Normothermic perfusion of donor lungs for preservation and assessment with the Organ Care System Lung before bilateral transplantation: a pilot study of 12 patients

doi:10.1016/S0140-6736(12)61344-0

The Lancet

Volume 380, Issue 9856, 24–30 November 2012, Pages 1851-1858

https://doi.org/10.1016/S0140-6736(12)61344-0 Get rights and content

Summary

Background

Cold flush and static cold storage is the standard preservation technique for donor lungs before transplantations. Several research groups have assessed normothermic perfusion of donor lungs but all devices investigated were non-portable. We report first-in-man experience of the portable Organ Care System (OCS) Lung device for concomitant preservation, assessment, and transport of donor lungs.

Methods

Between Feb 18, and July 1, 2011, 12 patients were transplanted at two academic lung transplantation centres in Hanover, Germany and Madrid, Spain. Lungs were perfused with low-potassium dextran solution, explanted, immediately connected to the OCS Lung, perfused with Steen's solution supplemented with two red-cell concentrates. We assessed donor and recipient characteristics and monitored extended criteria donor lung scores; primary graft dysfunction scores at 0, 24, 48, and 72 h; time on mechanical ventilation after surgery; length of stays in hospital and the intensive-care unit after surgery; blood gases; and survival of grafts and patients.

Findings

Eight donors were female and four were male (mean age 44·5 years, range 14–72). Seven recipients were female and five were male (mean age 50·0 years, range 31–59). The preharvest donor ratio of partial pressure of oxyen (PaO₂) to fractional concentration of oxygen in inspired air (F_IO₂) was 463·9 (SD 91·4). The final ratio of PaO₂ to F_IO₂ measured with the OCS Lung was 471·58 (127·9). The difference between these ratios was not significant (p=0·72). All grafts and patients survived to 30 days; all recipients recovered and were discharged from hospital.

Interpretation

Lungs can be safely preserved with the OCS Lung, resulting in complete organ use and successful transplantation in our series of high-risk recipients. In November, 2011, we began recruitment for a prospective, randomised, multicentre trial (INSPIRE) to compare preservation with OCS Lung with standard cold storage.

Funding

TransMedics and German Federal Ministry of Education and Research.

Introduction

Cold flush and static cold storage is the accepted standard for preservation of donor lungs in clinical transplantation and is a reasonably successful technique provided that ischaemia times are not excessive and the initial quality of the organ is high.¹ In the early days of combined heart and lung transplantations, normothermic autoperfusion of the organs was researched as a preservation method but was abandoned mainly because of the technique's complexity.2, 3 Renewed interest in ex-vivo lung perfusion has been triggered by the need to develop a method to assess marginal donor lungs (ie, those not fulfilling ideal donor criteria),⁴ which could include those with oedema or from non-heart-beating donors.⁵ All the normothermic lung perfusion systems that have been analysed in the medical literature are stationary and thus have restricted potential to reduce cold ischaemic time. This delay before normothermic perfusion affects the benefits of the procedure, which are usually restricted to no more than 4 h—ie, the maximum time that stationary ex-vivo lung perfusion was used in previous clinical studies.4, 6, 7

The integrated and portable Organ Care System (OCS) Lung (Transmedics, Andover, MA, USA) is an advanced ex-vivo lung perfusion system designed to assess and improve marginal lungs and potentially improve the condition of routine donor lungs. It has several potential advantages compared with conventional systems. OCS Lung can provide immediate and sustained lung recruitment starting at the donor site; substantially reduce cold ischaemic time, especially during transport (because it establishes normothermic perfusion); and allow continuous organ assessment and monitoring capability from donor to recipient. The device was CE marked in January, 2011.

In this pilot study, we investigated a series of 12 patients transplanted with lungs preserved with the OCS Lung at two European lung transplantation centres.

Section snippets

Study design and participants

Patients were transplanted at two academic lung transplantation centres (Hanover Medical School, Hanover, Germany and Hospital Universitario Puerta de Hierro, Madrid, Spain). Donor lungs offered to the investigatory sites were selected on the basis of the availability of both the OCS Lung and team members trained to use the system. We aimed to recruit 20 pilot patients.

All donor lungs offered to the two centres during the study were included except for those with air leakage due to lung injury.

Results

Between Feb 18, and July 1, 2011, 12 patients were transplanted with lungs perfused with OCS Lung. Three patients were transplanted at Hospital Universitario Puerta de Hierro and nine at Hanover Medical School. Table 1 shows recipient demographics. Because outcomes were good in the first 12 patients, the US Food and Drug Administration deemed further pilot patients unneccessary.

Eight of the nine patients transplanted at Hanover Medical School urgently needed transplantation, two of whom were

Discussion

Our first-in-man data for the use of the OCS Lung in clinical transplantation show the device's feasibility and provide the first evidence for good outcomes of lung transplantation in a high-risk recipient population (panel).

One of the most important factors in the design of pilot trials of new technologies for clinical medicine is the selection of the study population. Although ex-vivo lung perfusion is generally used in marginal or extended criteria donors, we decided to focus on regular

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Ex vivo lung perfusion (EVLP) has expanded the donor pool for lung transplantation. Pulmonary Staphylococcus aureus infection, especially that caused by multidrug-resistant strains, is a severe threat to posttransplantation outcomes. Sphingosine is a lipid compound that exhibits broad-spectrum antibacterial activity. Therefore, we aimed to evaluate the effects of S aureus infection on EVLP and whether sphingosine administration during EVLP prevents infection with S aureus.
Eighteen pigs were randomly assigned to 3 groups: uninfected, infected with S aureus with NaCl treatment, or infected with sphingosine treatment. Bacterial numbers were determined before and after treatment. Sphingosine concentrations in the lung tissues were determined using biochemical assays. Lung histology, lung physiological parameters, perfusate content, lung weight, and cell death were measured to analyze the effects of infection and sphingosine administration on EVLP.
Sphingosine administration significantly reduced the bacterial load. The concentration of sphingosine in the bronchial epithelium was elevated after sphingosine administration. S aureus infection increased pulmonary artery pressure and pulmonary vascular resistance. Lung edema, histology scores, lactate and lactate dehydrogenase levels in the perfusate, ΔPO₂ in the perfusate, static lung compliance, and lung peak airway pressure did not differ among the groups.
Infection of S aureus did not affect the lung function during EVLP but induced higher pulmonary artery pressure and pulmonary vascular resistance. Administration of sphingosine effectively eliminated S aureus without side effects in isolated, perfused, and ventilated pig lungs.
Nutrient capsules maintain tear film homeostasis for human corneal lenticule transplantation
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Citation Excerpt :
Organ transplantation has become one of the major directions for medical development in the 21st century and is the only effective radical treatment for end-stage organ failure [1,2]. A well-established and reliable process for organ acquisition, preservation, and transport is especially critical in improving the quality of donor organs and transplantation success rate [3,4]. After the isolation from the body, the blood circulation of the isolated organ stops, and a series of damage and secondary damage such as ischemia, hypoxia, and metabolite accumulation appear, leading to physiological, histomorphological, and ultrastructural changes of the organ.
Corneal lenticule transplantation can be applied in the correction of refractive errors and various corneal diseases. However, current techniques to preserve cornea are limited due to their short preservation time and the structures and optical retention of cornea tissues. Inspired by the composition of the natural human tear film, a nutrient hydrogel capsule that could maintain the homeostasis of tear film was constructed for preserving human corneal lenticules in this study. The nutritional preservation solution containing sodium alginate was coordinated with calcium ions by rapid diffusion to form a stereoscopic capsule, in which chondroitin sulfate interacted with the corneal lenticule surface electrostatically to form a lubricating layer for three-dimensional preservation and nutritional supply. The light transmittance, cell activity, and collagen fiber density of human corneal lenticules after mid-term preservation in nutrient capsules were higher than those traditional preservation methods. Furthermore, after human allogeneic transplantation, the implanted lenticules remained transparent without displacement or graft rejection, and the corrected distance visual acuity increased by two or more lines in 70% of the patients’ operated eyes after surgery. Nutrient capsules could provide not only a simple, safe, and controlled strategy for three-dimensional preservation, but also new approach for other living tissues preservation.
Ischaemia-free liver transplantation in humans: a first-in-human trial
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Background Ischaemia-reperfusion injury is considered an inevitable component of organ transplantation, compromising organ quality and outcomes. Although several treatments have been proposed, none has avoided graft ischaemia and its detrimental consequences.
Methods Ischaemia-free liver transplantation (IFLT) comprises surgical techniques enabling continuous oxygenated blood supply to the liver of brain-dead donor during procurement, preservation, and implantation using normothermic machine perfusion technology. In this non-randomised study, 38 donor livers were transplanted using IFLT and compared to 130 conventional liver transplants (CLT).
Findings Two recipients (5•3%) in the IFLT group experienced early allograft dysfunction, compared to 50•0% in patients receiving conventional transplants (absolute risk difference, 44•8%; 95% confidence interval, 33•6-55•9%). Recipients of IFLT had significantly reduced median (IQR) peak aspartate aminotransferase levels within the first week compared to CLT recipients (365, 238-697 vs 1445, 791-3244 U/L, p<0•001); likewise, median total bilirubin levels on day 7 were significantly lower (2•34, 1•39-4•09 mg/dL) in the IFLT group than in the CLT group (5•10, 1•90-11•65 mg/dL) (p<0•001). Moreover, IFLT recipients had a shorter median intensive care unit stay (1•48, 0•75-2•00 vs 1•81, 1•00-4•58 days, p=0•006). Both one-month recipient (97•4% vs 90•8%, p=0•302) and graft survival (97.4% vs 90•0%, p=0•195) were better for IFLT than CLT, albeit differences were not statistically significant. Subgroup analysis showed that the extended criteria donor livers transplanted using the IFLT technique yielded faster post-transplant recovery than did the standard criteria donor livers transplanted using the conventional approach.
Interpretation IFLT provides a novel approach that may improve outcomes, and allow the successful utilisation of extended criteria livers.
Funding This study was funded by National Natural Science Foundation of China, Guangdong Provincial Key Laboratory Construction Projection on Organ Donation and Transplant Immunology, and Guangdong Provincial international Cooperation Base of Science and Technology.
Panel: Research in context
Strategies to prolong homeostasis of ex vivo perfused lungs
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Ex vivo lung perfusion provides an innovative method to assess and repair donor lungs. The current Toronto ex vivo lung perfusion protocol can reliably and reproducibly preserve lungs for 12 hours. A longer ex vivo lung perfusion preservation time could enable the application of more advanced repair therapies and the rescue of more donor lungs for lung transplant. Our objective was to achieve stable 24-hour normothermic ex vivo lung perfusion.
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Only 1 lung in the control group completed 24-hour ex vivo lung perfusion. However, 24-hour perfusion was achieved in 4 lungs in the continuous replacement group, 3 lungs in the modified feed group, and 4 lungs in the total parenteral nutrition group. The total parenteral nutrition group achieved significantly longer stable perfusion time compared with control (P = .03). Lung function was significantly improved and inflammatory cytokine production was reduced in the continuous replacement and total parenteral nutrition groups compared with control.
Modifications of ex vivo lung perfusion perfusate toward achieving a stable homeostatic state can extend perfusion time for up to 24 hours. Although these modifications allow for prolonged ex vivo lung perfusion, further research will be required to develop stable lung support beyond 24 hours.
Common Criteria for Ex Vivo Lung Perfusion Have No Significant Impact on Posttransplant Outcomes
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Although it is intense in health care resources, by facilitating assessment and reconditioning, ex vivo lung perfusion (EVLP) has the potential to expand the donor pool and improve lung transplant outcomes. However, inclusion criteria used in EVLP trials have not been validated.
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From 705 lung donor referrals, 304 lung transplantations were performed (use rate of 42%); 212 of recipients (70%) met at least 1 of the commonly cited EVLP initiation criteria. There was no significant difference in primary graft dysfunction grade 3 or 30-day mortality between recipients with or without an EVLP indication (10.2% versus 7.8%, P = .51; and 2.4% versus 0%, P = .14, respectively). Multivariate analyses showed no significant relationship between commonly cited EVLP criteria and primary graft dysfunction grade 3 or survival time. Recipient outcomes were significantly associated with recipient diagnosis.
At least 1 commonly cited criterion for EVLP initiation was present in 70% of the transplanted donors, and yet it did not predict clinical results; acceptable outcomes were seen in both subgroups. To discover the true utility of EVLP beyond good clinical management and focus EVLP on otherwise unacceptable lungs, a reconsideration of EVLP inclusion criteria is required.
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^†: These authors contributed equally

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ArticlesNormothermic perfusion of donor lungs for preservation and assessment with the Organ Care System Lung before bilateral transplantation: a pilot study of 12 patients

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

J Heart Lung Transplant

Clin Chest Med

Ann Thorac Surg

Am J Transplant

Chest

J Heart Lung Transplant

J Heart Lung Transplant

J Heart Lung Transplant

J Heart Lung Transplant

Chest

J Heart Lung Transplant

J Thorac Cardiovasc Surg

J Heart Lung Transplant

J Thorac Cardiovasc Surg

Articles
Normothermic perfusion of donor lungs for preservation and assessment with the Organ Care System Lung before bilateral transplantation: a pilot study of 12 patients