Pulmonary graft function after long-term preservation of non-heart-beating donor lungs

doi:10.1016/S0003-4975(00)01234-0

The Annals of Thoracic Surgery

Volume 69, Issue 5, May 2000, Pages 1556-1562

https://doi.org/10.1016/S0003-4975(00)01234-0 Get rights and content

Abstract

Background. Critical organ shortage in lung transplantation could be attenuated by the use of non-heart-beating donor (NHBD) lungs. In addition, prolonged ischemic tolerance of the organs would contribute to the alleviation of organ shortage. The aim of this study was to investigate pulmonary graft function of NHBD lungs after long-term hypothermic storage.

Methods. Twelve native-bred pigs (bodyweight 20 to 30 kg) underwent left lung allotransplantation. In the heart-beating donor (HBD) group, lungs were harvested immediately after cardiac arrest. In the NHBD group, lungs were subjected to a warm ischemic period of 90 minutes before harvesting. After a total ischemic time of 19 hours, pulmonary grafts in both groups were reperfused and pulmonary graft function was assessed. All values were compared with a sham-operated control group.

Results. Pulmonary graft function in the HBD group was excellent. In the NHBD group, pulmonary gas exchange was impaired, but still provided good graft function compared with the excellent graft function in the HBD group. Pulmonary vascular resistance was even lower in the NHBD group. In the NHBD group, calculated intrapulmonary shunt fraction (Q_s/Q_t) was significantly increased compared with the sham-group. Histologic alteration and wet-to-dry ratio did not differ significantly between the HBD and NHBD group.

Conclusions. We conclude that NHBD lungs (90 minutes of warm ischemic time) have the potential to alleviate organ shortage in lung transplantation even after an extended total ischemic time.

Section snippets

Material and methods

All experiments were approved by the responsible government (AZ 211-2531-59/97) and carried out in accordance with the “Guide for the Care and Use of Laboratory Animals” of the National Institutes of Health (publication No. 85-23, revised 1985).

For premedication, all animals were sedated intramuscularly with atropine (0.05 mg/kg), azeperone (12 mg/kg), and ketamine (15 mg/kg) followed by inducing anesthesia with intravenous piritramide (0.5 mg/kg) and sodium-thiopental (6 mg/kg). All animals

Results

There were no significant differences in pulmonary gas exchange, hemodynamics, dynamic lung compliance, blood cell counts, and body weight of donor and recipient animals. Total ischemic period including the time needed for implantation did not differ between the HBD group (19 ± 0.1 hours) and the NHBD group (18.8 ± 0.08 hours).

One hour after pulmonary graft reperfusion, MAP measured during double-lung ventilation and perfusion was reduced to 62.5 ± 2.3 mm Hg as compared with baseline values in

Comment

The pulmonary allograft is particularly sensitive to ischemic reperfusion injury, because its function depends on the integrity of the alveolar capillary membrane network 9, 12. However, the lung represents the only organ that can be preserved aerobically through its own supply of oxygen. Date and coworkers [13] were able to demonstrate maintenance of an aerobic metabolism by using the oxygen in the alveoli. They showed that oxygen consumption during preservation was about 0.02 mL/g wet weight

Acknowledgements

We thank Annemarie Allmeling, Gudrun Hoebel, Sylvia Münzing, and Elke Schuetze for their technical expertise and excellent support during the laboratory studies. Furthermore, we thank Otto Frisch for the animal care and Rudolph A. Hatz, MD, for revising the manuscript.

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Cited by (35)

The impact of alteplase on pulmonary graft function in donation after circulatory death – An experimental study
2017, Annals of Medicine and Surgery
Citation Excerpt :
The increasing interest in DCD to increase donor organs has led to extensive research in the field of EVLP and the ideal preservation method. There is now convincing evidence that a time frame of 60 min of warm ischemia does not seem to compromise the pulmonary graft [14–16]. The golden standard in clinical transplantation today is to give the donor intravenous heparin prior to lung harvesting to avoid lung thrombosis in the lung grafts.
Lung transplantation is hampered by the lack of organs resulting in deaths on the waiting list. The usage of donation after circulatory death (DCD) lungs would dramatically increase donor availability. The most optimal organ preservation method, and the need for antithrombotic and fibrinolytic treatment to prevent thrombosis in the donor lungs is currently on debate. The present study investigated, in a simulated clinical DCD situation, whether the addition of alteplase in the flush-perfusion solution at the time of pulmonary graft harvesting could prevent thrombosis in the donor lung and thereby improve pulmonary graft function.
Twelve Swedish domestic pigs were randomized into two groups. All animals underwent ventricular fibrillation and were then left untouched for 1 h after declaration of death. None of the animals received heparin. The lungs were then harvested and flush-perfused with Perfadex^® solution and the organs were then stored at 8 °C for 4 h. In one group alteplase was added to the Perfadex^® solution (donation after cardiac death with alteplase (DCD-A)) and in the other, it was not (DCD). Lung function was evaluated, using ex vivo lung perfusion (EVLP), with blood gases at different oxygen levels, pulmonary vascular resistance (PVR), lung weight, and macroscopic appearance.
During EVLP, there were no significant differences between groups in PaO₂ at any investigated FiO₂ level (1.0, 0.5, or 0.21). At FiO₂ 1.0, the PaO₂ in the DCD and DCD-A was 51.7 ± 2.05 kPa and 60.3 ± 3.67 kPa, respectively (p = 0.1320). There were no significant differences between groups PVR levels, in the DCD (372 ± 31 dyne x s/cm⁵) and in the DCD-A (297 ± 37 dyne x s/cm⁵) groups (p = 0.1720). There was no significant difference between groups in macroscopic appearance.
All the lungs showed excellent blood gases after EVLP, and they all meet the criteria's for clinical lung transplantation. The use of alteplase did not seem to have any obvious benefit to the donor lungs in a DCD situation. The donor lungs treated with alteplas showed slightly better blood gases and slightly lower PVR compared to the group without alteplas, however the difference was not significant. DCD appears to be a safe and effective method to expand the donor pool.
Lung transplantation from donation after cardiocirculatory death: A systematic review and meta-analysis
2015, Journal of Heart and Lung Transplantation
Citation Excerpt :
Of the centers that perform transplantation with DCD donors, most limit eligibility to 60 minutes of warm ischemic time. The longest acceptable warm ischemic time is unknown but may be ≥90 minutes.38–40 The potential number of DCD donors would increase dramatically if uncontrolled donors were more widely used.
Lung transplantation (LTx) can extend life expectancy and enhance the quality of life for select patients with end-stage lung disease. In the setting of donor lung shortage and waiting list mortality, the interest in donation after cardiocirculatory death (DCD) is increasing. We performed a systematic review and meta-analysis to compare outcomes between DCD and conventional donation after brain death (DBD).
PubMed, CINAHL, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, and ClinicalTrials.gov were searched. We identified original research studies with 1-year post-transplant survival data involving >5 DCD transplants. We performed meta-analyses examining 1-year survival, primary graft dysfunction, and acute rejection after LTx.
We identified 519 citations; 11 observational cohort studies met our inclusion criteria for systematic review, and 6 met our inclusion criteria for meta-analysis. There were no differences found in 1-year mortality after LTx between DCD and DBD cohorts in individual studies or in the meta-analysis (DCD [n = 271] vs DBD [n = 2,369], relative risk [RR] 0.88, 95% confidence interval [CI] 0.59–1.31, p = 0.52, I² = 0%). There was also no difference between DCD and DBD in a pooled analysis of 5 studies reporting on primary graft dysfunction (RR 1.09, 95% CI 0.68–1.73, p = 0.7, I² = 0%) and 4 studies reporting on acute rejection (RR 0.72, 95% CI 0.49–1.05, p = 0.09, I² = 0%).
Survival after LTx from DCD is comparable to survival after LTx from DBD in observational cohort studies. DCD appears to be a safe and effective method to expand the donor pool.
Expanding the Donor Pool: Donation After Cardiac Death.
2015, Thoracic Surgery Clinics
Citation Excerpt :
Van Raemdonck and colleagues66 reported lung tolerance to WI up to 1 hour, and Greco and colleagues67 demonstrated successful LTx after WI intervals up to 90 minutes. Loehe and colleagues68 similarly showed acceptable graft function after 90 minutes WI and 19 hours of cold storage. One shortcoming of these experimental studies has been that the onset of cardiac death is abruptly induced and, therefore, does not reproduce the agonal phase of dying that occurs in the clinical setting of DCD procurement.
Peculiar mechanisms of graft recovery through anti-inflammatory responses after rat lung transplantation from donation after cardiac death
2012, Transplant Immunology
Although lung transplantation from donation after cardiac death (DCD), especially uncontrolled DCD, is limited by warm ischemic periods, the molecular mechanism of warm ischemia–reperfusion-injury (IRI) has not been well elucidated. The purpose of this study was to clarify the particular longitudinal mechanisms of molecular factors involved in warm IRI.
Cold ischemic-time (CIT)-group lungs were retrieved and subjected to 3-h of cold preservation, whereas warm ischemic-time (WIT)-group lungs were retrieved after 3-h of warm ischemia. Orthotopic rat lung transplantation was performed and the grafts were reperfused for 1 or 4-h. The graft functions, gene expression, and activation of inflammatory molecules in the grafts were analyzed. Exhaled-carbon-monoxide-concentration (ExCO-C) was measured during reperfusion.
Only the WIT-group showed obvious primary graft dysfunction at 1-h reperfusion, but the graft function was recovered during 4-h reperfusion. Most of pro-inflammatory cytokines and stress-induced molecules showed different expression and activation patterns between CIT and WIT groups. In the WIT-group, the expressions of anti-inflammatory molecules, IL-10 and HO-1, were significantly increased at 1-h reperfusion compared to the CIT-group, and these high levels were maintained through 4-h reperfusion. Furthermore, ExCO-C levels in the WIT-group increased immediately after reperfusion compared to the CIT-group.
This study indicates that warm IRI may involve a different mechanism than cold IRI and anti-inflammatory pathways may play important roles in the graft recovery after lung transplantation from uncontrolled DCD.
Acceptable warm ischemia time of tracheal grafts from nonheart-beating donors in rats
2011, Transplantation Proceedings
Citation Excerpt :
Egan et al1 have shown the possibility to use canine lungs from NHBDs after 1 hour of WI time for single-lung transplantation. In a swine model, Loche et al2 reported excellent gas exchange at 5 hours after transplantation when the lungs were retrieved from NHBDs at 90 minutes after death. However, these studies did not evaluate the long-term effects of WI on bronchial healing.
Warm ischemia (WI)-induced airway complications are common in clinical lung transplantation. However, the acceptable WI time of tracheal grafts from non–heart-beating donors (NHBDs) is unknown. The purpose of this study was to determine the acceptable WI time by observing tracheal epithelial regeneration among NHBD.
Forty-eight rats were randomly divided into four groups (each with 12 rats): WI-0 minutes (group A), WI-30 minutes (group B), WI-45 minutes (group C), and WI-60 minutes (group D). In each group, the tracheas from 6 rats were imbedded in the greater omentum of 6 other rats. Fourteen days later, the transplanted trachea was obtained from the recipient to evaluate epithelial thickness and regeneration. Six tracheas were obtained from living donors as a control group.
There were no significant differences in tracheal transplantation time (mean, 17.66 ± 1.21 minutes). There were no significant differences in epithelial thickness and regeneration between the controls and groups A, B, and C (P < .05). Group D showed no normal epithelial structure of the trachea only with monolayer cells.
The time limits of tolerance to WI of tracheal grafts from NHBDs may be 45 minutes.
Activations of mitogen-activated protein kinases and regulation of their downstream molecules after rat lung transplantation from donors after cardiac death
2011, Transplantation Proceedings
Accepting organs donated after cardiac death (DCD) is an effective approach to the donor shortage. However, lung transplantations from DCD donors show severe rapid pulmonary graft dysfunction (PGD) followed by warm ischemia–reperfusion injury (IRI). This study sought to clarify the molecular mediators in warm IRI, including activation of mitogen-activated protein kinase (MAPK) and the downstream cascades.
We performed single left lung transplantation using organs from male Sprague-Dawley rats after 0 (CIT group), 30 (30WIT group), or 180 (180WIT group) minutes of warm ischemia time. Pulmonary graft functions were estimated by blood gas analysis. At 1 hour after reperfusion, the phosphorylation status of MAPKs (ERK, p38, and JNK) and the gene expression levels of transcription factors (Egr-1 and ATF-3) and immune mediators (MCP-1, MIP-2, PAI-1, ICAM-1, TNF-α, IL-1β, IL-6, and COX-2) in the grafts were examined using Western blotting and real-time polymerase chain reaction assays.
Severe PGD was observed in the 180WIT group compared with transplanted lungs in the other groups, which exhibited good pulmonary graft function. ERK and JNK activations, as well as mRNA levels of transcription factors (Egr-1 and ATF3) significantly increased with greater warm ischemic times. The pattern of JNK activation correlated with the severity of PGD. MCP-1, ICAM-1, IL-1β, IL-6, and COX-2 were also up-regulated among the 180WIT group, although MIP-2 and PAI-1 showed no significant differences among the groups.
We suggest that the ERK and JNK pathways may play important roles to induce the injury caused by prolonged warm ischemia followed by reperfusion in the setting of lung transplantation from DCD donors.

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Original articles: General thoracicPulmonary graft function after long-term preservation of non-heart-beating donor lungs

Abstract

Section snippets

Material and methods

Results

Comment

Acknowledgements

J Heart Lung Transplant

Ann Thorac Surg

Transplant Proc

Ann Thorac Surg

Ann Thorac Surg

J Thorac Cardiovasc Surg

Ann Thorac Surg

Transplant Proc

Ann Thorac Surg

J Thorac Cardiovasc Surg

NHLBI workshop summary. Biology of lung preservation for transplantation

Am Rev Respir Dis

Original articles: General thoracic
Pulmonary graft function after long-term preservation of non-heart-beating donor lungs