Timing of heparin and perfusion temperature during procurement of organs with extracorporeal support in donors after circulatory determination of death.
ABSTRACT Despite successful resuscitation of donors after circulatory determination of death (DCD) with extracorporeal support (ECS), the technique is limited by ethical concerns about donor management (heparinization) and the complexity to operate the ECS circuit. This work studies different timing of heparin administration and the effects of ECS-perfusion temperature. Cardiac arrest (CA) was induced in swine. Heparin studies, three groups: 1) PRE5, heparin 5 minutes before CA; 2) POST5, heparin 5 minutes after CA, plus 2 minutes external chest compressions; and 3) POST30, heparin with the initiation of ECS after 30 minutes CA. Perfusion temperature study, two groups: 1) normothermic, ECS-38.5°C after 30 minutes CA and 2) room temperature, ECS-25.5°C for the first 90 minutes, followed by ECS-38.5°C. Heparin studies: ECS target flows (>50 ml/kg/min) were not achieved in the POST30 group, affecting local organ perfusion as observed with poor bile (<4 ml/min) and urine output (<25 ml/min), when compared with the other groups (normal values). Temperature study: In both groups, ECS target flows were reached, and urine/bile output was restored. Heparinization 5 minutes after CA is equivalent to premortem heparinization in this ECS-DCD model. Heparinization after CA could reduce ethical concerns. Donors after circulatory determination of death were successfully resuscitated at both temperatures, suggesting that the heat exchanger/water heater can be removed to simplify the ECS circuit.
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ABSTRACT: Organ shortage leads to usage of kidneys from donors after sudden cardiac death, or uncontrolled donors (UDCD). Ischemic injury due to cessation of circulation remains a crucial problem that limits adoption of UDCD. Our clinical investigation was to determine the applicability of kidneys obtained from UDCD and resuscitated by extracorporeal perfusion in situ after 60 minutes of asystole. In 2009-2011, organ procurement service of St. Petersburg, obtained kidneys from 22 UDCD with critically expanded warm ischemic time (WIT). No patients were considered as potential organ donors initially. All donors died after sudden irreversible cardiac arrest. Mean WIT was 61.4±4.5 minutes. For kidney resuscitation, the subnormothermic extracorporeal abdominal perfusion with thrombolytics and leukocyte depletion was employed. Grafts were transplanted into 44 recipients. The outcomes of transplantation of resuscitated kidneys were compared to outcomes of 87 KTx from 74 brain death donors (BDDs). Immediate functioning of kidney grafts was observed in 21 of the 44 recipients, with no cases of primary non function. By the end of the first post-transplant year there was an acute rejection rate of 9.1% (4 episodes of rejection) in the UDCD group versus 14.2% (13 episodes of rejection) in the BDD group. The actual 1-year graft survival rate was 95.5% (n = 42) in UDCD group, and 94.6% (n = 87) in BDD group. Creatinine levels at the end of the first year were 0.116±0.008 and 0.115±0.004 mmol/l in UDCD and BDD groups, respectively. UDCD kidneys with critically expanded WIT could be succefully used for transplantation if in situ organ "resuscitation" perfusion is included into procurement protocol. The results of 1-year follow-up meet the generally accepted criteria for graft survival and function. In situ reperfusion may exert a therapeutic effect on grafts before procurement. This approach could substantially expand the organ donors' pool.PLoS ONE 05/2013; 8(5):e64209. · 3.53 Impact Factor
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ABSTRACT: OBJECTIVE:: To evaluate the effects of prearrest heparin administration on lung quality in a model of donation after cardiac death (DCD), and to assess the potential application of ex vivo lung perfusion (EVLP) in the identification of better grafts from the DCD donor pool. METHODS:: Cardiac death was induced by electric shock in 10 pigs. One group received a prearrest heparin dose of 300 units/kg (H group, n = 5) and the other did not (NH group, n = 5). Animals remained at room temperature for 1 hour without ventilation, defining the warm ischemic time. After harvest, the lungs underwent 6 hours of cold ischemia before being evaluated with EVLP for 4 hours. RESULTS:: Static compliance 28 ± 3 versus 29 ± 2 (Cstat-cm H2O), pulmonary vascular resistance (PVR) 593 ± 127 versus 495 ± 70 (PVR-dyn·s/cm), and oxygenation 327 ± 32 versus 330 ± 28 (ΔPO2-mm Hg) remained stable from the beginning until the end of EVLP in the H group. In the NH group, Cstat started to decline after the first hour (25 ± 2 vs 21 ± 2), ΔPO2 after hour 2 (265 ± 44 vs 207 ± 44), and PVR started to increase after hour 3 (765 ± 132 vs 916 ± 168). Significant differences between the groups were observed at the end of EVLP (P < 0.001). Parameters of lung quality after EVLP also showed significant differences between the groups: wet weight-to-dry weight ratio (P < 0.001), protein in the bronchial lavage (P < 0.01), Na + K-ATPase activity (P < 0.001), and E-selectin (P < 0.001) in the perfusate. CONCLUSIONS:: Prearrest heparin administration improved organ function by preserving endothelial homeostasis. EVLP proved to be a useful platform for assessing DCD lungs, providing reliable means of discriminating injured grafts.Annals of surgery 10/2012; · 7.19 Impact Factor
Adult Circulatory Support
Timing of Heparin and Perfusion Temperature During
Procurement of Organs with Extracorporeal Support in
Donors After Circulatory Determination of Death
ALVARO ROJAS-PENA,* CANDICE M. HALL,† KEITH E. COOK,* ROBERT H. BARTLETT,* JUAN D. ARENAS,‡ AND JEFFREY D. PUNCH*
Despite successful resuscitation of donors after circulatory de-
termination of death (DCD) with extracorporeal support (ECS),
the technique is limited by ethical concerns about donor man-
agement (heparinization) and the complexity to operate the ECS
circuit. This work studies different timing of heparin administra-
(CA) was induced in swine. Heparin studies, three groups: 1)
PRE5, heparin 5 minutes before CA; 2) POST5, heparin 5 min-
utes after CA, plus 2 minutes external chest compressions; and
3) POST30, heparin with the initiation of ECS after 30 minutes
CA. Perfusion temperature study, two groups: 1) normothermic,
ECS-38.5°C after 30 minutes CA and 2) room temperature,
ECS-25.5°C for the first 90 minutes, followed by ECS-38.5°C.
Heparin studies: ECS target flows (>50 ml/kg/min) were not
achieved in the POST30 group, affecting local organ perfusion
as observed with poor bile (<4 ml/min) and urine output (<25
Temperature study: In both groups, ECS target flows were
reached, and urine/bile output was restored. Heparinization 5
minutes after CA is equivalent to premortem heparinization in
this ECS-DCD model. Heparinization after CA could reduce
ethical concerns. Donors after circulatory determination of
death were successfully resuscitated at both temperatures, sug-
gesting that the heat exchanger/water heater can be removed to
simplify the ECS circuit. ASAIO Journal 2011; 57:368–374.
Transplantation is a successful treatment for patients with
end-stage organ diseases, but the shortage of organs affects its
application. In the United States, by March 2011, there were
more than 110,000 persons enrolled in waiting lists, but only
about 28,000 will be transplanted from about 16,000 donors
(half are living kidney donors).1Multiple reasons for the short-
age of donors/organs have been identified: 1) decrease in the
motor vehicle crash injury and fatality rates2; 2) suboptimal
utilization of current donors (only 3.5 organs/per donor are
procured and transplanted successfully)3; and 3) the number of
living donors decreased by 10%, from 7,004 in 2004 to 6,310
in 2007.4,5Only a modest increment in the deceased donor
donation after aggressive educational programs.6
Alternative sources to increase the organ pool are split organ
donation; the use of organs from marginal brain dead donors or
donors after neurologic death (DND); and/or to use grafts from
donors after circulatory determination of death (DCD) or non-
heart beating donors.7Donors after circulatory determination of
death could be facilitated by the implementation of presumed
donation, instead of expressed consent, as a policy for organ
donation in the United States.8–11The use of organs from
DCD is not new,12,13but clinical practice has focused on
DND due to better outcomes and standardization of brain
death legislations in 1968.14Currently, organs are taken from
DCD by opening the abdomen as soon as possible after death is
declared, cooling the organs by topical ice and cold perfusion,
excising the kidneys and liver and flushing with cold perfusate, and
storing at ice temperature for transportation and transplantation (so-
called rapid recovery).15,16
Resuscitation of organ function by normothermic venoarte-
rial extracorporeal support (ECS) after circulatory determina-
tion of death could increase the availability of donor organs to
the point where available organs exceed demand. The largest
potential source is patients who are death on arrival (DOA) at
emergency rooms or fail resuscitation in emergency rooms
(so-called unexpected/uncontrolled DCD).17Another source is
patients who are electively removed from life support in in-
tensive care units with the expectation of death by cardiac
arrest (CA, expected/controlled DCD).18
In 2004, Department of Health and Human Services (DHHS)
and the Greenwall Foundation asked the Institute of Medicine
(IOM) to study the issue, resulting in a 340 page report published
in 2006 entitled Organ Donation; Opportunities for Action. The
recommendation to increase donated organs is focused on DCD,
building on similar recommendations from the IOM in 1997 and
2000. The report estimates that 22,000 donors could be good
candidates for DCD after unexpected CA. The IOM report rec-
ommends to expand the population of potential donors by im-
plementing initiatives to increase DCD donation and increasing
research on organ quality and enhanced organ function.19
The use of ECS after cardiac death to resuscitate organs for
transplantation from DCD has been practiced in the United
States by the teams at the University of Michigan,20Bowman
Gray School of Medicine with controlled DCD, and in Spain at
the Hospital Clinic of Barcelona,21and the Hospital Clinico
San Carlos in Madrid22with uncontrolled DCD, for the past
From the *Division of Transplantation, General Surgery Department,
University of Michigan Health System, Ann Arbor, Michigan; †General
Surgery Department, Louisiana State University, Baton Rouge, Louisi-
ana; and ‡Division of Transplantation, General Surgery Department,
UT Southwestern, Dallas, Texas.
Submitted for consideration April 2011; accepted for publication in
revised form May 2011.
Reprint Requests: Alvaro Rojas-Pena, MD, 1150 W. Medical Center
Drive-B560 MSRBII, Ann Arbor, MI 48109. Email: firstname.lastname@example.org.
ASAIO Journal 2011
years. This approach has resulted in routinely successful re-
suscitation of kidneys and livers with organ function equal to
transplantation from heart beating brain dead donors23; 20%–
30% of donors in those centers are ECS-assisted DCD, which
could add at least 3,000 additional donors if those protocols
were adopted across the country.20Furthermore, ECS provides
a period of support during which organ function can be as-
sessed before procurement.24Although these centers have
demonstrated a remarkable success with ECS after expected
cardiac death (Maastricht 3 category),25the technology has not
been widely adapted. The reasons are 1) the practical avail-
ability of a simple, reliable perfusion system; 2) procedural and
ethical issues related to cannulation for perfusion and hepa-
rinization of the potential donor before CA26,27; 3) the need for
laboratory study of ECS-assisted DCD donation to optimize the
procedure. We are addressing these limitations by developing
a simple automatic perfusion system specifically for organ
resuscitation, and laboratory studies which will lead to modi-
fying the clinical protocol. This report addresses the timing of
anticoagulation and the effect of temperature during organ
recovery from DCD donors using ECS.
Materials and Methods
This study was approved by the University Committee on
Use and Care of Animals (UCUCA) of the University of Mich-
igan, following all standards, policies, and regulation for large
Swine ?30 kg, were sedated with an intramuscular (im) mix
of 5 mg/kg Tiletamine HCl and Zolepam HCl (Telazol Wyeth
Holdings Corporation; Carolina, Puerto Rico) and 3 mg/kg
Xylazine (TranquiVed Vedco Inc; St. Joseph, MO). Animals
were intubated and ventilated with 100% O2and 1%–3%
isofluorane (Hospira, Inc.; Lake Forest, IL). Initial mechanical
ventilator settings were adjusted to keep PCO2at 35–45 mm Hg
and peak inspiratory pressures ?25 cm H2O. The right carotid
artery and right internal jugular vein were catheterized to
monitor mean arterial blood pressure (MAP), heart rate, and to
collect blood samples. A central line was placed in the internal
jugular vein to monitor central venous pressure (CVP) and fluid
administration. For ECS outflow, the right atrium was cannu-
lated with two 20–23 Fr venous cannulae by both external
jugular veins. For ECS inflow, 12 Fr arterial cannulae were
advanced into the abdominal aorta by both femoral arteries. A
midline laparotomy was performed. The common hepatic duct
was distally ligated, a 5–8 Fr silastic catheter was introduced in
the proximal duct for bile output (BO), and the proximal cystic
duct was ligated to prevent bile flow from the gallbladder. A
perivascular 4–6 mm flow probe (Transonic System Inc;
Ithaca, NY) was placed around the left hepatic artery for blood
flow monitoring, and a Foley catheter was placed into the
bladder for urine output (UO). At the end of surgical instru-
mentation and before baseline (BL) data collection, a 20-
minute acclimation period was allowed for organ recovery
Venoarterial ECS Circuit
The ECS circuit (Figure 1) includes a roller pump (Cobe
Cardiovascular; Lakewood, CO), an external heat exchanger
(Seabrook Medical System Inc; Cincinnati, OH), and a mem-
brane oxygenator (Affinity NT, Medtronic Inc., Minneapolis,
MN). Extracorporeal support venous cannulae were connected
to the oxygenator using 3/8? Tygon PVC tubing (Tygon Saint-
Gobain Performance Plastics Corporation, Akron, OH). The
arterial cannulae were connected using1⁄4? silicone tubing
(Nalgene 50, Rochester, NY) and then step up to 3/8? tubing to
connect them to the oxygenator outlet. The pump flows were
continuously monitored using a T208 monitor (Transonic Sys-
tem Inc., Ithaca, NY). The membrane oxygenator was primed
with lactate of Ringer’s, plus 50 mEq of HCO3and maintained
The different variables that were collected during the exper-
iment are summarized in Table 1: hemodynamics; bile (BO)
and UO; venous and arterial blood gases and a chemistry
panel for liver enzymes. Baseline data were collected after
surgical instrumentation and preinduction of CA, and this data
point gave us the normal values for healthy swine under
anesthesia for each variable studied; and end of CA was col-
lected after criteria for circulatory death was reached.
Experimental Design: Anticoagulation Timing
Three groups received heparin (200–300 U/kg) at different
times: 1) PRE5 received heparin 5 minutes before CA (this is
the control group, because correlates with the standard care);
2) POST5 received heparin 5 minutes after CA followed by 2
minutes of external chest compressions; and 3) POST30 re-
ceived heparin with the initiation of ECS after 30 minutes of
CA. In all cases, ECS was run at 38°C ? 1°C. Cardiac arrest
was induced in all animals by 1 g KCl intravenous (iv). This
model was chosen to create an exact time of arrest for all
animals to avoid effects of hypotension/hypoperfusion (as op-
posed to an apneic model which is more relevant clinically).
This study was designed to evaluate resuscitation of abdom-
inal organs to transplantable status when ECS is used during
procurement (but not actual transplantation), after achieving
anticoagulation at different times, to assess the clinical-ethical
concerns of premortem anticoagulation of donors. Other stud-
ies in our laboratory have demonstrated that organs resusci-
tated to this level of function can be successfully transplanted,
but that was not required for this study.
Figure 1. Donors after circulatory determination of death (DCD)-
extracorporeal support (ECS) swine model at the extracorporeal life
support (ECLS) laboratory.
HEPARIN AND ECS TEMPERATURE DURING ORGAN DONATION
Experimental Design for the ECS Temperature Studies
When ECS is used for organ donation, the majority of the
centers use normothermic perfusion, followed by rapid flush/
cooling of grafts. Two groups were studied: 1) normothermic,
ECS (38.5°C ? 1°C) for 3 h (this is our control group) and 2)
room temperature, ECS (25.5°C ? 2°C) for the first 90 minutes
of reperfusion, followed by normothermic ECS (38.5°C ? 1°C)
for the last 90 minutes of ECS to assess organ function at
normal core temperature. In all cases, ECS was initiated after
30 minutes of asystole and run for 3 h. Heparin (200–300
U/kg) was administered 5 minutes before asystole. Cardiac
arrest was induced to the animals in this study by iv 1.5–2 g
Lidocaine HCl (Hospira, Inc; Lake Forest, IL). Lidocaine (1 g) was
readministered if cardiac activity was observed during ECS.
This study was designed to assess the options to simplify the
ECS circuit during organ donation, aiming to develop a com-
pact circuit without heat exchanger that can be easily carried
and used but not experts in the field.
A mixed model was performed within SPSS 12.0 (Chicago, IL)
to examine the effect of heparin infusion time or ECS temperature
between groups. The pig/experiment number is the repeated
measure variable, and the independent variables were the exper-
imental group and the experimental time. The dependant vari-
ables were MAP, ECS flow, left hepatic artery flow (LHAF), BO,
UO, serum creatinine, aspartate transaminases (AST), and alanine
aminotransferase (ALT, described in the Data Acquisition sec-
tion). Finally, posthoc analysis using a Bonferroni-corrected
confidence interval was used to determine differences between
experimental groups. Values of p ? 0.05 were considered statis-
tically significant. Results are expressed as mean values with
errors bars representing standard error.
In all groups, ECS ran without complication. The pH was
?7.0 after 30 minutes of asystole, and it was rapidly corrected
during the first 30 minutes of ECS and thereafter maintained
from 7.30 to 7.35. The CVP was kept between normal ranges
(10 ? 5 mm Hg) during the surgical procedures and ECS in all
groups. No significant hemodilution was seen over the course
of the experiment (hematocrit ? 33% ? 6%). Heart activity
returned during ECS only in two pigs of the PRE5 group,
requiring additional KCl administration.
During the surgical procedure and 20 minutes before initi-
ation of the experimental time, the average MAP was 80 ? 15
mm Hg for all animals. After CA and ECS, the MAP averaged
68 ? 7 mm Hg, 55 ? 8 mm Hg, and 50 ? 7 mm Hg in PRE5,
POST5, and POST30 groups, respectively (Figure 2, left axis).
MAP was significantly higher during ECS in the preheparinized
group than in the other two groups (p ? 0.001). However, in
POST5 group, MAP raised to the same level as the PRE5 group.
ECS pump flow rates are represented in Figure 2, right axis.
In the PRE5 and POST5 groups, target flows (?50 ml/kg/min)
were achieved and maintained during the whole experiment.
These flows were about 62% of the normal cardiac output
(2.8 ? 0.4 L/min). In the POST30 group, it was not possible to
achieve target flows, despite crystalloid fluid administration up
to a CVP of 15 mm Hg. Neck and abdominal edema were
evident at the end of ECS in this group. Accordingly, ECS pump
flow rates were significantly higher (p ? 0.001) in the PRE5
and POST5 groups when compared with POST30 (p ? 0.079).
The average LHAF during BL (normal) data was 120 ? 35
ml/min. The LHAF increased in all groups during the course of
Table 1. Summary of Data Acquisition
Variable TypeFrequency MethodDescription
Hemodynamics Continuously but recorded every
Biopac MP150* MAP, mean arterial pressure; CO/ECS flow,
cardiac output/ECS pump flow; LHAF,
left hepatic artery flow
Bile and urine output collectionOrgan perfusion BL and every 30 min during ECSDirect collection and
ABL and OSM3
Venous and arterial
BL; end of CA; ECS (5, 15, 30, 60,
90, 120, and 180 min)
Blood pH; gas content in blood (PCO2and
PO2); Hb; Htc; O2Sat; electrolytes (Na, K,
Ca, Cl, and HCO3)
AST, aspartate aminotransferase; ALT,
alanine aminotransferase; LDH, lactate
dehydrogenase; and bilirubin
Chemistry panel BL; end of CA; ECS (60, 120, and
*BIOPAC Systems Inc., Goleta, CA.
†Radiometer A/S; Copenhagen, NV-Denmark.
‡Animal Diagnostic Lab U. Michigan.
BL, baseline data point; CA, cardiac arrest; ECS, extracorporeal support.
Figure 2. Extracorporeal support (ECS) perfusion characteristics
(flow and pressure)—heparin study (error bars ? SEM).
ROJAS-PENA ET AL.
the ECS (Figure 3) and correlates with ECS flows for each
group. In the PRE5 group, LHAF reached 80% of the pre-CA BL
value (97 ml/min) after 30 minutes of support and was main-
tained at this level for the 120 minutes of ECS. In the POST5
group, flows were slightly lower than the preheparinized
group, but no significant differences in LHAF were seen be-
tween these groups during the last 60 minutes of ECS. Signif-
icantly lower LHAF (?60 ml/min) were observed at all times in
the POST30 group, when compared with the other two groups.
Bile output during BL (normal) data collection was 10.5 ? 2
ml/h. During ECS (Figure 4), BOs were similar in the PRE5 and
POST5 groups, reaching ?75% of BL values at the end of ECS.
Bile output was significantly lower (3 ? 1 ml/h) in the POST30
group (p ? 0.001).
Urine output is represented in Figure 5. Urine was produced
by all animals as soon as ECS was initiated. Urine output
reached normal values (?50 ml/h) after 60 minutes of support
in the PRE5 and POST5 groups. In the POST30 group, UO was
significantly lower (?25 ml/h), and normal values were never
reached (p ? 0.001), when compared with the other two
Baseline AST levels were 45 ? 10 U/L. In all the groups, AST
increased over the course of ECS (Figure 6). In the PRE5 and
the POST5 groups, AST levels were significantly lower than in
the POST30 group (p ? 0.05). In this latter group, the AST
levels reached 5 times BL. There were no significant difference
between the PRE5 and POST5 groups.
There were no significant differences between groups in
ALT, lactate dehydrogenase (LDH), and creatinine concentra-
tions. Alanine aminotransferase (43 ? 5 U/L) and plasma
creatinine (1.0 ? 0.3 mg/dl) levels did not change through the
experiment compared with BL values in all groups. Lactate
dehydrogenase increased from 450 ? 100 U/L at BL to 700 ?
50 U/L at the end of ECS in all the groups. Finally, bilirubin
levels were unchanged throughout the experiment in all
The temperature course for each group is represented in
Figure 7. The room temperature group was rapidly cool down
with a heat exchanger to target temperature (25°C) and main-
tained for 90 minutes, then the same group was rewarmed to
38.5°C for another 90 minutes to assess graft function.
In a similar fashion to the previous study, the pH was 7.15 ?
0.05 after 30 minutes of CA but was rapidly corrected during
the first half hour of ECS to 7.35 ? 0.05. There were no
significant differences in ECS flow rates and LHAF between
groups (Table 2). However, MAP was slightly higher at the end
of ECS in the normothermic group.
Figure 3. Extracorporeal support (ECS) left hepatic artery blood
flow—heparin study (error bars ? SEM).
Figure 4. Extracorporeal support (ECS) bile output—heparin
study. Error bars ? SEM.
Figure 5. Urine output in extracorporeal support (ECS)—heparin
study. Error bars ? SEM.
Figure 6. Extracorporeal support (ECS) aspartate transaminases
(AST) levels—heparin study (error bars ? SEM).
HEPARIN AND ECS TEMPERATURE DURING ORGAN DONATION
Urine output is represented in Figure 8A. Baseline (normal)
UO was 60 ? 15 ml/h for all animals. Animals from both
groups were oliguric during the first 60 minutes of ECS, but
after this point, UO increased to ?100 ml/h in both groups.
However, UO was significantly lower in the room temperature
group compared with the control group (normothermic), this is
due to the effects of cold perfusion (decrease in oxygen con-
sumption and renal function). After rewarming, UO in this
group increased to normal values.
The average BL (normal) BO was 13 ? 1 ml/h for all the pigs.
Bile output (Figure 8B) was restored early after reperfusion in
the normothermic animals with values reaching ?90% of BL
(11 ? 1.5 ml/h) at the end of ECS. In the hypothermic group,
almost no bile was produced during the first 90 minutes of cold
perfusion. After rewarming, BO was ?75% of BL (9 ? 1.5
ml/h) at the end of ECS.
Finally, AST and LDH concentrations in plasma were higher
in both groups without differences: AST (288 ? 81 and 209 ? 63)
and LDH (1,510 ? 357 and 1,714 ? 258) for the normothermic
and room temperature group, respectively, when compared with
BL (normal) values (AST: 32 ? 4; LDH: 1,200 ? 150). No
changes were seen in GGT, BUN, and creatinine in both groups.
Extracorporeal support could play an important clinical role
during DCD organ recovery by restoring organ function and
facilitating assessment of in situ organ function before procure-
ment. In this DCD porcine model, warm ischemia was sus-
tained for a total of 30 minutes, resulting in a severe metabolic
acidosis and poor organ function at the initiation of ECS. The
acidosis was corrected quickly after the initiation of ECS,
however, and it was shown that organ function could be
returned under the appropriate conditions.
Heparin Administration and the Premortem DCD
High doses of heparin (30,000 U) are given to all DND
before surgical removal to prevent formation of blood clots in
the grafts. Heparin is not given for the benefit of the patient,
and some clinicians are concerned that administration may
hasten death due to the potential adverse reactions, like hem-
orrhage.28In the case of DND, the administration of heparin
occurs after declaration of brain death, in the operating room
and few minutes before surgical recovery of the organs. During
organ donation from DCD, however, there are major ethical
considerations to heparin administration. First, if heparin were
given after cardiac death, stasis in the vasculature could lead to
significant clotting and, thus, limit the effectiveness of ECS
perfusion. Delivering the large DND heparin dose (30,000 U)
could significantly hasten cardiac death. Thus, certain condi-
tions must be met for heparin delivery in this setting. Heparin
is ethically accepted to administer in DCD if:
1. The dose is based on the patient’s weight and small
enough to not hasten death.
2. Active bleeding is not known to exist.
3. The risk to the patient is deemed minimal by the patient’s
4. The decision to heparinize before declaration of death is
made by the family of the patient with the counsel of the
patient’s attending physician.
These recommendations are consistent with the work of
DuBois et al.,29who published a 2007 report related to the use
of heparin during organ recovery. They concluded that “with
the consent of donors or their surrogates, heparin should rou-
tinely be administered at the time of extubation when patients
have sufficient circulation to distribute the heparin throughout
their vital organs.”
This experimental model assessed the effects of hepariniza-
tion time to address ethical concerns regarding the heparin-
ization of premortem donors.6,19Specifically, the goal of this
study was to determine whether heparinization after CA still
Figure 7. Donors after circulatory determination of death (DCD)-
extracorporeal support (ECS) perfusion temperature course. Error
bars ? SEM.
Table 2. Summary of Main Values During ECS Temperature Study
DCD Group Variables30 min 60 min 90 min 120 min150 min 180 min
NormothermicMAP (mm Hg)
ECS pump flow
MAP (mm Hg)
ECS pump flow
43 ? 3
1.6 ? 0.1
42 ? 2
1.6 ? 0.1
55 ? 8
1.6 ? 0.1
62 ? 10
1.6 ? 0.1
63 ? 10*
1.6 ? 0.1
67 ? 8*
1.6 ? 0.1
121 ? 32
37 ? 2
1.6 ? 0.1
124 ? 29
42 ? 4
1.6 ? 0.1
101 ? 16
43 ? 4
1.6 ? 0.1
123 ? 18
47 ? 3
1.6 ? 0.1
111 ? 20
47 ? 2
1.6 ? 0.1
158 ? 28
46 ? 3
1.6 ? 0.1
88 ? 25 136 ? 43 159 ? 61 122 ? 27 140 ? 19118 ? 21
Larger (n) is required to see significant difference.
*Higher values were seen in MAP during the last 60 min of ECS in the normothermic group.
DCD, determination of death; LHAF, left hepatic artery flow; ECS, extracorporeal support; MAP, mean arterial pressure.
ROJAS-PENA ET AL.
allowed for perfusion of the organ and the return of organ
function. The result is promising, suggesting that hepariniza-
tion of the premortem donor before CA is not necessary.
Circuit and hepatic artery flows while on ECS were identical in
animals heparinized 5 minutes before and after cardiac death,
and urine and bile production were similar for both groups
after 2 hours of ECS support. This suggests similar organ via-
bility before transplantation. These same variables, however,
were significantly worse when heparinization occurred 30
minutes after cardiac death, suggesting that these organs
would not be suitable for transplantation at least with 2 h of
ECS only. Okazaki et al.30studied the optimal time for post-
mortem heparinization of DCDs for lung transplantation, ob-
taining adequate lung function after 30 minutes of postmortem
heparinization, suggesting that intravascular clotting in the
lung is different than abdominal organs. Other groups have
studied the use of thrombolytics, such as urokinase, during the
recovery or ex vivo preservation of DCD lungs.31–33Combined
anticoagulant and fibrinolytic therapy may allow for a longer
postmortem period without intervention while maintaining or-
gan function. Further studies are needed to assess its effects in
abdominal organs and clinical practice.
Conclusion. This study indicates that heparinization 5 min-
utes after CA is equivalent to premortem heparinization in this
model of DCD-ECS. Heparinization after CA could reduce
ethical concerns and may increase the rates of consent by
Perfusion Temperature During ECS of DCD
Organ resuscitation after DCD with normothermic ECS is
much better than rapid cooling and cold perfusion.20–23In nor-
mothermic ECS, organs from DCD sustained some degree of
warm ischemic injury from the time of CA until organ recovery.
These organs will require a procurement technique that is able to
ameliorate the ischemic cellular changes. Normothermic ECS
during DCD perfusion until surgical removal of the organs has
been shown to do so by restoring total and mitochondrial levels
of adenosine 5?-triphosphate (ATP) in porcine livers and kid-
neys.22,34However, room temperature perfusion could be advan-
tageous, as it improves oxygen delivery, decreases oxygen
consumption, and thus restores cellular energy levels. Further-
more, the ECS system could be simplified and miniaturized by
removing the water bath and the heat/cooler exchanger, facilitat-
ing clinical use. Our study did not show any major differences
between normothermic or hypothermic ECS of the DCD. Despite
the fact that organ metabolism is reduced during room tempera-
ture perfusion and BO and UO are affected, but once rewarming
(normothermic ECS) was performed to assess organ viability, BO
and UO were restored. This suggests that a simple, smaller ECS
circuit is appropriate for organ resuscitation in the DCD.
Limitations of the Study
In this study, CA was induced by overdose of KCl or lido-
caine, in healthy anesthetized and paralyzed swine. The clin-
Figure 8. Extracorporeal support (ECS) urine (A) and bile output (B)—heparin study. Error bars ? SEM.
HEPARIN AND ECS TEMPERATURE DURING ORGAN DONATION
ical scenario for this type of donors typically includes a longer
time course to cardiac death after withdrawal of mechanical
support. This includes a period of poor circulation and resul-
tant tissue hypoxia before declaration of death. This may ex-
acerbate organ injury. We did not measure organ weight to
assess edema after ECS; however, solid organs in this acute
model appeared normal with no signs of edema. The majority
of the fluid collection/edema was located in the bowel, soft
tissue, and it was directly related to the extent of the warm
ischemia/CA time and the length of the ECS. In our previous
publications, solid organ edema was not a significant issue.35,36
In addition, organ viability must ultimately be accessed by
transplantation of grafts and long-term assessment of organ
function. Thus, future studies will include an apnea model to
better simulate a clinical scenario and will include long-term
assessment of organ function.
Conclusion. In a swine model of ECS-DCD, liver and kid-
ney were successfully resuscitated by perfusion for 90 minutes
at 38° and 25°C. Heparinization, before and after 5 minutes of
arrest were equally effective with a small effect on ECS flows
when heparin is given 5 minutes after death. Delaying hepa-
rinization until ECS initiation (30 minutes of asystole) does
affect ECS and organ perfusion.
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