another explanation is that normothermic oxygen delivery to tissue can allow for constant regeneration of ATP and NAD, maintaining normal nucleotide metabolism, and most importantly preventing the accumulation of potentially toxic metabolites.(18, 19) The number of organs recovered per donor was 2.59 (Table 3). Aside from the scientific advantages described above, practical advantages of E-DCDD are that (1) withdrawal of
Renal graft survival of DCDD kidneys transplanted at UM.
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TABLE 3. Issue
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Organ recovery in DCDD: comparison of procurement technique RR-DCDD
E-DCDD
Organs donated Kidneys/selective livers All, except heart Goal Deep cooling/decrease metabolism Restore warm circulation and oxygenation/normal metabolism Time to organ procurement Urgent Elective Cold storage Routine/pump perfusion Pump perfusion not necessary Organ assessment During pump perfusion or at transplantation At recovery, during pump perfusion or at transplantation Limitations Rapid cooling and operative room time Cannulation and ECS management Post Tx function 40%Y60% DGF 8%Y30% DGF
support is carried out in the ICU rather than in the operating room, and (2) organ retrieval is semi-elective rather than emergent. E-DCDD is the preferred method of organ recovery in controlled DCDD in our institution. Our ECS technique is essentially the use of a standard VA-ECS. Cannulas placed in the femoral vessels are large enough to provide more than 45 mL/kg/min of flow. The temperature is maintained at 37-C throughout. Anticoagulation with systemic heparin maintains the activated clotting time greater than 300 sec. In our initial experience, we assumed that the brain was totally dead (documented by examination) after the agonal period plus 5 min of no circulation, and we maintained CA with a large dose of 1 to 2 g lidocaine. Later, we instituted the use of a thoracic aortic balloon cannula during perfusion to prevent both coronary artery flow and any residual brain blood flow. E-DCDD support can be carried out in any hospital with cardiac surgery capability. The practical and ethical issues with E-DCDD are often more challenging than the scientific issues. There is common agreement that there should be a distinct separation between the treatment team (withdrawing support and declaring death) and the transplant team (procure and transplant organs). There is also consensus that any intervention should not be done that actively hastens CA in the donor, the heparinization of the premortem donor being the most relevant (3, 20). In E-DCDD, good communication between the treatment team and transplant team is required, and both should communicate with the family at the same time (3). When the family requests organ donation, we place catheters for E-DCDD and flush them with heparinized solution before withdrawing care, and obviously before actual CA. Our hospital institutional review board (IRB) agreed with this approach. Our IRB and legal experts believe that there is no legal issue, only local interpretation of consensus policies. This hospital policy has never been challenged. However, if this is a potential limitation to E-DCD, our laboratory studies have shown that anticoagulation, cannulation, and perfusion can all be done 5 min or more after declaration of death with successful ECS. We have studied many of the details of E-DCDD in the laboratory, using a porcine model of apneic CA (21, 22). We have learned that heparin given 5 min after CA is as effective as heparin given before; that the perfusion temperatures can be allowed to gradually drop from 37-C to room temperature, obviating the need for a heat exchanger and water bath in the circuit (23); that kidneys and livers can be successfully resuscitated by ECS after more than 30 min of warm ischemic time; and that lungs can be successfully resuscitated by ECS (relying on bronchial flow
from the distal aorta) and lung function can be evaluated despite the fact that there is no pulmonary circulation (24). We are currently investigating the use of thrombolytic drugs and other measures to extend the tolerable warm ischemic time to more than 60 min. Our IRB agreed that placement of cannulas before death fulfilled the wishes of the family that organ donation should be optimized. However, cannulas can be placed after death by percutaneous puncture with ultrasound guidance if desired. The initial protocol included the use of phenobarbital during perfusion because some reviewers worried that some brain stem activity might be restored, even after 5 min of no circulation. We discontinued phenobarbital after instituting aortic occlusion. In addition to removing any concern regarding brain function, another reason for aortic occlusion is to prevent perfusion of the upper body after death, which can be misleading to the family. All monitors were removed at the bedside to spare the family the agony of watching pressure and ECG tracing deteriorate over many minutes. This is the policy for any elective withdrawal of treatment at UM ICUs. Monitors at the nursing station document absence of circulation and cardiac rhythm, and death is declared by examination at the bedside. A group from Wake Forest University School of Medicine have reported recovery and transplantation of 19 E-DCDD kidneys with a similar technique with 21% DGF (25, 26). Three large transplant centers in Spain (La Corun˜a, Madrid, and Barcelona) have been studying E-DCDD and RRDCDD for several years in animals and patients. The group from La Corun˜a has reported renal grafts from uncontrolled DCDD with higher rates of DGF (84%) and PNF (16%) when manual CPR and in situ cooling is used, compared to CPR+ abdominal counterpulsation without cooling (26% and 10%, respectively) (9). The liver experience of this group suggested that uncontrolled DCDD grafts require some type of support and preconditioning aiming to minimize WI time to reduce the high rate of biliary complications (41.7%), and to obtain 2-year graft survival rates, comparable to livers from controlled DCDD (27, 28). The group from Madrid has been using normothermic ECS for uncontrolled DCDD since 2005. They recently reported experience with 20 livers recovered with ECS and compared the results to 40 DNDD livers. The incidence of PNF was 10% (2.5% DNDD), and cholangiopathy was 5% (0% DNDD) with equivalent graft and patient survival at 1 year between both groups (29). The group from Barcelona have widely studied E-DCDD in porcine models and identified the benefits of normothermic
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preconditioning of hepatic grafts before total body cooling after 40 min of WI, and suggested that hypothermic preservation conditions endothelial and Kupffer cell injury leading to graft failure (30Y32). The same group, most recently reported their clinical experience (33, 34). Fondevila et al. reported the 12-year uncontrolled E-DCDD Barcelona liver program. Thirty-four liver transplants (9%) from 400 potential donors were performed, a very low applicability. One-year recipient and graft survivals were 82% and 70%, respectively (median follow-up 24 months). The authors suggested that with better preservation technology and expanded transplant criteria, livers from these donors will be used more frequently (35). The National University Hospital in Taipei, Taiwan, reported using ECS for 31 DCDD renal grafts using 4-C perfusion for 60T5 min, with 42% DGF rates (36). Several other centers have reported using cold femoral perfusion RRDCDD (37). A review of all of these studies shows that DGF
FIGURE 2.
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rates are higher when colder perfusion is used. All of this information raises the question of possible deleterious effects of immediate cold perfusion on early kidney function. This experience in controlled DCDD, and our laboratory experience with porcine models indicating that organs can be recovered by ECS after a warm ischemic period greater than 30 min, has prompted us to evaluate ECS in uncontrolled DCDD (15). We are currently establishing the protocol for instituting ECS in the emergency room in patients who arrive in CA or in whom cardiac resuscitation attempts have failed. The use of E-DCDD in uncontrolled CA (emergent DCDD) would have an even greater impact on the number of organs available for transplantation.
CONCLUSION ECS is an effective method to restore abdominal organ function after cardiac death. The results of kidney, liver, and
UM E-DCDD protocol (A) and schematic of the UM E-DCDD circuit (B).
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pancreas transplantation after E-DCDD are equal to those from brain-dead donors and better than RR-DCDD. Any medical center that is equipped to do cardiac surgery can implement the ECS technique in controlled-DCDD situations. If this technique were widely used, it could significantly increase the number and quality of abdominal organs for transplantation. The technique of E-DCDD developed here in controlled conditions could result in a major increase in donor organs if applied to the much larger group of potential uncontrolled DCDD.
MATERIALS AND METHODS A single-center retrospective review of E-DCDD cases from October 1, 2000 to July 31, 2013 includes controlled DCDD abdominal graft donors in which the kidneys, livers or pancreas, or both, were procured after declaration of death by CA after planned withdrawal of mechanical or pharmaceutical life support. Recipient outcome data for all patients who received renal grafts from DCDD procured at UM were gathered from the Scientific Registry of Transplant Recipients database. This study was approved by the UM Health System IRB.
E-DCDD Case Selection We considered donors less than 65 years old for abdominal organ recovery using the following criteria: Those who had severe, acute irreversible brain injury but did not meet criteria for brain stem death. Patients in the ICU on mechanical ventilation and other supportive care. Care was going to be withdrawn because of futility with the understanding of the family. The family wished to donate organs. There were no contraindications to transplantation of donated organs. When patients met all these criteria, a sample was taken for tissue typing and documentation of adequate abdominal organ function. Figure 2A summarizes the UM-DCDD protocol, and Figure 2B shows the ECS circuit schematic used in E-DCDD.
ECS Circuit The ECS circuit consists of a blood pump, membrane lung, heat exchanger, and access cannulas. The circuit was prepared by the ECS team and was essentially the same circuit used for emergency cardiac support during CPR. The pump was a roller or centrifugal pump and membrane lung was a microporous Affinity NT oxygenator (Medtronic, Inc. Minneapolis, MN). The circuit was primed with 0.75 to 1 L Normosol-R solution (Hospira Inc., Lake Forest, IL), 50 mEq of HCO3, 50 g Albumin (Human) (Flexbumin; Baxter, Westlake Village, CA), 20,000 U heparin sodium (AAP Pharmaceuticals, Schaumburg, IL), and 50 g mannitol (Hospira). Before withdrawal of life support, the right femoral and vein were cannulated percutaneously. Large cannulas were placed over a guidewire into these vessels before withdrawal of support. For adult patients, these cannulas were 18 to 23 Fr for venous drainage, typically 21 Fr, and 15 to 19 Fr for arterial reinfusion, typically 19 Fr. After placement, the cannulas were loaded with a heparinized saline solution to prevent clotting during the time from withdrawal of care to cessation of spontaneous circulation (agonal period).
Withdrawal of Life Support and Donation All of these patients were on mechanical ventilation, and although all had potential for spontaneous breathing, no evidence of cortical brain function was observed. All were on intravenous support and most were on vasoactive drugs to sustain cardiac function and blood pressure. When support was withdrawn, the patient was extubated with no supplemental oxygen. Intravenous fluids and medications were stopped, and the bedside monitors turned off. During the agonal period, the family may be at the bedside. When there was no spontaneous respiration, no palpable pulse, and no apparent circulation, the absence of cardiac activity was determined by stethoscope and death declared. Typically, the agonal period lasted 5 to 30 min; if the agonal period
333
lasted less than 90 min, E-DCDD was not started because of the potential for organ damage during a prolonged period of poor perfusion.
ECS Management After declaration of death, a 5-min waiting period was instituted, assuring no return of breathing or circulation. ECS was then turned on in venoarterial (VA) fashion at normothermiaV37-C. As described in our initial publication, in our early experience we perfused the entire body, giving 2 g lidocaine to prevent return of cardiac rhythm. We did not have any sign of brain stem recovery, but changed the protocol to balloon aortic occlusion to prevent brain and coronary perfusion. When an aortic occlusion catheter was not used, 1 to 2 g lidocaine was infused preventing return of cardiac activity. Perfusion was maintained at greater than or equal to 45 mL/kg/min. The family could return if they wished for final goodbyes. The patient was then taken electively to the operating room.
Organ Recovery In the operating room, the abdomen was prepared in standard fashion. A midline incision was made and the abdominal organs evaluated. The aorta was cross-clamped at the diaphragm. ECS continued while the abdominal organs were dissected. The effectiveness of abdominal organ resuscitation was judged by gross appearance for liver, kidney, and pancreas, and urine output for kidneys. If the organs were considered suitable for transplantation, the vessels were completely dissected and prepared for in situ flush. In 2003, the Michigan Organ Procurement Organization (Gift of Life) standardized their protocol for in situ organ flushing with cold heparinized Custodiol (h-HTK). The ex situ flush is performed while the donor perfusate (blood) is exchanged for 2 to 8 L h-HTK during ECS, and then organs are removed and placed in iced cold storage.
Cold Machine Perfusion All E-DCDD renal grafts at the UM were machine perfused with the Organ Perfusion System using Kidney Perfusion Solution (KPS-1) before transplantation. All transplanted grafts had renal resistive indexes less than 0.50 mm Hg/mL/min (Fig. 2).
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