「様式３－B」

課題番号（Project number）: 49

Strategies of donor lung preservation
after cessation of circulation［１］組織（Research group）
代表者（Principal Investigator (PI)）：
Marcelo Cypel(Division of Thoracic Surgery, Toronto
General Hospital, University HealthNetwork, University of Toronto)
対応者（Host researcher at IDAC）：
Yoshinori Okada(Division of Thoracic Surgery, Instituteof Development, Aging and Cancer)
分担者（Co-investigator）：
Yui Watanabe(Latner Thoracic Research Laboratories,Toronto General Research Institute,
University Health Network, Universityof Toronto)
研究費(Expenditure report of research funds)：
物件費 400,000 YEN［２］研究経過（Research setup）
Lung transplantation (LTx) is alifesaving therapy for patients with end-stagelung diseases. However, the number of patients
waiting for LTx greatly exceeds the number ofdonors available. In order to overcome theshortage of lungs, many lung transplant
programs are interested in using organs fromdonors after circulatory death (DCD). However,about 40-50% of potential cDCD are declined
because death does not occur in a suitable timeframe currently accepted of 120 min fromwithdrawal of life support therapies (WLST) andcardiac arrest (Machuca TN, Cypel M, et al. Am J
Transplant. 2015;15:993-1002, Figure 1).
Therefore, improved strategies to preserve lungs
after death may enable teams to recover lungs
from more cDCDs, even if few hours of nocirculation, that is warm ischemia time (WIT),
occurs until recovery teams can arrive to donor
hospitals.

Carbon monoxide (CO) is a lipid-soluble,
endogenously produced gaseous messenger
molecule, collectively known as a gasotransmitter,
which has been shown to exert anti-inflammatory,
anti-apoptotic,
anti-proliferative,
andvasodilatative properties in multiple organs
following ischemic injury, including the lung. In
the ex vivo lung perfusion (EVLP) system, lungs
can be ventilated and perfused in a highly
controlled environment, providing an ideal
platform to assess the effects of CO on
ischemia-reperfusion injury in both animal andhuman tissue. The first purpose of this study wasto verify whether CO administration during
warm ischemia time and/or EVLP may exert
beneficial effects in lung utilization.
In addition, prone positioning in acuterespiratory distress syndrome (ARDS) has beenshown to provide a more homogeneous
distribution of alveolar distending pressure, toreduce lung injury, and to improve outcomes.
However, there have been no reports about prone
positioning for management of organ donors. We
hypothesized prone positioning during WIT after
cardiac death could decrease atelectasis andhomogeneously distribute alveolar inflation (acritical feature of lung preservation) leading toimproved lung function during ex vivo lungperfusion (EVLP). The secound purpose of thisstudy was to determine the effect of donor
positioning on the quality of lung preservation
after cardiac arrest.

［３］成果（Research outcomes）（３－１）研究成果（Results）
The established pig cDCD model closely
simulated clinical cDCD scenario with averagetime from WLST to arrest of 27 minutes. CO
during both WIT and EVLP was able to extend
the acceptable WIT to 3 hours, have a significant
impact in increasing lung utilization in cDCDs.
However, a limitation of this strategy was that
CO gas was not able to be distributed if there
were atelectatic area in the lungs.
Second step of this study was performed
to overcome this limitation. In the same
experimental model of cDCD, prone positioning
provided better alveolar air redistribution andprevented the development of lung atelectasis(Figure 2) and cell death during WIT, with aconsequent dramatic improvement of lungfunction during the assessment phase in theEVLP platform. The more homogeneous
distribution of alveolar distending pressure inprone compared to supine position may be crucial
to maintain alveolar recruitment in lung donors,
thereby improving lung preservation andfunction.

（ ３ － ２ ） 波 及 効 果 と 発 展 性 な ど （ Futureperspectives）
CO application and prone positioning of
DCD donors may increase the number of organs
suitable for lung transplantation and recipientoutcomes. In this study, there were dramatic
improvements of lung function during EVLP even
if only prone positioning of DCD donors. However,there have been no reports about prone
positioning for management of organ donors eventhough it is simple strategy and available in all
donor hospitals. The results would help many
donor management teams to try the prone
positioning in several settings.

［４］成果資料（List of Papers）(1) Watanabe Y, Galasso M, Watanabe T, Ali A,
Chan HHL, Qaqish R, Summers C, Ramadan K,
Pinto Ribeiro RV, Zhang Y, Gazzalle A, Waddell
TK, Liu M, Keshavjee S, Del Sorbo L, Cypel M.
Prone Positioning Attenuates Lung Injury During
Warm Ischemia in a Large Animal Controlled
Donation after Cardiac Death Model. The
International Society for Heart and Lung
Transplantation 38th Annual Meeting andScientific Sessions. Nice, France. April 11-14,2018.
(2) Watanabe Y, Galasso M, Watanabe T, Ali A,Chan HHL, Ramadan K, Pinto Ribeiro RV, Zhang
Y, Gazzalle A, Liu M, Keshavjee S, Del Sorbo L,Cypel M. Prone positioning attenuates lunginjuries during warm ischemia time in a swine
donation after cardiac death model. Medicine byDesign 2nd Annual ymposium. Toronto, Canada.
December 5, 2017.
(3) Watanabe Y, Galasso M, Watanabe T, Ali A,Chan HHL, Ramadan K, Pinto Ribeiro RV, Zhang
Y, Gazzalle A, Liu M, Keshavjee S, Del Sorbo L,
Cypel M. Prone positioning attenuates lunginjuries during warm ischemia time in a swine
donation after cardiac death model. TGRI
Research day 2017. Toronto, Canada. October 11,2017.
(4) Watanabe Y, Nakajima D, Taniguchi Y, Pipkin
M, Chen M, Ohsumi A, Takahashi M, Watanabe
T, Qaqish R, Caldarone L, Summers C, Waddell
TK, Liu M, Keshavjee S, Okada Y, Cypel M.
Strategies of Lung Preservation after Absence ofCirculation. International session of the 117th
Annual Congress of the Japan Surgical Society.
Tokyo, Japan. April 27-29, 2017.
(5) Watanabe Y, Nakajima D, Taniguchi Y, Pipkin
M, Chen M, Qaqish R, Caldarone L, Watanabe T,Ohsumi A, Kanou T, Takahashi M, Gazzalle A,Galasso M, Ali A, Summers C, Waddell TK, Liu M,Keshavjee S, Cypel M. Carbon Monoxide Can
Rescue Lungs from Controlled Donors afterCardiac Death and Prolonged Warm Ischemia.
The International Society for Heart and Lung
Transplantation 37th Annual Meeting andScientific Sessions. San Diego, CA, USA. April 5-8,
2017.