OVERVIEW

Ex Vivo Lung Perfusion: A Comprehensive Review of

the Development and Exploration of Future Trends
Marius A. Roman, Sukumaran Nair, Steven Tsui, John Dunning, and Jasvir S. Parmar
There is a critical mismatch between the number of donor lungs available and the demand for lungs for transplantation. This has created unacceptably high waiting-list mortality for lung transplant recipients. Currently (2012)
in the United Kingdom, there are 216 patients on the lung transplant waiting list and 17 on heart and lung transplant
list. The waiting times for suitable lungs average 412 days, with an increasing mortality and morbidity among the
patients on the lung transplant list. Ex vivo lung perfusion (EVLP) has emerged as a technique for the assessment,
resuscitation, and potential repair of suboptimal donor lungs. This is a rapidly developing field with significant
clinical implications. In this review article, we critically appraise the background developments that have led to our
current clinical practice. In particular, we focus on the human and animal experience, the different perfusionventilation strategies, and the impact of different perfusates and leukocyte filters. Finally, we examine EVLP as a
potential research tool. This will provide insight into EVLP and its future development in the field of clinical lung
transplantation.
Keywords: Ex vivo lung perfusion, Lung transplantation, Perfusion, Donor optimization.
(Transplantation 2013;96: 509Y518)

ung transplantation is a therapeutic option for a variety

of end-stage cardiopulmonary conditions. Lung transplantation is dependent on organ availability and their match
with the pool of recipients. Currently, 15% to 20% of lungs
from multiorgan donors are deemed suitable for lung transplantation. Between 2011 and 2012, 175 lung transplants were
performed in the United Kingdom. The waiting times for
suitable lungs are long and average 412 days. This comes with
an unacceptable mortality on the waiting list of up to 25% (1).
There is a critical mismatch between the number of donor
lungs and the demand for clinical transplantation. An increase
in the usability of lungs would improve the waiting-list mortality and morbidity. To address this mismatch, two approaches have been considered.

The authors declare no funding or conflicts of interest.

Department of Transplantation, Papworth Hospital NHS Foundation Trust,
Cambridge, United Kingdom.
Address correspondence to: Jasvir S. Parmar, Ph.D., F.R.C.P., Department of
Transplantation, Papworth Hospital NHS Foundation Trust, Papworth
Everard, Cambridgeshire, UK CB23 3RE.
E-mail: jasvir.parmar@papworth.nhs.uk
M.A.R. participated in the data collection, writing and review of the article,
performance of the research, and data analysis. S.N. participated in the
research design, writing and review of the article, and data analysis. S.T.
and J.D. participated in the writing and review of the article. J.S.P.
participated in the research design, writing and review of the article, and
data analysis.
Received 25 February 2013. Revision requested 28 December 2012.
Accepted 5 April 2013.
Copyright * 2013 by Lippincott Williams & Wilkins
ISSN: 0041-1337/13/9606-509
DOI: 10.1097/TP.0b013e318295eeb7

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& Volume 96, Number 6, September 27, 2013

One approach aiding the increase of the donor pool

has been the use of lungs retrieved from donation after
cardiac death (DCD) patients in addition to the routinely
used donation after brain death donors (DBD). Between
2011 and 2012, 436 DCD donors have been reported from a
total of 1088 organ donors, representing a significant amount
from the current donor pool (1). Reports suggest equivalent
short-term survival rates (2). Interestingly, there are reports of
improved inflammatory profiles in DCD lungs attributed to
the avoidance of cytokine storm encountered in DBD lungs
(3). One of the disadvantages of using DCD lungs is the insufficient evaluation time for the retrieval team to make a full
assessment. Ex vivo lung perfusion (EVLP) has emerged as a
technique to aid in this assessment.
Carrel and Lindbergh described the first normothermic ex vivo organ perfusion as early as 1935. Using cat and
rabbits as models, they have explanted thyroid glands with
their vascular pedicle and perfused in a Lindbergh apparatus
for up to a week. This proof of principle demonstrated that
organs could remain viable ex vivo for several days (4). In
2001, Steen et al. (5) used a blood-based perfusate to recondition lungs ex vivo from a DCD donor. Acellular perfusates
were pioneered, the technique being refined by using a
bloodless perfusion with Steen solution, a perfusate with optimal osmolarity and high dextran content (6).
The EVLP circuit (Fig. 1) consists of a centrifugal or
roller pump (a) that circulates the perfusate, while passing
through a membrane gas exchanger (b) and a leukocyte depletion filter (c), before entering the pulmonary artery. A filtered gas line for the gas-exchange membrane is connected to
a tank (d) with a special gas mixture of oxygen (6%), carbon
dioxide (8%), and nitrogen (86%). The heater/cooler (e)
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FIGURE 1. EVLP circuit. A centrifugal pump (a) is circulating the acellular perfusate, passing through a membrane gas
exchanger (b) and a leukocyte depletion filter (c), before entering the lung block through the pulmonary artery. A filtered
gas line for the gas-exchange membrane is connected to an H-size tank (d) with a special gas mixture of oxygen (6%), carbon
dioxide (8%), and nitrogen (86%). The heat/cooler (e) is connected to the membrane gas exchanger to maintain the
perfusate at the protocol temperature. Pulmonary artery flow is controlled by the centrifugal pump and measured using an
electromagnetic flow meter (f ). The outflow perfusate returns through the left atrial cannula to a hard-shell reservoir (g).
Catheters placed in situ continuously measure PAPs and left atrial pressures that are being controlled at desired values.
Temperature is measured via a temperature probe (h) to maintain the desired normothermia. Lungs are ventilated with a
standard ventilator (i), with settings specific to the protocol used. The lungs are contained in a special covered bath. During
the procedure bronchoscopies, BAL and biopsies are carried out. During EVLP, two phases are carried out: (1) priming in
which the gate clamp ( j) is applied and the shunt (k) is open and (2) reconditioning where the shunt is clamped and gate
clamp is removed.

warms the perfusate to the desired temperature. Pulmonary

artery flow is measured using an electromagnetic flow meter
(f ). The outflow perfusate returns through the left atrial
cannula or open atrium to a hard-shell reservoir (g). Catheters
placed in situ continuously measure pulmonary artery pressures (PAP) and left atrial pressures. A temperature probe
monitors the circuit temperature (h). The lungs are ventilated
with a standard intensive care unit ventilator (i) with settings
specific to the protocol used. The lungs are contained in a
special covered bath. During the procedure bronchoscopies,

bronchoalveolar lavage (BAL) and biopsies are carried out (7).

The entire duration of EVLP can be divided into three phases:
(1) priming phase, at which stage the gate clamp (j) is applied
and the shunt (k) is open; (2) reconditioning phase, at which
stage the shunt is clamped and gate clamp removed; and (3)
evaluation, when the lungs are being assessed while ventilated
on 100% oxygen.
The objective of our review is to summarize the current evidence on experimental and clinical EVLP existing
in the literature as well as identify the future trends and

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development needed in the technique and equipment. We

have searched MEDLINE and EMBASE databases between
year 1990 and October 2012 using the following search
terms individually or combined: ex, vivo, lung, perfusion, and
transplantation. From the reviewed literature, 4.1% were level
A evidence articles, 87.6% are level B evidence articles, and
8.2% were level C articles. We have included in the level A
evidence group one review article and one nonrandomized
control study (HELP Trial) with its 1- and 3-year follow-up
reports. We will review the studies that have contributed
significantly to the development of EVLP, excluding case
report publications (level C evidence) or publications
unrelated to EVLP. Through this, we are able to provide an
insight into the possible future directions in the development of this procedure.

ANIMAL RESEARCH MODELS

The porcine model offers the closest relationship to the
human lung and is the preferred animal model (8). Using this
model, Steen et al. (9) studied DCD lungs, which have been
shown to be transplantable after 6 hr of cooling and 60 min
of EVLP assessment. The mode of death of the animal has
importance in early allograft function. Ventricular fibrillation
and asphyxia in DCD rat models were compared in a 75-min
ex vivo circuit setting. Asphyxia affects lung more severely
than ventricular fibrillation. This is attributed to the development of pulmonary edema, damage of alveolar wall, and
type 2 pneumocyte rather than inflammatory cytokines (10).
Perfusate and Preservative Composition
In a rabbit model, Chang et al. (11, 12) demonstrated
that a perfusate with a concentration 5 g/dL albumin reduces edema formation compared with a 0.1 g/dL solution.
Avsar et al. (13) concluded in a pig model that lung architecture and oxygenation were satisfactory using hyperoncotic
nonalbumin solution. Comparisons of Perfadex with other
perfusates, such as the Kyoto perfusates (14), showed no difference in pulmonary vascular resistance (PVR) and oxygenation. Initially, Steen et al. (9) as well as others (15, 16)
popularized cellular perfusion for EVLP. An acellular perfusate reduces the incidence of red cell lysis and may avoid
mechanical lung injury over extended periods of lung perfusion (17, 18).
Theoretically, the perfusate should be replenished periodically to prevent accumulation of circulating inflammatory mediators; however, in a ventilator-induced lung injury
mouse model, there was no evidence that cytokines impair
lung compliance or worsen lung injury (19). The routine
change of perfusate remains debatable. There are data
suggesting that the removal of a quantity of the perfusate
may avoid hyperkalemia (14).
Different preservation solutions have been evaluated
as alternatives to the standard Perfadex. Perfadex led to
better graft function when compared with saline as shown
by Inci et al. (20) in their porcine DCD model study (n=5).
They have shown reduced PVR, improved graft function,
and reduced proteins and nitrites with Perfadex perfusion
for up to 3 hr. SCOT-15, a low potassium fluid, had lower
PVR and no difference in lung edema (21). Menezes et al.
(22), in a rodent model, showed that both Celsior and
normal saline lead to an increase in lung edema. Interestingly,

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511

the PVR in the Celsior group remained low but went up in the
saline group. Low potassium dextran glucose solutions
(LPDG) in comparison with Perfadex have been shown to
cause worsening of lung mechanics and edema but had no
effect on gas exchange (23).
Based on these studies, the ideal perfusate should be
hyperosmolar and hyperoncotic and maintain an adequate
supply of energy and electrolytes (24). Current opinions
support acellular perfusates, which have the advantage of less
edema and better lung mechanics. There is an ongoing debate
over the role of non-albumin-based solutions in comparison
with albumin solution (LPDG solution).
Perfusion-Ventilation Protocols
Comparing flush preservation (preservation of lungs
after retrieval by using Perfadex perfusion) against static
cold storage (SCS) (storage of lungs on ice at 4-C), Erasmus
et al. (25) demonstrated increased macroscopic edema with
the SCS in lungs subjected to EVLP. Nakajima et al. (26) had
similar findings in a beagle-dog model but also demonstrated
improved pulmonary compliance and wet/dry ratios (ratio
between the weight of a lung sample and the weight of the
same sample after being dried in an oven at 65-C for 48 hr)
using flush preservation.
An interesting finding by Wipp et al. (27) shows that,
using the rotary pump in comparison with a centrifugal
pump, the pulmonary deflation index was significantly better
with correspondingly lower wet/dry ratios; however, there was
no significant difference in oxygenation, pulmonary compliance, or PVR.
In a rat model, Fisher et al. (28) demonstrated that low
flow perfusion at 12 mL/g/min was superior to 25 mL/g/min
in protecting from pulmonary edema. Sasaki et al. (29), in
their rabbit model, tested different perfusion pressures,
concluding that 10 to 15 mmHg pressures were not associated with pulmonary edema, whereas less than 5 or more
than 20 mmHg resulted in increased pulmonary edema and
poor function of the lung. The transpulmonary pressure
gradient (the difference between the alveolar and intrapleural
pressures) influences capillary permeability and edema formation. Endothelial injury and interstitial edema rise as the
transpulmonary pressure gradient increases from 5 to 20 cm
H2O (30).
With a low pressure perfusion protocol (40% of cardiac output), Cypel et al. (7) demonstrated satisfactory lung
function after ex vivo perfusion of both pig and human
lungs for up to 12 hr.
A protective mode of mechanical ventilation is preferred
during EVLP with low ventilation volumes (6Y8 mL/kg) and
repeated alveolar recruitment maneuvers.
Lung Metabolism
Lung tissue is rich in lactate dehydrogenase, which
catalyses the conversion of pyruvate plus NADH into lactate
plus NAD+. Lactate inhibits glycolysis and can thereby affect lung viability by reducing glucose availability. One of
the findings in lung metabolism is the high level of lactate
produced (31). Using standardized human EVLP protocol
in a porcine model, Valenza et al. (32), demonstrated that
high glucose consumption determined worse lung function
and lung edema. Although lactate production and washout
is a continuous process, lactate/pyruvate (L/P) and glucose

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levels could be indicators for poor prognosis, as shown in

a porcine model by Koike et al. They have found that L/P
ratios were significantly higher at 4 hr for the rejected lungs
(33, 34).
In a rodent model, hypothermic EVLP decreased PVR
and increased oxygenation and pulmonary compliance. This
prevented ischemic reperfusion injury, being associated with
a decreased production of reactive oxygen species (21).
Lung Performance: Methods to Improve Lung
Function and Viability
EVLP opens up a number of possible therapeutic avenues. In a randomized study, salbutamol or placebo was
infused in a porcine model. Reduction in PAPs (16 vs. 21),
improved oxygenation, and lung mechanics were found in
the treatment group (28). Adenosine A2A agonist has been
shown to decrease wet/dry ratios and inflammatory cytokines
such as interferon-F, interleukin (IL)-1A, IL-6, and IL-8 when
used during EVLP (35).
In an acute lung injury porcine model, methylprednisolone and clarithromycin did not show any improvement
in lung edema, PVR, or lung compliance (36). Cardoso et al.
(37), in a rodent model, showed that intravenous and inhaled prostaglandin I2 administration was beneficial to lung
mechanics and reduced PAP when compared with saline.
Prophylactic surfactant inhalation has been shown to improve pulmonary compliance, decrease PVR associated with
an increase in ATP levels, and decrease mRNA of IL-6 and
IL-6/IL-10 ratios.
Preliminary evidence suggests promise in soluble trisaccharide polymer (GAS914) to bind >-Gal antibodies and
thus protect lung xenografts from hyperacute rejection. A
lower incidence of hyperacute rejection was noted in a
porcine model perfused with GAS914 (38).
Nitric oxide (NO) was found to have no effect on NO
synthase (39, 40) or reducing the effects of ischemiareperfusion injury and capillary leak in a DCD rodent
model. This was correlated with a reduction of the wet/dry
ratio and an increase in current good manufacturing practices (41).
Multiple other potential avenues are available for EVLP.
Gene vector delivery is tantalizing. Yeung et al. (42, 43)
performed adenoviral transfer of human IL-10 gene to pigs
randomized to ex vivo or in vivo groups, noting increased
lung function and reduced inflammation in the ex vivo group.
Another alternative in reducing pulmonary inflammation is
neutrophil elastase inhibitor (44Y46).
We consider EVLP as an active treatment for marginal
lungs before transplantation. Currently, there is limited evidence for adjunct interventions that improve success rates.
Current protocols use heparin, steroids, and antibiotics empirically in the perfusate.
EVLP as a Research Tool
Attempts have been made to use EVLP to reverse lung
injury in animal models of DBD and DCD (47Y49). Gastric
aspiration and its toxic effects in the airway are well known,
although human gastric aspiration is far more complex
compared with the animal models studied using hydrochloric
acidYinduced airway injury (48, 49).
Meers et al. (50) demonstrated in a porcine model that
EVLP could be used for 2 hr in lungs injured with gastric

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acid. These lungs had pulmonary edema, elevated PVR, and

lower compliance. In further studies, the authors also showed
(49, 51) impaired oxygenation and increased inflammatory
response to gastric acid injury. In addition, EVLP can be used
to detect features of gastric aspiration in the donor lung and
may predict early graft dysfunction (47).
Sahara et al. (52) have used human blood perfusion in
a GalT-KO (galactosyl transferase gene knockout) porcine
versus wild-type. They showed that PVR had a smaller increase in the GalT-KO group. However, this study did not
investigate the extravascular lung water content. It is proposed that the decrease in complement (C3a), platelet activation, and intrapulmonary platelet deposition protect
the lung from injury (53).

TRANSITION FROM ANIMAL MODELS

TO CLINICAL PRACTICE
Since the first EVLP performed in 2001 by Steen et al.,
this procedure has been adopted in selected centers. Because
the concept was novel, animal studies were vital to prove
safety and efficacy of this technique. In a 5-year retrospective
study, Cypel et al. (54) have shown that 15% to 20% of lungs
transplanted after EVLP were procured from DCD donors,
with similar outcomes when compared with DBD lungs.
Then, 30-day, 1-year, and 3-year proportional survival rates
were 95.7%, 84%, and 70%, respectively, in the DBD group
and 95%, 85%, and 64%, respectively, in the DCD group
(P90.05). Increasing numbers of DCD lungs are being resuscitated using EVLP following publication of retrospective
(54, 55) and prospective studies (56).
Perfusate and Preservative Composition
Early studies used a red cellYbased perfusate (7, 9, 57).
Although cellular perfusate has improved buffering, it has
the disadvantage of being more difficult to procure and the
risk of hemolysis during EVLP. Because the method evolved
with evidence from animal and human models, the use of
acellular perfusate and preservation became the method of
choice for EVLP (34, 58, 59). Steen solution is currently the
most commonly used acellular perfusate in EVLP (7, 57, 60).
Egan et al. (61) reported in their study that using Steen
solution during EVLP decreases the wet/dry ratios, with an
increase in the PO2/FiO2 ratios. Different lung preservation
solutions have been studied, several in animal and human
models (59). Euro-Collins and University of Wisconsin as
intracellular preservation solutions have been compared with
extracellular Perfadex and Papworth solutions in a French
multicenter study, showing a decrease in reperfusion edema
when using extracellular-based preservation solutions (62).
Other studies, comparing Euro-Collins with LPDG solution,
show evidence in favor of LPDG solution in terms of early
outcome, early oxygenation (63), lung compliance, and severe
primary graft dysfunction (50, 64Y66).
The evidence for combined human and animal models
suggest that hyperoncotic albumin-based solutions are superior perfusates used in EVLP. Perfadex showed less graft
dysfunction rates and is currently widely used as the preservation solution. Despite the buffering and oxygen delivery
advantages, the use of blood as part of the perfusate is more
infrequent in reporting centers.

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Perfusion-Ventilation Protocols
The best-established and most widely practiced protocols are the Lund and Toronto protocols (7, 60, 67, 68). The
two protocols have a difference in approach to temperature
regulation, perfusion, and ventilation strategies (Fig. 2).
The Lund protocol is based on a gradual increase in
temperature based on set points of temperature, whereas the
Toronto protocol aims for increasing temperatures at set
points of time. The maximum flow rate achieved in the
Lund protocol is 100% of cardiac output, whereas this is
only 40% to 60% of cardiac output in the Toronto protocol.
In both protocols, the maximum flow rate of the perfusate
is limited by a preset safe upper limit for PAP. In the reconditioning phase, the Lund protocol uses a FiO2 of 50%,
whereas the Toronto protocol uses 21%. The ventilation is
initiated at 32-C with tidal volumes and respiratory rates calculated on the weight of the donor at set temperatures in the
Lund protocol, whereas the Toronto and protocol uses 7 mL/kg
tidal volumes and a fixed number of breaths per minute.
There is consensus that ventilation should be lung
protective and that prolonged use of high flows of oxygen
can be detrimental. Currently, there are no data comparing
the two perfusion protocols, but we consider that challenging lungs at 100% of CO continuous flows is intuitive
because it reproduces graft behavior after transplantation.
Measuring the Impact of Leukocyte Filters
The role of leukocyte filters in the EVLP circuit is to
remove circulating inflammatory cells from the perfusate.
Leukocyte filters are a key component of the EVLP circuitry,
and its value has been confirmed in animal studies (69, 70).
Current models used are short-period use filters (G30 min).
Intracapillary pools of proinflammatory cytokines (IL-1A,

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513

IL-6, IL-8, and tumor necrosis factor [TNF]->) have been

identified to contribute to the lung injury during prolonged
lung perfusion (71). Kakishita et al. (69, 72) demonstrated a
significant reduction of IL-8 and TNF-> levels in the perfusate and lung tissue by using an adsorbent membrane
in a porcine model. However, this failed to yield any improvement in lung function after EVLP.
Fildes et al. (73) reported an increased percentage of
nonclassic monocytes (NCM, CD14+, and CD163j/+) cells
in the leukocyte filters in a porcine model by using flow
cytometry. Donor-derived monocytes contribute significantly to the initiation and progression of immune reactions leading to rejection episodes after transplantation
(74). Fildes et al. (70) showed that leukocyte filters remove
lung-derived nonclassic monocytes, representing 80% of
the circulating cell population in a porcine EVLP model.
This raises the possibility that EVLP donor lungs could be
less immunogenic than standard lungs (74).
Cytokine profiling studies of EVLP perfusate demonstrated an increase in the levels of IL-6, IL-8, granulocyte colony-stimulating factor, and monocyte chemotactic
protein-1. IL-1A, IL-4, IL-7, IL-12, interferon-F, and TNF->
remain unchanged during EVLP. This variation in cytokine
levels in the EVLP perfusate did not lead to pulmonary
edema or acute lung injury in a recent study (75). The rise
in EVLP perfusate levels of IL-6, IL-8, and IL-10 was observed mainly during the first 6 hr of EVLP and this was
attributed to a washout effect of the perfusate (58).
Current limited data show that leukocyte filters are
beneficial for removing inflammatory cells, which would
potentially differentiate into macrophages or dendritic cells.
Further studies in both animal and human models are needed
to confirm or infirm similar cell populations in EVLP models.

FIGURE 2. Comparison between Lund/Toronto EVLP protocols. The Lund protocol re-warms the lungs with set point temperatures, within 10- of venous perfusate temperature, whereas the Toronto protocol aims for increasing temperatures at set
points of time. The flow increases up to 100% of the cardiac output for Lund and up to 40% for Toronto while maintaining PAPs
under 20 and 10 to 15 mmHg, respectively. The ventilatory strategies are devised in a lung-protective fashion, with a controlled
FiO2, respiratory rate, and tidal volumes. Ventilation is initiated at 32-C. The Lund protocol tidal volumes and respiratory rates
are calculated at set temperatures, being representative for a 60 kg patient, whereas the Toronto protocol uses set values.

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There is an interest in evaluating the degranulation changes

in behavior of the leukocyte cells trapped inside the filters
in time.
Assessing the Potential of EVLP Lungs
for Transplant
A number of potential biomarkers for lung viability
have been studied during EVLP. Lactate metabolism in
the normal and the injured lung has been investigated and
reported in the past (76, 77). In a 12 lung cohort, Koike et al.
(34) demonstrated an increased level of lactate in human
lungs rejected for transplantation during EVLP. However,
in a latter larger study (24 lungs), the same authors could
find no correlation between the L/P ratio and early posttransplantation outcomes (78). These conflicting observations
are thought to represent a reduced lactate clearance.
Early studies have provided evidence for the use of
EVLP in marginal lungs (79Y81). In a 13 lungs prospective
study, Aigner et al. (82) showed suitability for transplant
of 9 lungs with no incidence of primary graft dysfunction
grade 2 or 3.
Wallinder et al., in a retrospective study, subjected to
EVLP seven bilateral lungs that were found unsuitable due
to pulmonary embolism (1) and chest infection (4). They
have found no posttransplantation difference in $PO2/FiO2
ratio, time to extubation, ITU length of stay, or mortality
when compared with standard lung transplants (57). Zych
et al. (83) reported a 100% survival rate at 3 months using
the Toronto protocol.
Endogenous NO synthase levels are higher in transplantable lungs, compared with the ones that are not successfully reconditioned with EVLP, and could potentially be
used as an early predictive marker for allograft function
(84). Medeiros et al. (18), when investigating the histologic

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changes during EVLP, reported no deterioration in lung tissue

structure after 1 hr of EVLP and a decrease in the number of
apoptotic cells.
An interesting microarray study, has found that during
EVLP genes involved in inflammation are down-regulated
(CCL5, CCR2, CCR5, CCL17, and TLR7) and genes involved
in cell signaling become up-regulated (SMAD3, HMGA1, and
FOXE3). This change in the gene expression profile may help
to explain the reduced rate of primary graft dysfunction (85).
A genome-wide RNA expression study, comparing DBD and
DCD lungs exposed to EVLP, showed initially higher expression of inflammatory genes in the DBD group. The largest
differences were noted in CSF3, IL8, IL6, and CXCL2. These
were reduced to three differences after EVLP when comparing
DBD and DCD and furthermore to one difference after transplantation (55). This is pointing to a potentially beneficial effect
of EVLP on the inflammation in resuscitated lungs.
Evidence shows that the suitability of post-EVLP lungs
for transplant is based on oxygenation capacity, inspection
and palpation, PVR, and compliance. No other markers have
been yet convincing as predictors for graft function despite
the multiple avenues explored.

CURRENT EVLP TRIALS AND

PROSPECTIVE STUDIES
The HELP Trial was a nonrandomized controlled trial
conducted by the Cypel et al. (56). This trial described 16
recipients transplanted using EVLP lungs and a control group
of 86 SCS (Fig. 3). The findings were encouraging, with 6%
primary graft dysfunction and comparable hospital and intensive care unit length of stay between both groups. This trial
suggested that the early clinical outcome of lungs subjected
to EVLP was similar to SCS. Cypel et al. subsequently reported

FIGURE 3. HELP Trial distribution. Cdyn denotes dynamic compliance; PO2/FiO2 ratio of the partial pressure of oxygen
to the fraction of inspired oxygen. Twenty-three EVLP assessments have been completed, with 20 transplants being
performed after EVLP, and compared with the outcomes of 116 standard lung transplants (68).

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* 2013 Lippincott Williams & Wilkins

1-year results of the original cohort of patients confirming

comparable survival rates between the groups and minimal
bronchial complications in the EVLP group (86). When analyzing retrospectively the last 50 cases of EVLP from a total of
317 lung transplants, Cypel et al. (87) showed similar survival
rates at 1 and 3 years between the EVLP reconditioned lungs
and standard transplanted lungs, with a lower rate of PGD 3.
A randomized control trial is awaited, but it would be difficult
to conduct from an ethical point of view, because the lungs
subjected to EVLP are marginal lungs that are normally not
accepted for standard transplantation. The number of cases
reported in the HELP Trial is currently the highest reported in
human EVLP literature, but power calculations or statistical
significance reports are still awaited.
In 2011, Fildes et al. (88) reported results of an open
multicenter trial, selecting 20 patients, with 8 EVLP transplants and 12 standard transplant patients. The composite
endpoint was the incidence of infection and acute rejection.
They reported significantly more acute rejection episodes
in the standard group at 3 and 12 months. No difference was
found in early and 1-year survival rates. They concluded
that posttransplantation rejection episodes might be reduced by the removal of donor-derived leukocytes, which
directly contribute to alloimmune reactivity. For this reason, the authors have proposed that all donor lungs should
be subjected to EVLP before transplantation. The limitations of the study are the difference in size for the compared
groups as well as the lack of power calculations. Because
the results of this trial have been promising, it has prompted
the start of a larger multicenter trial to add to the current
clinical evidence.
DEVELOP-UK is a nonrandomized trial currently being
undertaken in the United Kingdom to investigate the safety of
EVLP to prove its noninferiority compared with standard
cold preservation. This trial is being undertaken in the United
Kingdom and its results are eagerly awaited. The primary
endpoint of this trial is 30-day survival after lung transplantation. An essential component of this trial will examine the costeffectiveness of EVLP as a tool in clinical transplantation (19).
Despite the different protocols being used in the literature, there is good evidence that EVLP is successful in

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reconditioning marginal lungs. As further studies will emerge,

higher numbers and long-term results will contribute to popularizing the technique.

DISCUSSION AND FUTURE DIRECTIONS

EVLP has shown a great deal of promise, but there remains a need to consolidate its evidence base with randomized
control trials and long-term data. The opportunity to increase
the number of available lungs for transplantation by improving
function of the allograft may help to reduce waiting list mortality rates.
To summarize the current evidence, there are two
different approaches in the EVLP protocol. Whereas the
Toronto protocol uses an acellular Steen-based perfusion
for 4 to 6 hr, with a closed left atrium, flows of 40% to 60%
of cardiac output, and a centrifugal pump, the Scandinavian
group use a blood-based Steen solution (15% hematocrit)
for 4 to 6 hr, with an open atrium at flows of 100% of cardiac output and a roller pump. There is a consensus in
the preservation of the lungs by using Perfadex and cold
transportation on ice before subjecting them to EVLP. The
assessment of the lungs in terms of usability is similar
throughout the literature, by quantifying the PO2/FiO2 ratios, pulmonary edema (wet/dry ratios and X-ray appearance), PVR, lung compliance, and the inspection and palpation
of the lungs. A single efficient predictive parameter for lung
function and primary graft dysfunction incidence after
EVLP is yet to be identified.
Despite promising adjuvant therapies as salbutamol infusion/injection (28), adenosine A2A agonist (35), prostaglandin I2 (37), NO (39, 40), gene vector therapy (42, 43), or
neutrophil elastase inhibitor (46) being experimented in animal
models, none of these have translated into standard clinical
practice. The potential of EVLP as a research tool for novel
therapies in lung transplantation is still to be further explored.
The human evidence shows support for EVLP as a
procedure that allows the usage of marginal lungs (Fig. 4),
despite the two protocols used. Larger multicenter trials
and a consensus on the optimal protocol are still awaited.
A rise in extravascular lung water has been frequently
described in the donor lung and has a significant impact on

FIGURE 4. Clinical studies investigating the efficiency of EVLP. The table includes all studies that have tried to answer the
question if EVLP is a safe and efficient technique. All of the relevant studies have shown that EVLP is a promising technique
that can provide suitable lungs for transplant. Studies such as the HELP Trial by Cypel et al. showed promising comparative
results between EVLP and standard lung transplantation. The majority of the studies use acellular perfusates, with five of the
studies not specifying in the literature their entire protocol.

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516

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donor lung function. EVLP offers the chance to resuscitate

these lungs and potentially repair them. The currently established protocols offer good outcomes in carefully selected
lungs. However, further modification of perfusion times, types
of perfusates used, ventilation strategies, and indications for
EVLP could increase the number of usable donor lungs.
Pulmonary artery thrombosis in the peri-retrieval
period is one of the encountered complications. Tissue plasminogen activator was tested in rat models to prove a potential
anti-inflammatory effect by neutrophil activation suppression
(89). In the future, tissue plasminogen activator could be further investigated in lung transplant, due to the potential reduction in inflammatory response, as well as an adjunct
treatment in lungs that are being rejected due to pulmonary
thromboembolism, which have been shown to improve with
EVLP only (90).
Mesenchymal stem cell use has shown positive effects
on ischemia-reperfusion injuries of the kidney (91) and liver
(92). This technology could be potentially used for donor
lungs in the EVLP setting as well. Gene therapy as an innovative therapeutic measure has been proposed through
the specific use of AdhIL-10 gene therapy to reduce the inflammatory response in the lung in animal models (42, 43).
A beneficial effect in ex vivo perfused lungs was found by the
use of allogeneic mesenchymal stem cells, which restores
alveolar epithelial fluid transport and improves vascular
permeability. This finding was associated with the secretion
of keratinocyte growth factor (93).
New methods of producing immunotolerated decellularized lungs in mice, pigs, and primates are emerging
(94, 95). Despite the challenges encountered due to the
technical limitations, results show prolonged satisfactory
gas exchange in the biotransplants. This might be the future
in increasing the availability of organs, with EVLP being an
aiding platform.
Donor lung infection is a common complication of
lung transplantation. Administration of antibiotics during
EVLP perfusion in human lungs has proven its benefits.
Meropenem used empirically showed benefit in reducing
microbial load in BAL and subsequently decreased the colony forming units, without its systemic side effects (96). This
could potentially increase the yield of donor lung available.
Arginase activity may be a regulator for pulmonary
function by regulating the synthesis of NO. George et al. (97)
have demonstrated that early administration of a novel arginase inhibitor 2-S-amino-6-boronohexanoic acid determined
a transient increase in dynamic compliance, without change
in tissue arginase levels.
EVLP opens multiple avenues for further developments.
In a decreasing population of donors, it extends the criteria
for usability and assessment of donated lungs. This has shown
its great potential through the promising experience accumulated so far. It is under continuous improvement, providing a great opportunity as a physiologic platform for further
research. Future trials and exploring new therapies will prove
invaluable in defining the future in lung transplantation.

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REFERENCES
1.

NHSBT (2012). Organ Donation and TransplantationVActivity Figures for

the UK as at 7 September 2012. Available at http://www.organdonation.

29.

& Volume 96, Number 6, September 27, 2013

nhs.uk:8001/ukt/statistics/downloads/weekly_stats.pdf. Accessed September

17, 2012.
Wigfield CH, Love RB. Donation after cardiac death lung transplantation outcomes. Curr Opin Organ Transplant 2011; 16: 462.
Cypel M, Yeung J, Keshavjee S. Novel approaches to expanding the
lung donor pool: donation after cardiac death and ex-vivo conditioning. Clin Chest Med 2011; 32: 233.
Carrel A, Lindbergh C. The culture of whole organs. Science 1935; 81: 621.
Steen S, et al. Transplantation of lungs from a non-heart-beating
donor. Lancet 2001; 357: 825.
Steen S, Ingemansson R, Ericksson L. First human transplantation of a
nonacceptable donor lung after reconditioning ex vivo. Ann Thorac
Surg 2007; 83: 2194.
Cypel M, et al. Technique for prolonged normothermic ex vivo lung
perfusion. J Heart Lung Transplant 2008; 27: 1319.
Critser JK, et al. Proceedings of the conference on swine in biomedical
research. ILAR J 2009; 50: 89.
Steen S, et al. Transplantation of lungs from non-heart-beating donors
after functional assessment ex vivo. Ann Thorac Surg 2003; 76: 244.
Yamada T, et al. Injury of donor lungs from donation after cardiac
death in various settings; investigation by RT-PCR and pathology.
J Heart Lung Transplant 2010; 29: 1053.
Ohsumi A, et al. Protective effect of pre-recovery surfactant inhalation
on lungs donated after cardiac death in a canine lung transplantation
model. J Heart Lung Transplant 2012; 31: 1136.
Chang R, Wright K, Effros R. Role of albumin in prevention of edema
in perfused rabbit lungs. J Appl Physiol 1981; 50: 1065.
Avsar M, et al. Evaluating a novel albumin free lung perfusion solution in
a swine lung transplant model. J Heart Lung Transplant 2012; 31: 1053.
Okamoto T, et al. Comparison of extracellular-type-Kyoto solution
and Perfadex as a preservation solution in a pig ex vivo lung perfusion
model: impact of potassium level. Transplant Proc 2011; 43: 1525.
Kraft S, et al. Effect of blood and albumin on pulmonary hypertension
and edema in perfused rabbit lungs. J Appl Physiol 1995; 78: 499.
Hauge A, Lunde P, Waaler B. Vasoconstriction in isolated blood-perfused
rabbit lungs and its inhibition by cresols. Acta Physiol Scand 1966; 66: 226.
Pearse D, Sylvester J. Spontaneous injury in isolated sheep lungs:
role of resident polymorphonuclear leukocytes. J Appl Physiol 1992;
72: 2475.
Medeiros I.L, et al. Histologic and functional evaluation of lungs
reconditioned by ex vivo lung perfusion. J Heart Lung Transplant 2012;
31: 305.
UK Clinical Research Network: Portfolio Database. DEVELOPUK: A Study of Donor Ex-Vivo Lung Perfusion in United Kingdom Lung
Transplantation. ISRCTN 44922411, 2012. Available at http://england.ukcrn.
org.uk/StudyDetail.aspx?StudyID=11451. Accessed October 4, 2012.
Inci I, et al. Impact of topical cooling solution and prediction of
pulmonary graft viability from non-heart-beating donors. J Heart
Lung Transplant 2008; 27: 1016.
Nakajima D, et al. Hypothermic ex vivo perfusion prevents ischemia
reperfusion injury in rat lungs from non-heart-beating donors.
J Heart Lung Transplant 2011; 30: S142.
Menezes A, et al. Comparison between lungs preserved for 6 and
12 hours using celsior or perfadex in an ex-vivo perfusion rat lung
model. Heart Surg Forum 2011; 14: S57.
Soares PR, et al. Comparison between Perfadex and locally manufactured
low-potassium dextran solution for pulmonary preservation in an ex vivo
isolated lung perfusion model. Transplant Proc 2011; 43: 84.
Kerr J, et al. Effect of perfusate glucose concentration on rat lung
glycolysis. Am J Physiol 1979; 236: E229.
Erasmus ME, et al. Normothermic ex vivo lung perfusion of nonheart-beating donor lungs in pigs: from pretransplant function analysis towards a 6-h machine preservation. Transpl Int 2006; 19: 589.
Nakajima D, et al. Reconditioning of lungs donated after circulatory
death with normothermic ex vivo lung perfusion. J Heart Lung
Transplant 2012; 31: 187.
Wipp S, et al. Closed or open circuit during ex-vivo lung perfusion for
reconditioning of damaged donor-lungsVwhich shall we use? J Heart
Lung Transplant 2010; 29: S79.
Valenza F, et al. Beta-adrenergic agonist infusion during extracorporeal lung perfusion: effects on glucose concentration in the perfusion
fluid and on lung function. J Heart Lung Transplant 2012; 31: 524.
Sasaki M, et al. Influence of pulmonary arterial pressure during flushing
on lung preservation. Transplantation 1996; 61: 22.

Copyright 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Roman et al.

* 2013 Lippincott Williams & Wilkins

30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.

46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.

Fu Z, Costello M, Tsukimoto K. High lung volume increases stress

failure in pulmonary capillaries. J Appl Physiol 1992; 73: 123.
Ohsumi A, et al. A model explaining genotypic and ontogenetic variation of leaf photosynthetic rate in rice (Oryza sativa) based on leaf
nitrogen content and stomatal conductance. Ann Bot 2007; 99: 265.
Valenza F, et al. The consumption of glucose during ex vivo lung
perfusion correlates with lung edema. Transplant Proc 2011; 43: 993.
Otani N, et al. Enhanced hippocampal neurodegeneration after traumatic
or kainate excitotoxicity in GFAP-null mice. J Clin Neurosci 2006; 13: 934.
Koike T, et al. Lactate production during acellular normothermic ex vivo
pig and human lung perfusion. J Heart Lung Transplant 2010; 29: S96.
Emaminia A, et al. Adenosine A2A agonist improves lung function
during ex vivo lung perfusion. Ann Thorac Surg 2011; 92: 1840.
Meers CM, et al. Preemptive therapy with steroids but not macrolides
improves gas exchange in caustic-injured donor lungs. J Surg Res
2011; 170: e141.
Cardoso PF, et al. An experimental rat model of ex vivo lung perfusion
for the assessment of lungs after prostacyclin administration: inhaled
versus parenteral routes. J Bras Pneumol 2011; 37: 589.
Wiebe K, et al. Potential of an injectable polymer to prevent hyperacute
rejection of ex vivo perfused porcine lungs. Transplantation 2006; 82: 681.
Kurrek MM, et al. Inhaled nitric oxide does not alter endotoxininduced nitric oxide synthase activity during rat lung perfusion.
J Appl Physiol 1995; 79: 1088.
Lindberg L, et al. Inhalation of nitric oxide after lung transplantation.
Ann Thorac Surg 1996; 61: 956.
Dong BM, Abano JB, Egan TM. Nitric oxide ventilation of rat lungs
from non-heart-beating donors improves posttransplant function.
Am J Transplant 2009; 9: 2707.
Yeung JC, et al. Ex vivo adenoviral vector gene delivery results in
decreased vector-associated inflammation pre- and post-lung transplantation in the pig. Mol Ther 2012; 20: 1204.
Cypel M, et al. Functional repair of human donor lungs by IL-10 gene
therapy. Sci Translat Med 2009; 1: 4ra9.
Fujie K, Shinguh Y, Inamura N. Release of neutrophil elastase and its
role in tissue injury in acute inflammation: effect of the elastase inhibitor, FR134043. Eur J Pharmacol 1999; 374: 117.
Yoshikawa S, Tsushima K, Koizumi T. Effects of a synthetic protease
inhibitor (gabexate mesilate) and a neutrophil elastase inhibitor
(sivelestat sodium) on acid-induced lung injury in rats. Eur J
Pharmacol 2010; 641: 220.
Harada M, et al. Neutrophil elastase inhibitor improves lung function
during ex vivo lung perfusion. J Heart Lung Transplant 2012; 31: S221.
Khalife-Hocquemiller T, et al. Ex vivo perfusion worsened lung injuries induced by gastric acid aspiration in rigs. J Heart Lung Transplant
2011; 30: S135.
Wipper S, et al. Ex-vivo repair of donor pig-lungs damaged by aspiration. J Heart Lung Transplant 2009; 28: S237.
Meers CM, et al. A model of ex vivo perfusion of porcine donor lungs
injured by gastric aspiration: a step towards pretransplant reconditioning.
J Surg Res 2011; 170: e159.
Nath D, et al. Does Perfadex affect outcomes in clinical lung transplantation? J Heart Lung Transplant 2005; 24: 2243.
Meers CM, et al. A porcine model to study ex vivo reconditioning of
injured donor lungs. J Surg Res 2011; 166: e175.
Sahara H, et al. Prevention of hyper-acute pulmonary xenograft dysfunction using GalT-KO swine in an ex-vivo lung perfusion model.
Xenotransplantation 2011; 18: 299.
Nguyen BN, et al. Absence of Gal epitope prolongs survival of swine
lungs in an ex vivo model of hyperacute rejection. Xenotransplantation 2011; 18: 94.
Cypel M, et al. 5 years experience with lung donation after cardiac
death. J Heart Lung Transplant 2012; 31: 1053.
Zamel R, et al. Differential gene regulation between brain and cardiac
death donor lungs during ex vivo lung perfusion. J Heart Lung Transplant 2012; 31: S146.
Cypel M, et al. Ex vivo lung perfusion in clinical lung transplantationVthe
HELP trial. J Heart Lung Transplant 2010; 29: S88.
Wallinder A, et al. Ex-vivo perfusion and transplantation of initially
rejected donor lungs. J Heart Lung Transplant 2012; 31: S98.
Karamanou DM, et al. The effect of ex-vivo perfusion on the inflammatory profile of the donor lung. J Heart Lung Transplant 2010;
29: S165.

59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.

517

Van Raemdonck D. Thoracic organs: current preservation technology and

future prospects; part 1: lung. Curr Opin Organ Transplant 2010; 15: 150.
Cypel M, et al. Normothermic ex vivo perfusion prevents lung injury
compared to extended cold preservation for transplantation. Am J
Transplant 2009; 9: 2262.
Egan TM, et al. Ex vivo evaluation of human lungs for transplant
suitability. Ann Thorac Surg 2006; 81: 1205.
Thabut G, et al. Influence of preservation solution on early graft
failure in clinical lung transplantation. Am J Respir Crit Care Med
2001; 164: 1204.
Rega F, et al. Switch from Euro-Collins to Perfadex for pulmonary
graft preservation resulted in superior outcome in transplant recipients. J Heart Lung Transplant 2003; 22: S111.
Oto T, et al. Early outcomes comparing Perfadex, Euro-Collins, and
Papworth solutions in lung transplantation. Ann Thorac Surg 2006;
82: 1842.
Fischer S, et al. Low-potassium dextran preservation solution improves lung function after human lung transplantation. J Thorac
Cardiovasc Surg 2001; 121: 594.
Muller C, et al. Lung procurement by low-potassium dextran and
the effect on preservation injury. Munich Lung Transplant Group.
Transplantation 1999; 68: 1139.
Cypel M, Keshavjee S. Extracorporeal lung perfusion. Curr Opin
Organ Transplant 2011; 16: 469.
Cypel M, et al. Normothermic ex vivo lung perfusion in clinical lung
transplantation. N Engl J Med 2011; 364: 1431.
Kakishita T, et al. Suppression of inflammatory cytokines during
ex vivo lung perfusion with an adsorbent membrane. Ann Thorac Surg
2010; 89: 1773.
Fildes JE, et al. Ex-vivo lung perfusion reduces graft immunogenicity
via the removal of passenger monocytesVa porcine model. Transpl
Int 2011; 24: 0934.
Takai T, et al. Detection of a quantitative trait locus controlling carbon
isotope discrimination and its contribution to stomatal conductance
in japonica rice. Theor Appl Genet 2009; 118: 1401.
Yamamoto K, et al. Long-term survival after video-assisted thoracic surgery lobectomy for primary lung cancer. Ann Thorac Surg 2010; 89: 353.
Fildes JE, et al. Ex-vivo lung perfusion reduces graft immunogenicity
via the removal of passenger monocytes-a porcine model. Transpl Int
2011; 24: 225.
Fildes JE, et al. Ex-vivo lung perfusion removes donor derived nonclassical monocytes that rapidly differentiate into inflammatory dendritic cells? Transpl Int 2011; 24: 72.
Sadaria MR, et al. Cytokine expression profile in human lungs undergoing normothermic ex-vivo lung perfusion. Ann Thorac Surg
2011; 92: 478.
Evans CL, Hsu FY, Kosaka T. Utilization of blood sugar and formation
of lactic acid by the lungs. J Physiol 1934; 82: 41.
Fisher AB, Steinberg H, Bassett D. Energy utilization by the lung. Am J
Med 1974; 57: 437.
Koike T, et al. Kinetics of lactate metabolism during acellular normothermic ex vivo lung perfusion. J Heart Lung Transplant 2011; 30: 1312.
Slama A, et al. Ex vivo LungenperfusionVDer Probelauf vor der Transplantation. Eur Surg 2011; 43: 1682.
Pego-Fernandes PM, et al. Ex vivo lung perfusion: early report of
Brazilian experience. Transplant Proc 2010; 42: 440.
Pego-Fernandes PM, et al. Ex vivo lung evaluation and reconditioning.
Rev Bras Cirurg Cardiovasc 2010; 25: 441.
Aigner C, et al. Clinical ex vivo lung perfusionVpushing the limits.
Am J Transplant 2012; 12: 1839.
Zych B, et al. Early outcomes of bilateral sequential single lung
transplantation after ex-vivo lung evaluation and reconditioning.
J Heart Lung Transplant 2012; 31: 274.
George TJ, et al. Physiologic and biochemical profile of clinically
rejected lungs on a normothermic ex vivo lung perfusion platform.
J Heart Lung Transplant 2012, 31: S105.
Yeung JC, et al. Time-course microarray analysis of rejected human
donor lungs during 12 hours of acellular normothermic ex vivo lung
perfusion. J Heart Lung Transplant 2012; 31: S106.
Cypel M, et al. One year survival and functional status of patients
from the Human Ex vivo Lung Perfusion (HELP) trial. J Heart Lung
Transplant 2011; 30: S8.
Cypel M, et al. Experience with the first 50 ex vivo lung perfusions in
clinical transplantation. J Thorac Cardiovasc Surg 2012; 144: 1200.

Copyright 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

518
88.
89.
90.
91.
92.

www.transplantjournal.com

Transplantation

Fildes JE, et al. Improved clinical outcome of patients transplanted

with reconditioned donor lungs via evlp compared to standard lung
transplantation. Transpl Int 2011; 24: 77.
Stringer K, et al. Tissue plasminogen activator (tPA) inhibits interleukin1 induced acute lung leak. Free Radic Biol Med 1998; 25: 184.
Brown CR, et al. Donor lungs with pulmonary embolism evaluated
with ex vivo lung perfusion. ASAIO J 2012; 58: 432.
Lange C, Togel F, Ittrich H. Administered mesenchymal stem cells
enhance recovery from ischemia/reperfusion-induced acute renal
failure in rats. Kidney Int 2005; 68: 1613.
Kanazawa H, Fujimoto Y, Teratani T. Bone marrow-derived mesenchymal stem cells ameliorate hepatic ischemia reperfusion injury in a
rat model. PLoS One 2011; 6: e19195.

93.
94.
95.
96.
97.

& Volume 96, Number 6, September 27, 2013

Lee J, et al. Allogeneic human mesenchymal stem cells for treatment

of E. coli endotoxin-induced acute lung injury in the ex vivo perfused
human lung. Oric Batk Acad Sci YSA 2009; 106: 16357.
Ott HC, Clippinger B, Conrad C. Regeneration and orthotopic transplantation of a bioartificial lung. Nat Med 2010; 16: 927.
Song J, Kim S, Liu Z. Enhanced in vivo function of bioartificial lungs
in rats. Ann Thorac Surg 2011; 92: 998.
Karamanou DM, et al. The effect of ex-vivo perfusion on the microbiological profile of the donor lung. J Heart Lung Transplant 2010;
29: S94.
George TJ, et al. Novel nebulized arginase inhibitor increases human
lung compliance during normothermic ex vivo lung perfusion. J Heart
Lung Transplant 2012; 31: S106.

Contacting the Editorial Office

To reach the Transplantation Editorial Office, please use the following
contact information:
North American Editorial Office
Manikkam Suthanthiran, MD, Editor
Transplantation
New York-Presbyterian Hospital
Weill Medical College of Cornell University
525 East 68th Street, Box 310
New York, NY 10021, USA
Phone: 1-212-746-4422
Fax: 1-212-746-6894
E-mail: txpl@med.cornell.edu
European Editorial Office
Professor Kathryn J. Wood, Editor
Transplantation
Nuffield Department of Surgery
University of Oxford
John Radcliffe Hospital
Headington, Oxford OX3 9DU, UK
Phone: 44 1865-221310
Fax: 44 1865-763545
E-mail: transplantation@nds.ox.ac.uk

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