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DISCLAIMER: This Overview is published with the intention of providing information of interest. It is
based on information available at the time of research and cannot be expected to cover any
developments arising from subsequent improvements to health technologies. This Overview is based
on a limited literature search and is not a definitive statement on the safety, effectiveness or cost-
effectiveness of the health technology covered.
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This Overview was commissioned by Queensland Health, in its role as the Secretariat of the Health
Policy Advisory Committee on Technology (HealthPACT). The production of this Overview was
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States and Territories, the Australian and New Zealand governments and MSAC. It is a sub-
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This Overview was prepared by Linda Mundy from the HealthPACT Secretariat.
Description of the technology ................................................................................. 1
Licensing, reimbursement and other approval ....................................................... 4
Disease description and associated mortality and morbidity................................. 7
Number of patients ............................................................................................... 10
Current technology ............................................................................................... 13
Diffusion of technology in Australia ...................................................................... 13
Ethical, cultural or religious considerations .......................................................... 14
Evidence and Policy ............................................................................................... 15
Kidney .................................................................................................................... 15
LifePort Kidney Transporter ...................................................................... 16
Cost ............................................................................................ 17
Safety and effectiveness ............................................................ 17
Economic evaluation .................................................................. 21
RM3 and Waves ...................................................................................... 23
Cost ............................................................................................ 24
Safety and effectiveness ............................................................ 25
Economic evaluation.................................................................. 27
Airdrive hypothermic kidney perfusion transport system ..................... 27
Sherpa Pak .............................................................................................. 28
Kidney Assist .............................................................................................. 28
Ongoing research ...................................................................................... 29
Summary ................................................................................................... 30
Lung ....................................................................................................................... 32
XVIVO and XPS lung perfusion systems .................................................. 32
Cost ............................................................................................ 34
Safety and effectiveness ........................................................... 35
Economic evaluation ................................................................. 37
Vivoline LS1 ............................................................................................. 38
Cost ........................................................................................... 39
Safety and effectiveness ........................................................... 39
Organ Care System ................................................................................. 40
Ongoing research ...................................................................................... 42
Summary ................................................................................................... 44
Liver ....................................................................................................................... 45
Liver Assist- Hypothermic Oxygenated PErfusion - HOPE ......................... 46
OrganOx metra ....................................................................................... 47
Ongoing research ...................................................................................... 48
Heart ...................................................................................................................... 49
Organ Care System- OCS HEART .......................................................... 49
LifeCradle HR ........................................................................................... 51
Sherpa Pak .............................................................................................. 52
Ongoing research ...................................................................................... 53
Summary of findings ............................................................................................. 54
HealthPACT assessment ........................................................................................ 54
Search criteria to be used ..................................................................................... 55
References ............................................................................................................. 55
Appendix 1............................................................................................................. 62
Technology, Company and Licensing
Register ID WP186
Technology name New and emerging organ perfusion systems an overview
Patient indication Technologies for the preservation, optimisation and
transportation of solid organs for transplantation which may
maximise the number and condition of organs available to
patients on transplant waiting lists.
Reason for assessment
Innovative technology that may increase the number of organs able to be transplanted,
which in turn may have a significant impact on morbidity and mortality associated with long
organ transplant waiting lists.
Description of the technology
Transplantation is often the only treatment option for patients with end-stage organ failure.
To preserve organ function two strategies have been used: static cold storage (SCS) and
machine perfusion (MP). During the 1970s, hypothermic MP was the method of choice for
the preparation of organs for transplantation. 2 During hypothermic MP a preservative
solution in the temperature range of 0C to 4C is continuously pumped through the organ
at a controlled rate. Depending on the perfusate used, oxygen and nutrients can be
provided to the organ allowing metabolism to continue. In addition, toxins can be removed
if the perfusate is renewed or filtered. 3, 4 By the mid-1980s the use of MP decreased when
several studies found that there was no clear clinical benefit gained from the use of this
more expensive and labour intensive technology to preserve organs, in particular kidneys
from ideal donors, that is, high-quality kidneys, when compared to SCS. SCS then became
the method of choice for the preservation of high-quality organs. 2 During SCS the organ is
flushed through with a perfusion or preservation fluid and then kept on ice for up to 24-
hours, which has the effect of reducing damage to the organ by slowing the metabolic rate
by hypothermia. 5
As with most jurisdictions, the number of patients on the transplant waiting list in Australia
and New Zealand outweighs the number of organs available. Several strategies have been
proposed to increase the number or organs available for transplantation, including the
expansion of donor criteria to those previously deemed unsuitable, such as older donors
(>60 years) or those with pre-existing medical conditions, for example diabetes or high
blood pressure. Another strategy is the use of organs donated after circulatory death (DCD),
also referred to as non-beating heart donors. After withdrawal of therapy, cardiorespiratory
death may usually occur within 60 minutes but may take up to 3-days. Compared to organs
donated after brain death (DBD) which are perfused until the time of preservation, organs
donated after circulatory death may be exposed to long periods of warm ischaemia. The
deprivation of oxygen and nutrients may lead to permanent organ damage, which may
Uncontrolled
Controlled
DCD raises significant ethical and logistical concerns. The decision to withdraw therapy in
potential donors must be taken independently of any consideration of the potential for
DCD. The national protocol for DCD stipulates that a discussion regarding DCD must take
place only after the withdrawal of therapy has been discussed and agreed to by family
members. If DCD is agreed to, a number of ante-mortem interventions may be necessary to
maintain organ viability, determine organ suitability and allow identification of suitable
recipients. These interventions may include the administration of heparin to prevent
thrombi, bronchoscopy and serological tissue typing. 7 It should be noted that individual
Australian states and territories may have enacted laws that prohibit ante-mortem
interventions such as those described.
With the expansion of the donor pool by using marginal organs, the optimisation of organ
viability between retrieval and implantation is of great importance. This need has resulted in
a renewed interest in MP, which, despite higher initial costs, may result in cost-savings from
a reduced risk of delayed graft function and therefore increased graft survival and improved
long-term outcomes when compared to SCS. 2 In the past most MP systems were
hypothermic and designed to preserve kidneys; however more systems are being developed
XVIVO
Listed on the ARTG: 177195
XVIVO Organ Intended to be used as a temporary receptacle for isolated donor lungs in CE marked
Chamber (manual) Distributed by Vitrolife Lung preparation for eventual transplantation into a recipient. Not FDA approved
Pty Ltd, Victoria
XPS Normothermic XPS
Not approved by TGA, FDA or CE Marked
Vivoline Medical, Lund, Intended for ex-vivo reconditioning, evaluation and preservation of lungs after Listed on the ARTG: 188872 and 188873
Sweden. Distributed by donation and before transplantation for up to 24 hours. (chamber set)
Vivoline LS1 Lung
Magee Medical Pty Ltd CE marked
Normothermic
(NSW, Australia) Not FDA approved
A portable perfusion, ventilation, and monitoring system used to support and Listed on the ARTG: 146269 (organ not
OCS HEART maintain an organ in a near-physiologic state especially during transport to the specified)
Organ Care System Transmedics Pty Ltd
OCS LUNG receiver hospital until it is transplanted. CE marked
Normothermic Not FDA approved
Kidney: Kidney:
Organ Recovery Listed on the ARTG: 164957
A portable MP unit designed to contain and perfuse a transplantable kidney under
Systems Inc (Chicago FDA approval in 2003
Kidney cold and aseptic conditions.
LifePort Kidney USA) European CE mark in 2004
Transporter Distributed by Emergo Liver Hypothermic
Asia Pacific Pty Ltd Liver:
In use at the Princess Alexandria Hospital in Queensland Submission to the FDA
(Sydney, Australia)
Kidney Assist Portable oxygenated hypothermic MP for kidney, lung and liver.
Lung Assist Organ Assist, Kidney
Liver Assist Groningen, The Lung ECOPS: Extra Corporal Organ Perfusion System of Organ Assist. For pulsatile,
All CE marked
Netherlands Liver normothermic and oxygenated perfusion of in-situ abdominal donor organs (liver,
ECOPS kidneys, small bowel and pancreas).
Portable Organ
Airdrive Perfusion, Amsterdam, Kidney A portable, disposable sterile hypothermic organ perfusion transport system. CE marked
The Netherlands Seeking 510k from FDA in Q3 of 2014
Organ Transport
LifeCradle HR Systems, Inc (Texas, Heart Hypothermic portable cardiac perfusion system. CE marked
USA)
ARTG = Australian Register of Therapeutic Goods, MP = machine perfusion, FDA = the US Food and Drug Administration
Figure 1 Number of new cases of ESKD, by treatment status and age at ESKD onset,
2003-07 13
In Australia at the end of 2009 there were 10,300 patients receiving dialysis, and of these,
11 per cent were on the kidney transplant waiting list, with 20 per cent of these patients
having already received a transplant. At the same time point, 7,900 patients had a
functioning kidney transplant. 13 The number of end stage kidney disease (ESKD) patients is
a
GFR less than 15 mL/min/1.73 m2
Figure 2 The number of new patients commencing renal replacement therapy (dialysis or transplantation) in
Australia and New Zealand 14
Heart failure
Heart failure is a progressive condition where the heart is unable to maintain a strong
enough blood flow to meet the bodys needs. Although heart failure can occur suddenly, it
usually develops slowly over many years, with the heart becoming weaker and working less
efficiently over time. Most patients will progress to end-stage heart failure despite optimal
medical care. Treatment options for patients with end-stage heart failure include
implantation with a left ventricular assist device or heart transplantation.15 The true
prevalence of heart failure is difficult to estimate, however in 200708 the National Health
Survey estimated that 1.3 per cent, or 277,800 Australians had heart failure or oedema, with
the prevalence increasing with age. 15 In Australia during 2009-10 there were 45,004 public
hospital separations for the principal diagnosis of heart failure (I50).16 In New Zealand
during the period 2010-11 there were 8,646 public hospital separations for heart failure.17
It should be noted that one patient may have multiple hospital separations and that only a
small proportion of these patients would be eligible or require heart transplantation.
Few heart transplants are performed in Australia due to a shortage of organs. Of the 76
transplants performed in 200708, a high proportion were performed in young patients less
than 35 years (>25%) and the majority of patients were male (71%).15 In the period 1984-
2012, the majority of patients had a pre-transplant diagnosis of idiopathic dilated
cardiomyopathy (40%) or ischaemic heart disease (35%). Of the 84 patients on the heart
b
NYHA = New York Heart Association classification. NYHA III: Marked limitation in activity due to
symptoms, even during less-than-ordinary activity, e.g. walking short distances (20100 m). Comfortable only
at rest. NYHA IV: Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients.
c
Eisenmenger's syndrome is caused by a congenital heart defect in the fetal heart causes increased flow through
the pulmonary vasculature, causing pulmonary hypertension.
Number of patients
In Australia the overall rate of deceased organ donation rose slightly from 15.1 in 2011 to
15.6 per million population (dpmp) in 2012. The rate of donation in New Zealand remained
steady at 8.6 dpmp. These figures translate to 354 and 38 donors in Australia and New
Zealand, respectively, however only 342 and 34 donors were considered to have suitable
An average of 3.1 and 2.9 organs per donor were transplanted, and 3.1 and 3.0 recipients
were transplanted per donor in Australia and New Zealand, respectively. The number and
type of recipient are summarised in Table 3.24
Table 3 Type of organ transplant recipient from deceased donors, 2012 24
Heart-lung 4 (0.2)
Intestine 1 (0.04)
Transplant overseas 1
Died on list 7 29 8 14 2
Graft survival can be defined as the ability of the transplanted organ to sustain life without
other organ replacement therapy. A loss of graft function may result in death or re-
transplantation, or in the case of kidneys and the pancreas, resumption of dialysis and
insulin therapy, respectively.
Speciality Transplantation
Technology setting Specialist hospital
Impact
Current technology
The current gold standard method used to maintain and preserve the viability of high-
quality solid organs between the time of retrieval and time of transplantation is static cold
storage (SCS). During preservation with SCS, the donated organ is flushed with a cold
preservation solution via the arterial supply and suspended in a bath of the storage media
on ice. A number of SCS solutions exist on the market, some of which are organ specific,
such as Perfadex a low potassium dextran solution used for lungs, however the most
commonly used solution is the University of Wisconsin (UW) solution, a lactobionate-based
static storage solution. The role of the organ storage solution is to prevent injury to the
stored organ induced by cold temperature and hypoxia, and reduce damage that may occur
from mechanical injury during the preservation process.25
Kidney
By far the most mature evidence base for machine perfusion of organs relates to the use of
MP for the preservation of kidneys for transplantation. During MP the kidney is attached to
the perfusion system via the renal artery. Further surgical preparation of the kidney is then
required to make the seal to the perfusion device airtight. Although it would appear to be
accepted practice that organs obtained from expanded criteria donors would benefit from
MP, the evidence base is unclear. In addition, its use and results in DCD donors is variable.3
Several recent systematic reviews comparing the use of MP to SCS for the preservation of
kidneys were identified. It is difficult to make conclusions in respect to these systematic
reviews as many of the studies included were conducted more than 20-years ago, used a
variety of devices and included a relatively small number of patients. The methodological
quality of these studies was poor or uncertain. In addition, comparisons are difficult due to
confounding from advances in surgical technique, and differences in perfusate and
immunosuppression regimens, and perfusion pressures used.5
Two systematic reviews included studies that used kidneys donated from both DCD and DBD
donors, one of which included only RCTs (n=7) 5 and the other included both RCTs (n=7) and
non-RCTs (n=11) but stratified results.26 When only the RCTs were considered, O'Callaghan
et al found that the relative risk (RR) of delayed graft function was lower with MP than with
SCS (RR= 081, 95% CI [071, 092], p=0002), with no significant heterogeneity. When results
were stratified according to donor type, there was no significant difference between MP
and SCS in the rate of delayed graft function for DBD kidneys (RR=0.84, 95% CI [0.69, 1.03],
p=0.09) or for DCD kidneys (RR= 0.80, 95% CI [0.62, 1.04], p=0.094). Graft survival results
varied greatly between the included studies, with one study (LifePort Kidney Transporter
device, study summarised below)27 finding that graft survival improved with MP compared
to SCS (hazard ratio (HR)=0.52, p=0.03) with the effect appearing to persist for 3-years.
Three trials found no difference in 1-year graft survival (Watson et al, summarised below),
however two studies appeared to favour MP over SCS but were underpowered to show an
effect. One of these two studies was conducted in 1985 and the other in 2001 with a
Gambro MP system that does not appear to be in current manufacture. There was no
overall difference between MP and SCS for the rate of primary non-function (RR = 1.15, 95%
CI [0.46, 290], p=0.767), however there was moderate heterogeneity across the trials. One
year patient survival was reported by three of the RCTs. Two studies reported patient
survival at 17 and 22 months. No relationship between patient survival and preservation
method was reported.26
Although the systematic review by Lam et al also included seven RCTs, two studies differed
from those assessed by O'Callaghan. The majority of the included RCTs were conducted with
the Waters MOX-100 (n=5), mostly in the 1980s, using DBD kidneys. The remaining two
0.60
Overall transplanted kidneys(n=672) 91% 87% 0.04
[0.37, 0.97]
0.54
Kidneys from DBD donors (n=588) 91% 86% 0.02
[0.32, 0.90]
1.16
Kidneys from DCD donors (n=164) 90% 92% 0.78
[0.41, 3.28]
* Extended criteria donors are donors aged >60 years, or those aged between 50 and 60 years with either a history of hypertension, death due to
cerebrovascular causes, serum creatinine >132mol/L before removal of kidney
A further analysis of the data from extended criteria DBD donors reported that at 1-year,
MP reduced the risk of delayed graft function (OR 0.46, p=0.047) and significantly lowered
the incidence of primary non-function (p=0.04). In recipients who did experience delayed
graft function, 3-year graft survival was significantly higher in those recipients who received
a MP kidney compared to controls (68.7% vs 32.9%, p=0.0089).36
Several papers have reported similar results when reporting on the use of kidneys donated
from DCD donors only. An earlier RCT reported on the results of 82 kidney pairs obtained
from consecutive, controlled DCD donors (level II intervention evidence). The incidence of
delayed graft function was reduced in the LifePort MP recipients compared to controls (OR
0.43 95% CI [0.20, 0.89], p=0.025), although 1-year patient and graft survival rates were
similar in both groups (93.9% vs 95.1%). The median duration of delayed graft function was
d
Expanded criteria donors are donors aged >60 years, or those aged >50 years with either a history of
hypertension, death due to cerebrovascular causes, serum creatinine >150 mol/L before removal of the kidney
Another area of interest is the use of perfusion parameters during MP, such as flow,
resistance and pressure, as predictive or prognostic indicators of long-term kidney
transplant function and success, allowing for early therapeutic intervention. Patel et al
e
The European MP trial used mainly DBD with some DCD donors and the UK pulsatile perfusion trial used all
DCD donors.
f
QALYs = quality-adjusted life-years
Table 9. A major part of the costs for each outcome was hospital stay (41.5-53.9%), followed
by graft explantation (20.2%) and the need for dialysis in recipients who experience primary
non-function (16.0%). The budget impact per patient for the introduction of MP was $505.
However, when the incremental cost-effectiveness ratio (ICER) was calculated taking into
account the number of cases of delayed graft function and primary non-function avoided by
the use of the LifePort, machine perfusion was found to have a negative ICER of $3,369.
That is, machine perfusion is cost-effective in terms of savings for delayed graft function and
primary non-function when kidneys obtained from extended criteria donors are
transplanted.45
SCS
Control unit
Figure 6 The Waves portable MP device. When lids are closed the device is in transport mode, when open the
device is in perfusion mode (personal communication Waters Medical Systems).
Cost of the WAVES and RM3 devices
The current purchase price of the RM3 is US$37,669. The cost of a single kidney disposable
sterile cassette for the RM3 is US$848, with a dual kidney cassette costing US$990. Either
cassette requires one litre of Waters perfusate solution at a cost of US$197/litre. In
addition, the costs of sterile cannulas range from US$45 to $85 each.
The basic list price for the Waves device is US$25,625. To perfuse one kidney, the cost of the
disposable cassette and perfusate is US$1,538 and US$197/litre, respectively. Training is
Clinical outcome
An abstract presented to the 2011 American Transplant Congress reported the longest
follow-up data with the 4-year outcomes of patients from a series of 66 kidneys obtained
from expanded criteria DCD donors (ECD) and perfused with either the RM3 or the LifePort
device. The outcomes from these patients were compared to 92 age-matched historical
controls that underwent transplantation with ECD kidneys preserved by SCS (level III-3
intervention evidence). There was no significant difference in either the donor or recipient
characteristics between the MP and SCS groups. However, kidneys that underwent MP
experienced a significantly longer cold ischaemic time (31.1 9.8 vs 24.7 7.8 hours,
p<0.001). Patient survival at 4-years was better in the MP group (89.7% vs 72%, p=0.02).
Delayed graft function tended to be reduced in the MP group, however this did not reach
significance (24.2% vs 29.3%, p=0.59). Similarly, graft survival at 4-years was higher in the
MP recipients compared to the SCS group, but again did not reach significance (70.5% vs
57.7%, p=0.18).51
Only the preliminary results from three animal studies that used the Airdrive perfusion
system could be identified, and were therefore not included for assessment.53-55
Sherpa Pak
Although Paragonix announced that they had filed a submission for regulatory approval of
the Sherpa Pak for kidney transportation to the FDA in December 2013 56, their web site
only describes the Sherpa Pak for cardiac perfusion. No studies could be identified
describing the use of the Sherpa Pak for the perfusion of kidneys.
Kidney Assist
The Kidney Assist provides hypothermic oxygenated perfusion in a transportable unit that
has a battery life of 24-hours (Figure 8). No studies that assessed the clinical use of the
Kidney Assist could be identified. The only papers that could be identified were those that
described the advantages of oxygenated hypothermic perfusion.8 The company was
contacted for information in respect to regulatory status, diffusion and cost but no
information was supplied.
A total of seven machine perfusion systems for kidneys were identified. Of these, only the
LifePort is listed on the ARTG. Of the remaining six systems, two are approved by the FDA
(Waters Waves and RM3), two are seeking FDA approval (Airdrive and Sherpa Perfusion),
one is CE marked (Kidney Assist) and one is still investigational.
As of the end of 2012, there were 1,190 Australian and New Zealand patients on the kidney
transplant waiting list. In that same year, a total of 661 kidneys were transplanted.
The evidence base for machine perfusion of kidneys is the most mature of all organs.
Several systematic reviews were identified, however, there was a great deal of
heterogeneity between studies included in these reviews due to the age of the studies, small
numbers of patients, variation in perfusion systems and variations in clinical practice. Two
reviews assessed outcomes in recipients who received organs from DCD and DBD donors.
When only RCTs were considered, the overall relative risk of delayed graft function (DGF)
was significantly reduced with MP compared to SCS (RR= 0.81-0.83), with no difference in
outcomes when stratified by DCD or DBD organs. Mixed results were reported for graft
survival but there was no difference in the rate of primary non-function (PNF) between MP
and SCS treated kidneys. Two systematic reviews assessed outcomes in recipients who
received organs from only DCD donors. When only RCTs were considered, MP significantly
reduced the odds of DGF (OR= 0.56) compared to SCS, however, as before, there was no
difference in the rate of PNF between MP and SCS treated kidneys. One-year graft and
patient survival tended towards favouring MP but did not reach significance. These results
indicate that the use of DCD donors may result in good outcomes for patients.
Of the seven MP devices identified, only two hypothermic devices (LifePort and the RM3)
had published peer-reviewed clinical studies.
LifePort device
The largest RCT to date included DCD and DBD donors (n=672). Overall, the odds of DGF
were lower and the 1-year graft survival was higher in recipients who received MP kidneys
compared to SCS treated kidneys. Graft survival remained superior at 3-years in the MP
group. When stratified to donor type, graft survival was poor in MP kidneys from DCD
donors but superior in MP kidneys from DBD or extended criteria donors. These results were
supported by another RCT (n=82), however a small (n=45) RCT by Watson et al found no
difference in any outcomes between MP and SCS treated kidneys.
Mixed results were reported when only extended criteria kidneys were transplanted. Of the
two good quality RCTs, one reported reductions in DGF and PNF with organs obtained from
DBD extended criteria donors. The other study reported on transplants with organs obtained
from DCD extended criteria donors and found no difference between MP and SCS in the rate
of development of DGF.
Three economic analyses were identified that compared costs and outcomes using the
LifePort. The most relevant of these to the Australian and New Zealand health systems was
conducted by NICE in the United Kingdom. Cost-effectiveness varied depending on the data
used to populate the model. Using the data from the largest RCT, MP was cost-effective
compared to SCS, however when using data from the small Watson RCT, SCS was more cost-
effective.
RM3
The evidence base for the RM3 device was poor. Two studies compared the use of the RM3
to the LifePort device, in extended criteria and DCD donors. One study found that 4-year
patient and graft survival was greater in recipients of MP kidneys compared to matched
historical controls, and that DGF tended to be reduced in MP recipients. No conclusions
regarding the effectiveness of the RM3 could be drawn from the large case series.
Hardware for the manual system is generally off-the-shelf standard cardiac bypass
equipment and requires a:
After 1-hour of EVLP, the median PO2:FiO2 ratio improved from 334 to 478 mmHg, and again
improved to 513 mmHg after 4-hours of EVLP (p=0.001). Post-transplant outcomes are
summarised in Table 13. There was no difference in any of the reported outcomes between
EVLP treated lungs and controls. Although EVLP tended to have less primary graft
dysfunction, this was not significant. It may be expected that outcomes in the EVLP group
may be poorer for lungs obtained from DCD compared to DBD donors, however when
results were stratified by donor type there was no difference in outcomes. . In addition,
there was no difference in survival in EVLP recipients who were transplanted with donor
lungs with a PO2:FiO2 less than 300 mmHg compared to those donor lungs with a higher
A small study conducted in Austria by Aigner et al (2012) using DBD donors, whilst not
explicitly stating that they used the XVIVO system, reported on the use of the Toronto
protocol to recondition 13 lungs considered unacceptable for transplantation. Outcomes
from these transplanted lungs were compared to 119 standard lungs transplanted during
the same period (level III-2 intervention evidence). The Toronto protocol was followed, with
a period of warming, followed by ventilation once normothermia had been reached and
functional assessment was conducted after 15 minutes at a FiO2 of 100 per cent.63
All donated marginal lungs had a PO2:FiO2 less than 300 mmHg (median 216 mmHg),
compared to a median value of 447 mmHg for the standard donated lungs. Donor cause of
death, age, duration of intubation and length of ICU stay in EVLP donated lungs were
comparable to standard lungs. Median total ischaemic time was 577 minutes (range 486-
678 minutes). EVLP was performed for 2-4 hours on all lungs. EVLP was discontinued on four
lungs, which were discarded, due to deterioration or poor gas exchange with the
development of lung oedema.63
In the nine transplanted lungs, PO2:FiO2 improved to a median of 466 mmHg (range 434 to
525 mmHg). The rejected lungs had a median PO2:FiO2 of 372 mmHg. One patient with
g
ECMO = extracorporeal membrane oxygenation
Figure 11 The Vivoline LS1 lung perfusion system, showing the disposable lung chamber 66
h
On 16th July 2014, 99,000 = $143,434 and 9,500 = $13,764
As with the XVIVO, the Organ Care System is designed to recondition marginal lungs and
to assess the viability of perfused lungs prior to transplantation. Oxygenated blood (15-25%
red blood cells) is circulated through the lung via a pulsatile pump, using a proprietary
perfusate that contains nutrients and other substrates. 70 The OCS protocol is designed for
normothermic transportation of lungs.60
The company was contacted for information in respect to regulatory status, diffusion and
costing, however no response was received.
Only one study could be identified that reported on the use of the Organ Care System in a
small pilot study (n=12), which was conducted by the lead author of the ongoing INSPIRE
RCT (described below) (level IV intervention evidence). 69 All lungs were donated and
transplanted within the same centre and lungs were all obtained from DBD donors bar one
category I DCD donor. Donor lungs were ranked according to a lung quality score, with
factors including increased age, impaired oxygenation capacity or evidence of abnormalities,
such as pneumonia, increasing the score. Those scoring less than nine were considered ideal
lungs for transplantation, however, six of the donated lungs scored seven or six out of nine.
Donated lungs were required to have a PO2:FiO2 >300 mmHg, with the mean reported ratio
at time of donation of 463.9 91.4 mmHg.
The mean perfusion time was 303 105 minutes (range 188-622 mins), with no donor lungs
being lost. The mean PO2:FiO2 after perfusion was 471.6 127.9 mmHg, which was not
significantly different from the mean baseline measure (p=0.72). At time of follow-up, 11/12
patients had survived, with survival time post-transplant ranging from 414 to 529 days. The
one remaining patient died on day 140 post-transplant due to cardiomyopathy of unknown
origin. Two recipients required an extended period of mechanical ventilation (117 and 456
A total of three machine perfusion systems for lungs were identified. Of these, two are listed
on the ARTG, the XVIVO and the Organ Care System, however the OCS listing does not
specifically state whether it is for OCS HEART or OCS LUNG. The remaining system, Lung
Assist is CE marked.
As of the end of 2012, there were 107 Australian and New Zealand patients on the lung
transplant waiting list. In that same year, a total of 157 lung and four heart-lung
transplants were performed.
The majority of XVIVO published peer-reviewed clinical studies describes the reconditioning
of marginal lungs using the XVIVO system. No economic analysis could be identified.
XVIVO
Three non-randomised studies were identified that reported on outcomes of ex-vivo lung
perfusion (EVLP) with the XVIVO system compared to controls. In the largest study (n=50),
there was no difference between the EVLP group and controls in any of the outcomes
measured. Unlike the studies conducted in kidneys, equivalent results between EVLP and
control lungs can be considered in a favourable light as these reconditioned EVLP lungs
would otherwise have been rejected for transplant.
Vivoline system
There was limited recent published evidence available describing the Vivoline system. The
results from these preliminary studies demonstrate that the system is feasible for the
reconditioning of marginal lungs.
Only one small case series describing the outcome in patients transplanted with EVLP
treated lungs all obtained from DBD donors. No conclusions as to the effectiveness of this
system can be made due to the non-comparative nature of the study, however the system
appears safe with survival time post-transplant ranging from 414 to 529 days.
i
MELD = model for end-stage liver disease, a scoring system for assessing the severity of chronic liver disease
and uses values for serum bilirubin, serum creatinine, and the international normalised ratio for prothrombin
time (INR) to predict survival. The higher the score, the lower the likelihood of survival. Scores of >40
associated with 71% mortality, 30-39 = 53% mortality, 20-29 = 20% mortality.
Primary non-function 0 0
Vascular complications 0 1
Biliary complications 2 4
OrganOx metra
No clinical studies could be identified that described the use of the OrganOx metra device.
Only preliminary animal studies and studies describing the advantages of normothermic
perfusion for donated livers were identified. In addition, the company was contacted for
information in respect to regulatory status, diffusion and costing of the OrganOx metra
device, however no response was received. The companys web site states that the system
will be commercially available in 2014.
Organ access: there are implications for national rotational referral lists for heart and
lung as previously WA was only on SA list due to ischaemic time limitations (personal
communication Western Australia Department of Health).
The OCS HEART device is also being trialled at St Vincents Hospital, Sydney. The trial is
comparing the OCS device to cold storage especially in extended criteria or marginal donors.
Current experience with the OCS HEART is that the device fits into a standard retrieval
aircraft (personal communication NSW Ministry of Health).
Figure 15 A schematic describing the use of the OCS HEART 78 and the perfusion module
Transmedics cites benefits of the OCS HEART include health system cost-savings from
reductions in waiting list costs, such as the need for left ventricular assist devices, ICU usage
and multiple hospital admissions, and reductions in post-transplant costs due to reduced
complications.
LifeCradle HR
The LifeCradle is a lightweight, portable device that is capable of extending the
preservation time to more than 12 hours. The donated heart is placed into the temperature-
controlled LifeCradle capsule and after connection, an oxygenated, hypothermic perfusate
is pumped through the organ (Figure 16). 1 The company was contacted for information in
respect to regulatory status, diffusion and costing, however no response was received.
Apart from one abstract presented to the 2009 Society for Heart and Lung Transplantation
conference, only animal studies could be identified. The abstract by Cobert et al described
the performance of the LifeCradle device when used to perfuse donated hearts that were
Sherpa Pak
The Sherpa Perfusion Cardiac Transport System is a fully disposable oxygenated perfusion
system (Figure 17), capable of extending ischaemic time to 12-hours, designed specifically
for the transportation of donor hearts.80
HealthPACT assessment
Organ perfusion technologies may have the potential to significantly impact on health care
in Australia and New Zealand. The most mature evidence base regarding the use of
perfusion systems for the preservation of kidneys indicates reduced rates of delayed graft
function, which may represent significant savings to the health system. It is too early in the
development phase to make conclusions in respect to cardiac and lung perfusion systems as
the evidence base is still maturing, however lung perfusion may result in an increased
number of organs able to be transplanted.
Some jurisdictions, where distance and remote locations are an issue, may choose to invest
in this technology, whilst others may not. In Australia, organ procurement by some states
References
1. Organ Transport Systems Inc (2012). Our Technology. Available from:
http://organtransportsystems.com/OurTechnology.html [Accessed 4th February
2014].
2. Wight, J. P., Chilcott, J. B.et al (2003). 'Pulsatile machine perfusion vs. cold storage of
kidneys for transplantation: a rapid and systematic review'. Clinical transplantation,
17 (4), 293-307.
3. Balfoussia, D., Yerrakalva, D.et al (2012). 'Advances in machine perfusion graft
viability assessment in kidney, liver, pancreas, lung, and heart transplant'.
Experimental and clinical transplantation : official journal of the Middle East Society
for Organ Transplantation, 10 (2), 87-100.
4. Van Raemdonck, D., Neyrinck, A.et al (2013). 'Machine perfusion in organ
transplantation: a tool for ex-vivo graft conditioning with mesenchymal stem cells?'.
Current opinion in organ transplantation, 18 (1), 24-33.
5. Lam, V. W., Laurence, J. M.et al (2013). 'Hypothermic machine perfusion in deceased
donor kidney transplantation: a systematic review'. The Journal of surgical research,
180 (1), 176-82.
6. Neyrinck, A., Van Raemdonck, D.& Monbaliu, D. (2013). 'Donation after circulatory
death: current status'. Current opinion in anaesthesiology, 26 (3), 382-90.
7. NHMRC (2010). National Protocol for Donation after Cardiac Death, Australian Organ
and Tissue Donation and Transplantation Authority, Canberra
http://www.donatelife.gov.au/Media/docs/DCD%20protocol%20020311-0e4e2c3d-
2ef5-4dff-b7ef-af63d0bf6a8a-1.PDF.
8. Hosgood, S. A., Nicholson, H. F.& Nicholson, M. L. (2012). 'Oxygenated kidney
preservation techniques'. Transplantation, 93 (5), 455-9.
9. van Smaalen, T. C., Hoogland, E. R.& van Heurn, L. W. (2013). 'Machine perfusion
viability testing'. Current opinion in organ transplantation, 18 (2), 168-73.
Report for Clinical Access and ReDesign Unit (CARU) for the New Technology Funding and
Evaluation Program (NTFEP), Queensland Health.
An overview of the ex-vivo lung perfusion technology (EVLP) that was acquired in October
2011 as a result of funding from the Queensland Policy and Advisory Committee for New
Technology.
Oxygenator
Sampling ports
Extracorporeal pump
The Vivoline system allows for an unprecedented period up to 12 hours of observation and
treatment of marginal donated lungs once removed from the deceased to assess and
improve function prior to transplantation. It is estimated that since 19892011 there have
been 848 potential lung donors in Queensland of which 460 or 54 per cent have not resulted
in transplantation. Common reasons for organs not being utilised for transplantation include
poor gas exchange, infection, age of the donor, trauma to the organ and logistical concerns.
With the Vivoline ex-vivo system, organs are retrieved in the usual manner and then
transferred to a protective transparent bubble like chamber in theatre 11 at The Prince
Charles Hospital, ventilated and perfused with an acellular solution called Steen solution
whilst gas exchange is assessed. The temperature is incrementally increased until it reaches
37C over approximately 30 minutes. Various therapeutic manoeuvres can be performed
whilst regularly evaluating lung function with key indicators including oxygenation, airway
pressure and lung compliance. Therapeutic manoeuvres consist of recruitment manoeuvres
on the ventilator, airway toilet with bronchoscopy, administration of antibiotics and careful
titration of pulmonary flow to avoid injury to the lung parenchyma.
The overall aims of EVLP are to:
1. Minimise ischaemia reperfusion injury by improving solutions used for
extracorporeal preservation of organs and tissues;
2. Extend the safe extracorporeal preservation time for organs prior to transplantation;
and
Population Need
The intended donor organs for application of this EVLP technology have been lung donors
with potentially reversible pathology that may be improved with ex-vivo resuscitation.
Guidelines for ex-vivo donor lung eligibility criteria were as follows:
Last donor PaO2 < or equal to 300 mm Hg on the FiO2 of 100 per cent MPEEP of 5;
Poor lung compliance or PEEP dependent donor lungs in the absence of mechanical
trauma or significant structural lung disease;
Donor lungs with acceptable gas exchange but evidence of pneumonia, persistent
purulent secretion on bronchoscopy or minor structural lung lesions including
localised bullous emphysema or focal nodularity requiring frozen section or
definitive resection for histopathological assessment;
Lungs from donors aged > 45 years with a projected ischaemic time in excess of 6
hours (typically lung donors in Darwin or Perth);
Donors with potentially unfavourable parameters including disseminated
intravascular coagulation, massive transfusion requirement (guide > or equal to 10
units of packed red blood cells), prolonged mechanical ventilation or pulmonary
oedema detected on CXR, bronchoscopy or palpation of lungs; or
Recipients who have a predicted or actual difficult explant in order to limit impact of
lengthy ischaemic time.
PaO2 >300 mmHg measured on FiO2 1.0 at two consecutive time points within the 4
hour maximum period of XVIVO perfusion.
Stability or improvement of other lung function parameters during XVIVO including
pulmonary vascular resistance, compliance and airway pressures.
Achieving full flow in the circuit (70ml/kg/min) at normal pulmonary artery pressures
ie low resistance (target PVR <500 dynes).
Normal collapse test (if performed, remember to first reduce flow to avoid tracheal
oedema).
Surgeon clinically satisfied with lung evaluation.
The Technology
As stated above EVLP consists of a sterile chamber, a heating reservoir, closed circuits,
temperature probes and pressure catheters along with a monitoring interface and external
connections to a mechanical ventilator and a complex gas mixture of nitrogen and carbon
dioxide. The marginal donated lung is placed in the sterile chamber and covered with a clear
fibreglass dome. The initial temperature of lungs placed on the circuit is approximately 15
and they are connected accordingly to their respective circuits including a pulmonary artery
and tracheal connection. The temperature of the circuit is slowly increased with an open
circuit perfusion of red blood cells mixed with Steen solution. Steen solution contains
human serum albumin providing above normal oncotic pressure to prevent interstitial
oedema. In addition, Steen solution contains dextran which is a mild oxygen scavenger
which coats and protects endothelium from subsequent excessive leucocyte interaction and
thrombogenesis. The electrolyte composition of the solution resembles the extracellular
fluid with a low potassium content to reduce free radical generation and avoid vascular
Training
In terms of the training involved a total of six staff members one anaesthetist, one
perfusionist, two transplant physicians and two cardiac surgeons attended a training
workshop just outside of Lund in Sweden for three days in August 2011. Following our
attendance at the workshop a broader educational workshop was rolled out for additional
TPCH staff members who were unable to attend the workshop in Sweden. A total of over 10
perfusionists, one cardiac surgeon, two transplant physicians and six transplant retrieval
staff were orientated to the EVLP system upon our return from the workshop. We were in a
position to accept referrals of marginal donated lungs in October 2011 and shortly
thereafter in November 2011 received our first referral for ex-vivo lung perfusion. Between
November 2011 and May 2013 a total of eight referrals have been received with six leading
to clinical transplantation, an overall acceptance rate of 75 per cent.
Evaluation Design
A research project titled Prospective Audit of Lung Transplant Outcomes After Different
Modes of Clinical Lung Donation Traditional Brainstem Death, Donation after Cardiac
The primary outcome evaluated for the research study was recipient mortality at 30
days post-transplant.
Secondary outcome measures were as follows:
Results
A number of organisational and logistical challenges were experienced following the
introduction of EVLP technology at TPCH. These issues were addressed essentially at the
outset following careful consultation with members of the EVLP team, theatre staff and
pharmacy personnel. The first issue was in reference to where the technology would reside.
A designated area in a theatre has been set aside for EVLP transplant evaluation. There is no
clinical case load that impacts upon EVLP being undertaken in this theatre currently at TPCH
Campus. The next barrier was in reference to obtaining a medical grade gas mixture of 93
per cent nitrogen and seven per cent carbon dioxide. This was eventually manufactured by
BOC Medical of a sufficient standard to be recommended for use with human tissue. With
reference to staff training we were able to internally run a workshop to educate other
relevant staff members to the EVLP system and this responsibility was left with those who
In terms of continuation of this technology the Queensland Lung Transplant Service would
consider this technology now part of our standard practice given the success of this pilot
program. We are confident that marginal lung donors which we would otherwise reject can
often now be referred for EVLP resuscitation and reconditioning. Our results indicate in this
early assessment that the outcomes of our first 6 cases are at least equivalent and in many
respects superior to standard transplantation. Given the reduced mortality we have
experienced on the waiting list and the net increase in transplant numbers we believe the
technology has been cost effective in providing greater access to lifesaving transplantation
for Queenslanders with end stage respiratory failure. The Prince Charles Hospital is the only
facility in Australia with the EVLP system and will continue to advocate for other transplant
programs across the nation to adopt this technology.
Figure 20 An example of lungs not utilised for transplant post-EVLP showing pulmonary infarcts and persistent
lower lobe oedema