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Ex vivo lung perfusion (EVLP) is a preservation method for donor lungs, which keep lungs viable in a physiological environment outside of a body for a short period of time. EVLP is established clinically for lung transplantation. Experimental applications for EVLP are e.g. lung cancer research or medical device development and testing. For preservation, a lung is ventilated artificially in an organ chamber and perfused antegrade through the pulmonary artery. Here we introduce a thermoregulation system for an experimental EVLP system to be used for translational research approaches as well as for training medical staff. To implement physiological culture conditions that are a prerequisite for lung preservation and tissue homeostasis, a thermoregulation is needed to rewarm the explanted lung tissue (storage temperature 4°C). Technically, the EVLP system must be thermally insulated, so loss of caloric is avoided. For monitoring, temperature sensors are integrated within the lung, in the organ chamber and in the afferent perfusate tube, whereby the measured values determine the thermoregulation. Initial tests using thermal packs (cooled to 4-6°C) placed on a heating mat, as a part of the perfusion circuit, showed that the perfusate temperature falls to 34°C, but restores after approximately 60 minutes (36.5°C), whereby the thermal pack is warmed. With this setup longer perfusion times should be obtained rather than without thermoregulation due to normothermic perfusion of the lung.
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Current Directions in Biomedical Engineering 2019;5(1):293-296
Open Access. © 2019 Christina Pongratz et al., published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0 License.
Christina Pongratz*, Jens Ziegle, Axel Boese, Helena Linge, Thorsten Walles, Michael
Friebe
Temperature Controlled and Monitored Ex
Vivo Lung Perfusion System for Research
and Training Purposes
Abstract: Ex vivo lung perfusion (EVLP) is a preservation
method for donor lungs, which keep lungs viable in a
physiological environment outside of a body for a short period
of time. EVLP is established clinically for lung
transplantation. Experimental applications for EVLP are e.g.
lung cancer research or medical device development and
testing. For preservation, a lung is ventilated artificially in an
organ chamber and perfused antegrade through the pulmonary
artery. Here we introduce a thermoregulation system for an
experimental EVLP system to be used for translational
research approaches as well as for training medical staff. To
implement physiological culture conditions that are a
prerequisite for lung preservation and tissue homeostasis, a
thermoregulation is needed to rewarm the explanted lung
tissue (storage temperature 4°C). Technically, the EVLP
system must be thermally insulated, so loss of caloric is
avoided. For monitoring, temperature sensors are integrated
within the lung, in the organ chamber and in the afferent
perfusate tube, whereby the measured values determine the
thermoregulation. Initial tests using thermal packs (cooled to
4-6°C) placed on a heating mat, as a part of the perfusion
circuit, showed that the perfusate temperature falls to 34°C,
but restores after approximately 60 minutes (36.5°C), whereby
the thermal pack is warmed. With this setup longer perfusion
times should be obtained rather than without thermoregulation
due to normothermic perfusion of the lung.
Keywords: Ex vivo lung perfusion, ex vivo, lung perfusion,
temperature control, temperature adjustment
https://doi.org/10.1515/cdbme-2019-0074
1 Introduction
Lung transplantation has been established as the ultimate
solution for patients with end-stage lung diseases. Due to a
rising number of patients awaiting lung transplantation on one
hand, and an increasing shortage of donor lungs on the other
hand, about 50% of listed patients die while waiting for a
transplantation [1–3]. Moreover, many donor lungs deteriorate
following explantation and only 15-20% of donated lungs
fulfill the functional requirements for lung transplantation
[2,4,5]. To increase the number of transplantations, the quality
of explanted donor lungs must be enhanced [2].
Ex vivo lung perfusion (EVLP) is a lung-preservation
technique, where the donor lung is perfused and ventilated
outside of the living body at body temperature for several
hours. Commercially available EVLP systems mimic real
physiologic conditions, for example, the provision of nutrients
using a perfusion solution instead of blood, called perfusate,
the body temperature by implementing a temperature
adjustment and the ventilation of the lung using a ventilator.
Using EVLP, a more accurate evaluation and eventually a
reconditioning of potential donor lungs can be achieved [1, 4].
If pulmonary parameters are restored, it is possible to
transplant this donor lung with a good outcome for the patient.
Preclinical studies show that after a treatment using EVLP,
both, normal and injured lungs, showed excellent lung
function after transplantation. [4]
2 State of the art
There are four commercialized systems available on the
market: the XPS™ system (XVIVO Perfusion, Göteborg,
Sweden), LS1 (Vivoline Medical, Göteborg, Sweden), Lung
Assist (Organ Assist, Groningen, Netherlands) and Organ
Care System™ Lung (TransMedics, Andover, Massachusetts,
U.S.A.) [6]. All systems are slightly different in their setup and
in their concept of clinical use. The XPS™ is a device, which
______
*Corresponding author: Christina Pongratz: INKA Institute of
Medical Technology, Otto-von-Guericke-University (OVGU),
Magdeburg, Germany, e-mail: christina.pongratz@ovgu.de
Jens Ziegle, Axel Boese, Michael Friebe: INKA Institute of
Medical Technology, OVGU, Magdeburg, Germany
Helena Linge, Thorsten Walles: Department of Thoracic Surgery,
University Clinic for Cardiac and Thoracic Surgery, Otto-von-
Guericke University, Magdeburg, Germany
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C. Pongratz et al., Temperature Controlled and Monitored Ex Vivo Lung Perfusion System for Research and Training Purposes — 294
was designed for the requirements of the Toronto lung
transplantation protocol. The LS1 (or LS) system from
Vivoline Medical and the Lung Assist are other static systems.
The most recent commercial system, the Organ Care System™
Lung, is, as opposed to the other three systems, a portable
system. [6 – 10]
At the Magdeburg University, an EVLP system has been
developed for translational research purposes and medical
training. Specifications of this prototype are: 1. Lean design to
afford transportation, 2. easy-to-use, 3. cost-effectiveness by
implementation of clinically established components and
devices, and 4. open design to facilitate technical
modifications and re-arrangements according to intended
research application.
3 Materials and methods
The goal of this work, was to develop temperature
monitoring and adjustment of the perfusate running through
the explanted lung to mimic body temperature within the
EVLP system, to improve biological function and outcome
and increase perfusion times. The temperature of the organ
should reach a temperature of 35°C with a range of ±2°C with
a permanent temperature of 36°C to 37°C. A new setup of the
system is necessary to prevent loss of caloric and to allow
heating of the perfusate.
3.1 Organ chamber
For the development of temperature monitoring and
adjustment, a new setup of the organ chamber is necessary, to
minimize the loss of heat during perfusion. Besides the heat
insulation of the organ chamber, appropriate accessories to
interconnect subsystems to the organ chamber are needed. For
a successful imaging of the perfused lung, the organ chamber
must consist of a material with low X-ray absorption,
otherwise the image quality would be limited. The proposed
devices are not permitted to impair the imaging. The new
developed organ chamber is shown in figure 1.
3.2 Perfusion circuit
For the perfusion circuit a heating of the lung through the
perfusate is used. Therefore, the perfusion circuit must be
adjusted, so the perfusate can be slowly heated up to the
intended temperature. The simplest solution is adding counter
flow tubes to the current perfusion circuit. For that, a large tube
carrying the heated water of the thermostat and a small tube,
through which the perfusate flows are necessary. The small
Figure 1: Test setup of the new organ chamber consisting of (1) a
gastronorm box of GN size 2/3, (2) perfusion tube, connected (3) tube
adaptor, (4) endotracheal tube, (5) clamp for the endotracheal tube, (6)
heat and moisture exchanger, (7) patient valve, (8) bacteria filter, (9)
Pt1000 sensor for leaking perfusate temperature, (10) Pt1000 sensor for
air temperature in organ chamber, (11) cable sleeves, (12) transducers,
(13) grid for avoiding an occlusion of the (14) effluent, (15) stillage of the
organ chamber, (16) cool pack as substitute of a 4°C cold lung that is
wrapped around a (17) heating mat.
Figure 2: Overview about the experimental setup of the new perfusion
circuit including the main parts for heating the perfusate. The perfusate
circuit is labelled with green arrows, the heated water circuit with yellow
ones. (1) Roller pump, (2) perfusate reservoir, (3) counter flow tubes, (4)
afferent perfusate tube, (5) Pt100 sensor for adjusting the perfusate
temperature, (6) efferent perfusate tube, (7) Huber CC-E thermostat, (8)
efferent water tube from the Huber thermostat, (9) afferent water tube to
the Huber thermostat
tube needs to have a very thin wall, so the amount of caloric
transmitted through the wall is maximized. The new setup of
the perfusion circuit is shown in figure 2 and for better
visibility, the organ chamber, temperature sensors and stillage
are removed. In the final setup, all parts of the circuit carrying
perfusate are insulated to minimize the loss of caloric.
3.3 Temperature monitoring and
adjustment devices
The new setup includes different temperature sensors, so
the monitoring and adjustment can be achieved. There are
three thermal sensors, one is integrated within the introductory
perfusion tube. This is a Pt100 sensor connected to the Huber
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thermostat. The thermostat adjusts the perfusate temperature
to the desired temperature. Another Pt1000 sensor is based
within the lung, more precisely in the pulmonary vein. Both
sensors, the Pt100 and the Pt1000, indicate how the
temperature of the perfusate reduces whereas the lung
increases its temperature due to heat transfer. The third sensor
is placed within the organ chamber to observe the temperature
within the organ chamber.
For an overview of all measured temperatures, a software
tool was developed that reads all measured temperatures,
shows them in graphic plots and writes the values into log files.
The signals from the Pt1000 thermistors are add to transducers
which finally read out with the software LabVIEW 2018
(National Instruments, Austin, Texas, U.S.A.) via the data
acquisition device NI-DAQ USB-6009 (National Instruments,
Austin, Texas, U.S.A.). In LabVIEW, the voltages are
converted into temperatures using the linearity of Pt1000 and
the correlation between resistance and temperature of the
Pt1000. Finally, the temperatures and corresponding time
stamps are saved into log files.
The third sensor, a Pt100 sensor, is directly plugged into
the Huber thermostat that calculates the temperature
internally. The measured external temperatures are integrated
in LabVIEW by using a serial interface. After configuring the
serial port, a request is sent to the thermostat. The response
contains the desired external temperatures and are saved in the
log file with the corresponding time stamp.
3.4 Verification of the new test setup
The new setup of the EVLP system was tested to verify the
method of warming the porcine lungs using only the perfusate.
To generate a suitable test environment, the setup was reduced
on the main temperature regulatory parts, which include the
organ chamber, the Huber thermostat, appropriate tubes, a
pump and a perfusate reservoir. The measured values were
shown in the running software on the computer.
A substitute for a cold porcine lung was used for the test
setup consisting of an Irrigation Fluid Warming Set (Model
24750, 3M, Maplewood, Minnesota, U.S.A), called heating
mat, and a cool pack (8-10°C). The initial temperature of a
porcine lung is usually about 8-10°C due to preparation
arrangements at room temperature, which was the required
starting point for the cool pack as well. The placement of the
cool pack and heating mat is shown in figure 1.
The heating mat was drained by the perfusate, which
should warm the cool pack up to approximately 35°C. During
this test, the in-house compounded perfusion solution was
substituted with water that had similar behavior within heating
processes.
Before starting a test, the system was warmed, until a
perfusate temperature of at least 35°C was measured (Pt100).
Then, the cool pack was positioned within the organ chamber.
This imitated the maximum warming of the cool pack as it is
happening in the same way in a porcine lung.
4 Results and discussion
We performed three tests with one large cool pack with
nearly the same results. As an example, one graph with
measurements of temperatures is shown in figure 3.
At the beginning of the measurements, the cool pack was
wrapped around the heating mat. The perfusate temperature
was at the beginning about 35.2°C and the air temperature
measured 28°C. The sensor, which measured the cool pack
temperature noticed a large negative gradient of this
temperature and displayed a temperature of about 21.7°C. As
the cool pack was placed within the organ chamber, the air
temperature of the organ chamber decreased, due to a removal
of the organ chamber lid, causing a loss of caloric towards the
surroundings. The perfusate temperature decreased a few
seconds later, because the cooled perfusate needed to pass the
whole circuit until a temperature loss of the perfusate was
noticeable. Sequentially, the cool pack was heated up through
the heating mat and reached a temperature of nearly 34°C. The
air temperature increased continuously up to 30.1°C.
Considering the three tests with cool packs, at all events it
was possible to warm a porcine lung with the actual setup. As
the porcine lungs weighed less than the large cool pack (lung:
approximately 150 g depending on the weight of the pig vs.
cool pack: 386 g) and the porcine lungs have a smaller specific
caloric capacity than the cooling liquid within the cool packs,
it will need less time to warm the porcine lung up to 35°C to
37°C than during the tests with the cool packs. The new EVLP
system setup is suitable for the warming cases, there is enough
caloric transferred from the heated water from the thermostat
to the perfusate. The lid of the organ chamber was useful to
Figure 3: Measured air temperature (red), cool pack temperature (blue)
and perfusate temperature (black) during one test using a cool pack and
the test setup
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C. Pongratz et al., Temperature Controlled and Monitored Ex Vivo Lung Perfusion System for Research and Training Purposes — 296
develop a constant environment regarding a constant
temperature within the organ chamber. Additionally, the usage
of the lid avoided an unnecessary loss of caloric during the
tests.
5 Conclusion
The introduced temperature adjustment works well and a
temperature adjustment of an EVLP device is possible. This
will probably be achieved faster than the warming of the cool
pack, due to a lower specific caloric coefficient, a lower
weight, and a better perfusion of the lung tissue. For validating
the development of edema during EVLP or an impact on the
duration of EVLP by the temperature adjustment further tests
with porcine lungs must be realized.
Regarding the accuracy of the sensors, corrections of the
values might be necessary for a higher accuracy of the
measured values. For now, the transducers of the Pt1000
sensors are calibrated at a temperature of 36°. One of the
transducers could be calibrated to 30°C, as this sensor
measures the air temperature within the organ chamber.
Otherwise, other transducers could be used.
The Pt100 sensor, that adjusts the temperature of the
perfusate, has a high deviation from the real actual value. This
is caused by the variations of this sensor. It is necessary to use
a Pt100 sensor, as it is the only supported type of sensor by the
Huber thermostat. It needs to have a diameter of maximum 2
mm, so the sleeve for this sensor for protecting it from water
is fitting. The used sensor has initially a cable length of only
30 cm. This was lengthened, probably causing a change in the
overall resistance of the Pt100. These adaptions lead to a non-
linear temperature offset, so a simple correction of it could not
be achieved that easy.
The actual implemented electronics are fixed at the stillage
of the organ chamber. Using a housing with at least protection
category IP 55, a protection against dust or water could be
implemented.
As the new setup shall be used in translational research,
there have to be some changes in the process of EVLP.
Regarding the intended Toronto protocol, the warming of the
lung needs to take place before the ventilation is initiated [11].
The perfusion rate should be set to 5 or 6 milliliters per minute
to heat the perfusate as much as possible. After initiating the
ventilation, it is also possible to change the perfusate flow rate,
so the experiment can take place under fixed circumstances.
For further development, more sensors, e.g. pH-sensors,
perfusate pressure sensors or humidity sensors within the
organ chamber, could be included. Further tests can be realized
to prove, whether the implemented temperature adjustment is
suitable for the heating of a porcine lung, to investigate,
whether the temperature adjustment has an impact on the
outcome of the actual EVLP results and whether angiography
can be proceeded with this setup.
Author Statement
Research funding: The author state no funding involved.
Conflict of interest: Authors state no conflict of interest.
Informed consent: Informed consent was not required for this
study. Ethical approval: Ethical approval was not required for
this study.
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Article
Full-text available
Ex vivo lung perfusion (EVLP) is a powerful experimental model for isolated lung research. EVLP allows for the lungs to be manipulated and characterized in an external environment so that the effect of specific ventilation/perfusion variables can be studied independent of other confounding physiologic contributions. At the same time, EVLP allows for normal organ level function and real-time monitoring of pulmonary physiology and mechanics. As a result, this technique provides unique advantages over in vivo and in vitro models. Small and large animal models of EVLP have been developed and each of these models has their strengths and weaknesses. In this manuscript, we provide insight into the relative strengths of each model and describe how the development of advanced EVLP protocols is leading to a novel experimental platform that can be used to answer critical questions in pulmonary physiology and transplant medicine.
Article
Donor lung shortage has been the main reason to the increasing number of patients waiting for lung transplant. Ex vivo lung perfusion (EVLP) is widely expanding technology to assess and prepare the lungs who are considered marginal for transplantation. the outcomes are encouraging and comparable to the lungs transplanted according to the standard criteria. in this article, we will discuss the history of development, the techniques and protocols of ex vivo, and the logics and rationales for ex vivo use.
Article
Backround In Germany only 40–50% of lungs from multiorgan donors are transplanted. Thus, it is of utmost importance to use every potential transplantable organ. Normothermic ex vivo lung perfusion (EVLP) offers the possibility to reevaluate donor lungs that were previously deemed unsuitable for transplantation. Material and methods The technique of normothermic acellular EVLP is described in detail. Especially practical aspects of the handling are addressed. Since January 2016 we have performed 56 lung transplantations. In this period 11 lungs which initially did not conform to the standard criteria were reevaluated by the use of EVLP and of these 9 were transplanted. According to the Toronto protocol the lungs were reconditioned for 4 h. Before lung transplantation (LuTx) the ∆ pO2/FIO2 ratio between arterial and venous perfusion should be >350 mmHg. In a retrospective analysis, we examined donor and recipient data, organ perfusion data and postoperative course. Results The mean age of donors with LuTx was 54 ± 14 years and for non-transplanted donors (non-LuTx) 51 ± 8 years (not significant n. s.). Before explantation the partial oxygen pressure (pO2) with an inspiratory oxygen fraction (FIO2) of 1.0 was: LuTx 324 ± 72 mmHg vs. non-LuTx 382 ± 88 mmHg (n. s.). Donor ventilation time was: LuTx: 104 ± 44 h and non-LuTx 245 ± 180h (n. s.) The ∆ pO2/FIO2 for LuTx after 4 h was 389 ± 49 mmHg and 254 ± 0 mmHg for non-Tx (n. s.). Lungs were transplanted with a mean out of body time after implantation of the second lung of 724 ± 133 min. Postoperative ventilation time was 232 ± 305 h and the length of intensive care stay was 274 ± 293 h. The 30-day mortality was 9% for EVLP recipients. Conclusion Normothermic EVLP procedures can safely be used in the evaluation of lungs initially considered unacceptable for transplantation. This experience from a single center shows that transplantation of 81% of donor lungs initially classified as unsuitable for transplantation is possible. The perioperative results are comparable to standard lung transplantation.
The number of patients listed for lung transplantation largely exceeds the number of available transplantable organs because of both a shortage of organ donors and a low utilization rate of lungs from those donors. A novel strategy of donor lung management - Ex vivo Lung Perfusion (EVLP) - that keeps the organ at physiological protective conditions have shown a great promise to increase lung utilization by re-evaluating, treating, and repairing donor lungs prior to transplantation. Clinical trials using EVLP has shown the method to be safe and allow for reassessment and improvement in function from high risk donor lungs from both brain death and cardiac death donors prior transplantation. Pre-clinical studies have also shown a great potential of EVLP as a platform for the delivery of novel therapies to repair injured organs ex vivo and thus further improve lung transplantation outcomes. Herein we describe detailed steps for a successful EVLP procedure.
Article
Normothermic ex vivo lung perfusion is a novel method to evaluate and improve the function of injured donor lungs. We reviewed our experience with 50 consecutive transplants after ex vivo lung perfusion. A retrospective study using prospectively collected data was performed. High-risk brain death donor lungs (defined as Pao(2)/Fio(2) <300 mm Hg or lungs with radiographic or clinical findings of pulmonary edema) and lungs from cardiac death donors were subjected to 4 to 6 hours of ex vivo lung perfusion. Lungs that achieved stable airway and vascular pressures and Pao(2)/Fio(2) greater than 400 mm Hg during ex vivo lung perfusion were transplanted. The primary end point was the incidence of primary graft dysfunction grade 3 at 72 hours after transplantation. End points were compared with lung transplants not treated with ex vivo lung perfusion (controls). A total of 317 lung transplants were performed during the study period (39 months). Fifty-eight ex vivo lung perfusion procedures were performed, resulting in 50 transplants (86% use). Of these, 22 were from cardiac death donors and 28 were from brain death donors. The mean donor Pao(2)/Fio(2) was 334 mm Hg in the ex vivo lung perfusion group and 452 mm Hg in the control group (P = .0001). The incidence of primary graft dysfunction grade 3 at 72 hours was 2% in the ex vivo lung perfusion group and 8.5% in the control group (P = .14). One patient (2%) in the ex vivo lung perfusion group and 7 patients (2.7%) in the control group required extracorporeal lung support for primary graft dysfunction (P = 1.00). The median time to extubation, intensive care unit stay, and hospital length of stay were 2, 4, and 20 days, respectively, in the ex vivo lung perfusion group and 2, 4, and 23 days, respectively, in the control group (P > .05). Thirty-day mortality (4% in the ex vivo lung perfusion group and 3.5% in the control group, P = 1.00) and 1-year survival (87% in the ex vivo lung perfusion group and 86% in the control group, P = 1.00) were similar in both groups. Transplantation of high-risk donor lungs after 4 to 6 hours of ex vivo lung perfusion is safe, and outcomes are similar to those of conventional transplants. Ex vivo lung perfusion improved our center use of donor lungs, accounting for 20% of our current lung transplant activity.
Article
More than 80% of donor lungs are potentially injured and therefore not considered suitable for transplantation. With the use of normothermic ex vivo lung perfusion (EVLP), the retrieved donor lung can be perfused in an ex vivo circuit, providing an opportunity to reassess its function before transplantation. In this study, we examined the feasibility of transplanting high-risk donor lungs that have undergone EVLP. In this prospective, nonrandomized clinical trial, we subjected lungs considered to be high risk for transplantation to 4 hours of EVLP. High-risk donor lungs were defined by specific criteria, including pulmonary edema and a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PO(2):FIO(2)) less than 300 mm Hg. Lungs with acceptable function were subsequently transplanted. Lungs that were transplanted without EVLP during the same period were used as controls. The primary end point was primary graft dysfunction 72 hours after transplantation. Secondary end points were 30-day mortality, bronchial complications, duration of mechanical ventilation, and length of stay in the intensive care unit and hospital. During the study period, 136 lungs were transplanted. Lungs from 23 donors met the inclusion criteria for EVLP; in 20 of these lungs, physiological function remained stable during EVLP and the median PO(2):FIO(2) ratio increased from 335 mm Hg in the donor lung to 414 and 443 mm Hg at 1 hour and 4 hours of perfusion, respectively (P<0.001). These 20 lungs were transplanted; the other 116 lungs constituted the control group. The incidence of primary graft dysfunction 72 hours after transplantation was 15% in the EVLP group and 30% in the control group (P=0.11). No significant differences were observed for any secondary end points, and no severe adverse events were directly attributable to EVLP. Transplantation of high-risk donor lungs that were physiologically stable during 4 hours of ex vivo perfusion led to results similar to those obtained with conventionally selected lungs. (Funded by Vitrolife; ClinicalTrials.gov number, NCT01190059.).
Animal models of ex vivo lung perfusion as a platform for transplantation research. The Lancet Respiratory Medicine
  • L Munshi
  • S Keshavjee
  • M Cypel
L. Munshi, S. Keshavjee, and M. Cypel. Animal models of ex vivo lung perfusion as a platform for transplantation research. The Lancet Respiratory Medicine; 2013.