Effect of ischemic time on survival in clinical lung transplantation

doi:10.1016/S0003-4975(99)00903-0

The Annals of Thoracic Surgery

Volume 68, Issue 6, December 1999, Pages 2015-2019

Presented at the Thirty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 25–27, 1999.

https://doi.org/10.1016/S0003-4975(99)00903-0 Get rights and content

Abstract

Background. While there is convincing evidence that prolonged ischemic times correlate with reduced long-term survival in heart transplantation, the effect of ischemic time on outcome in clinical lung transplantation remains controversial. To assess the effect of ischemic time on outcomes in lung transplantation, we reviewed our experience.

Methods. The study was performed by retrospective chart review.

Results. First-time lung transplantation was performed on 392 patients between 1988 and 1998. All grafts were flushed with cold crystalloid preservation solution and stored on ice. Ischemic time data were available for 352 of 392 (90%) patients. Ischemic times were grouped as follows: 0 to 4 hours (n = 91), 4 to 6 hours (n = 201), more than 6 hours (n = 60). Ischemic time did not correlate with survival: 3-year actuarial survival = 56% (0 to 4 hours), 58% (4 to 6 hours), 68% (> 6 hours), p = 0.58. There was no significant difference in the incidence of biopsy-proven diffuse alveolar damage in the first 30 days after transplantation (31%, 32%, 38%), episodes of acute rejection in the first 100 days after transplantation (1.9, 1.8, 1.7), duration of intubation (median 3, 4, 3 days), or incidence of obliterative bronchiolitis (23%, 28%, 26%) between the three groups (0 to 4 hours, 4 to 6 hours, > 6 hours, respectively). A diagnosis of diffuse alveolar damage was associated with a significantly worse outcome (1-year survival = 82% versus 54%, p < 0.0001).

Conclusions. In contrast to heart transplantation, pulmonary allograft ischemic time up to 9 hours does not appear to have a significant impact on early graft function or survival. The presence of diffuse alveolar damage on biopsy early after transplantation does not correlate with prolonged ischemic time, but is associated with substantially reduced posttransplantation survival.

Section snippets

Patients and methods

Between April 1988 and June 1998, 392 patients underwent first-time single or double-lung transplantation. Four recipients of living-related grafts were excluded. Recipient ages ranged from 9 to 68 years, with a median of 45 years. There were 217 women and 175 men.

Results

Ischemic time data were available for 352 of 392 (90%) patients. Ischemic times ranged from 65 to 538 minutes, with a median value of 289 minutes. Ischemic times were grouped as follows: 0 to 4 hours (n = 91), 4 to 6 hours (n = 201), more than 6 hours (n = 60). Actuarial survival was similar among the three groups (Fig 1). Mean follow-up for each of the three ischemic time groups was 3.5, 3.6, and 4.0 years (0 to 4 hours, 4 to 6 hours, > 6 hours, respectively, p = 0.51). There was no

Comment

Ischemic time exerts a strong influence on graft survival in cardiac transplantation. Opelz and associates demonstrated an 8% greater survival 3 years posttransplantation for hearts with ischemic times less than 4 hours, in comparison with those having ischemic times exceeding 4 hours [1]. The International Society for Heart and Lung Transplantation’s registry includes data on over 45,000 heart transplants, and clearly demonstrates a highly significant, stepwise negative effect of increasing

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Cited by (76)

The effect of allograft ischemic time on outcomes following bilateral, single, and reoperative lung transplantation
2024, Journal of Thoracic and Cardiovascular Surgery
To determine whether allograft ischemic times affect outcomes following bilateral, single, and redo lung transplantation.
A nationwide cohort of lung transplant recipients from 2005 through 2020 was examined using the Organ Procurement and Transplantation Network registry. The effects of standard (<6 hours) and extended (≥6 hours) ischemic times on outcomes following primary bilateral (n = 19,624), primary single (n = 688), redo bilateral (n = 8461), and redo single (n = 449) lung transplantation were analyzed. A priori subgroup analysis was performed in the primary and redo bilateral-lung transplant cohorts by further stratifying the extended ischemic time group into mild (≥6 and <8 hours), moderate (≥8 and <10 hours), and long (≥10 hours) subgroups. Primary outcomes included 30-day mortality, 1-year mortality, intubation at 72 hours' posttransplant, extracorporeal membrane oxygenation (ECMO) support at 72 hours' posttransplant, and a composite variable of intubation or ECMO at 72 hours' posttransplant. Secondary outcomes included acute rejection, postoperative dialysis, and hospital length of stay.
Recipients of allografts with ischemic times ≥6 hours experienced increased 30-day and 1-year mortality following primary bilateral-lung transplantation, but increased mortality was not observed following primary single, redo bilateral, or redo single-lung transplants. Extended ischemic times correlated with prolonged intubation or increased postoperative ECMO support in the primary bilateral, primary single, and redo bilateral-lung transplant cohorts but did not affect these outcomes following redo single-lung transplantation.
Since prolonged allograft ischemia correlates with worse transplant outcomes, the decision to use donor lungs with extended ischemic times must consider the specific benefits and risks associated with individual recipient factors and institutional expertise.
Commentary on: Risk of prolonged ischaemic time linked to use of cardio-pulmonary bypass during implantation for lung transplantation in the United Kingdom
2023, Journal of Heart and Lung Transplantation
Lung transplantation using allografts with more than 8 hours of ischemic time: A single-institution experience
2021, Journal of Heart and Lung Transplantation
Citation Excerpt :
Acceptable long-term outcomes are also necessary to support broader use of lungs with IT >6 hours. Several studies found an association between IT >6 hours and compromised post-LTx survival,6,27 while others found no difference in survival among recipients of allografts with ITs above and below this threshold.5,8 Recently, large registry studies found similar long-term survival with IT ≥6 hours and <6 hours, despite differential survival at 30 days.10,11
Six hours was historically regarded as the limit of acceptable ischemic time for lung allografts. However, broader sharing of donor lungs often necessitates use of allografts with ischemic time >6 hours. We characterized the association between ischemic time ≥8 hours and outcomes after lung transplantation using a contemporary cohort from a high-volume institution.
Patients who underwent primary isolated bilateral lung transplantation between 1/2016 and 5/2020 were included. Patients bridged to transplant with extracorporeal membrane oxygenation or mechanical ventilation, and ex-vivo perfusion cases were excluded. Recipients were stratified by total allograft ischemic time <8 hours (standard) vs ≥8 hours (long). Perioperative outcomes and post-transplant survival were compared between groups.
Of 358 patients, 95 (26.5%) received long ischemic time (≥8 hours) lungs. Long ischemic time recipients were more likely to be male and have donation after circulatory death donors than standard ischemic time recipients. On unadjusted analysis, long and standard ischemic time recipients had similar survival, and similar rates of grade 3 primary graft dysfunction at 72 hours, extracorporeal membrane oxygenation post-transplant, acute rejection within 30 days, reintubation, and post-transplant length of stay. After adjustment, long and standard ischemic time recipients had comparable risks of mortality or graft failure.
In a modern cohort, use of lung allografts with “long” ischemic time ≥8 hours were associated with acceptable perioperative outcomes and post-transplant survival. Further investigation is required to better understand how broader use impacts post-lung transplant outcomes and the implications for smarter sharing under an evolving national allocation policy.
Local versus distant lung donor procurement does not influence short-term clinical outcomes
2021, Journal of Thoracic and Cardiovascular Surgery
The purpose of this study was to recognize clinically meaningful differences in lung transplant outcomes based on local or distant lung procurement. This could identify if the lung allocation policy change would influence patient outcomes.
This single-center retrospective cohort study analyzed adult patients who underwent lung transplant from 2006 to 2017. Donor and recipient data were abstracted from a collaborative, prospective registry shared by our local organ procurement organization, and tertiary medical center. Short-term outcomes, 1-year survival, and hospitalization costs were compared between local and distant lung transplants defined by donor service area.
Of the 722 lung transplants performed, 392 (54%) had local donors and 330 (46%) had distant donors. Donors were similar in age and cause of death. Recipients were significantly different in diagnosis and local recipients had lower median lung allocation scores (local, 37.3 and distant, 44.9; P < .01). Distant lung transplants had longer total ischemic times (local, 231 ± 52 minutes and distant, 313 ± 48 minutes; P < .01). The rate of major complications, length of hospital stay, and 1-year survival were similar between groups. Distant lung transplants were associated with higher median overall cost (local, $183,542 and distant, $229,871; P < .01). Local lung transplants were more likely to be performed during daytime (local, 333 out of 392 [85%] and distant, 291 out of 330 [61%]; P < .01).
Local lung transplants are associated with shorter ischemic times, lower cost, and greater likelihood of daytime surgery. Short- and intermediate-term outcomes are similar for lung transplants from local and distant donors. The new lung allocation policy, with higher proportion of distant lung transplants, is likely to incur greater costs but provide similar outcomes.
Pilot Trial of Extended Hypothermic Lung Preservation to Analyze Ischemia-reperfusion Injury in Pigs
2021, Archivos de Bronconeumologia
In lung transplantation (LT), the length of ischemia time is controversial as it was arbitrarily stablished. We ought to explore the impact of extended cold-ischemia time (CIT) on ischemia-reperfusion injury in an experimental model.
Experimental, randomized pilot trial of parallel groups and final blind analysis using a swine model of LT. Donor animals (n = 8) were submitted to organ procurement. Lungs were subjected to 6 h (n = 4) or 12 h (n = 4) aerobic hypothermic preservation. The left lung was transplanted and re-perfused for 4 h. Lung biopsies were obtained at (i) the beginning of CIT, (ii) the end of CIT, (iii) 30 min after reperfusion, and (iv) 4 h after reperfusion. Lung-grafts were histologically assessed by microscopic lung injury score and wet-to-dry ratio. Inflammatory response was measured by determination of inflammatory cytokines. Caspase-3 activity was determined as apoptosis marker.
We observed no differences on lung injury score or wet-to-dry ratio any given time between lungs subjected to 6 h-CIT or 12h-CIT. IL-1β and IL6 showed an upward trend during reperfusion in both groups. TNF-α was peaked within 30 min of reperfusion. IFN-γ was hardly detected. Caspase-3 immunoexpression was graded semiquantitatively by the percentage of stained cells. Twenty percent of apoptotic cells were observed 30 min after reperfusion.
We observed that 6 and 12 h of CIT were equivalent in terms of microscopic lung injury, inflammatory profile and apoptosis in a LT swine model. The extent of lung injury measured by microscopic lung injury score, proinflammatory cytokines and caspase-3 determination was mild.
En el trasplante de pulmón (TP), la duración del tiempo de isquemia es controvertida, ya que se estableció de forma arbitraria. Sería útil explorar el impacto del tiempo de isquemia fría (TIF) prolongado sobre la lesión de isquemia-reperfusión en un modelo experimental.
Ensayo piloto experimental aleatorizado de grupos paralelos y análisis ciego final utilizando un modelo de TP en cerdos. Se extrajeron los órganos de los animales donantes (n = 8). Los pulmones se conservaron durante 6 horas (n = 4) o 12 horas (n = 4) en hipotermia aeróbica. El pulmón izquierdo se trasplantó y reperfundió durante 4 horas. Se obtuvieron biopsias de pulmón (i) al comienzo del TIF, (ii) al final del TIF, (iii) 30 minutos después de la reperfusión y (iv) 4 horas después de la reperfusión. Los injertos de pulmón se evaluaron histológicamente mediante la puntuación de daño histológico pulmonar y la relación de peso húmedo y peso seco. La respuesta inflamatoria se valoró mediante la determinación de citoquinas inflamatorias. Se determinó la actividad de caspasa-3 como marcador de apoptosis.
No observamos diferencias en la puntuación de daño histológico pulmonar o en la relación de peso húmedo y peso seco en un momento dado entre los pulmones sometidos a 6 h-TIF o 12 h-TIF. Las IL-1β e IL-6 mostraron una tendencia ascendente durante la reperfusión en ambos grupos. El TNF-α alcanzó su punto máximo dentro de los 30 minutos posteriores a la reperfusión. Apenas se detectó IFN-γ. La inmunoexpresión de caspasa-3 se clasificó semicuantitativamente por el porcentaje de células teñidas. Se observó un 20% de células apoptóticas 30 minutos después de la reperfusión.
Observamos que 6 y 12 horas de TIF fueron equivalentes en términos de daño histológico pulmonar, perfil inflamatorio y apoptosis en un modelo de TP en cerdos. La extensión de la lesión pulmonar, medida por la puntuación de daño histológico pulmonar, las citoquinas proinflamatorias y la determinación de caspasa-3 fue leve.
Donor Selection and Management
2021, Encyclopedia of Respiratory Medicine, Second Edition
As a result of its increasing success over the last decades, lung transplantation as the ultimate treatment for patients suffering from end-stage lung disease is still hampered by the shortage of available donors and transplantable organs. Beside post-transplantation outcome in terms of survival and quality of life, the success of any lung transplant program as a whole should be evaluated based on both the acceptance rate of potential recipients (referred/screened/listed) as well as the conversion of potential donors (offered/evaluated/recovered).
On the one hand, suitable transplant candidates with increased risk factors may never get listed. On the other hand, it is well known that short and long-term clinical outcome after lung transplantation is related to donor lung quality. Based on fear for inferior outcome, donor lungs not meeting the pre-set standard criteria may never be accepted in less experienced lung transplant centers.
Donor lung utilization rate can be largely boosted by careful selection of non-standard-criteria donors, active donor management and donor lung assessment in the donor hospital.
This chapter aims to update the currently available evidence on how to identify, select, and manage potential lung donors to maximally increase the organ yield and to offer lung transplantation to a large number of potential recipients.

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Original Articles: General ThoracicEffect of ischemic time on survival in clinical lung transplantation

Abstract

Section snippets

Patients and methods

Results

Comment

Ann Thorac Surg

Clin Chest Med

Ann Thorac Surg

J Heart Lung Transplant

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

Ann Thorac Surg

The influence of HLA compatibility on graft survival after heart transplantation. The collaborative transplant study

N Engl J Med

NHLBI workshop summary. Biology of lung preservation for transplantation

Am Rev Respir Dis

The vascular biology of heart and lung preservation for transplantation

Thromb Haemost

Revision of the 1990 working formulation for the classification of pulmonary allograft rejectionLung Rejection Study Group

J Heart Lung Transplant

Primary graft failure following pulmonary transplantation

Transplantation

The Registry of the International Society for Heart and Lung Transplantationfifteenth official report—1998

J Heart Lung Transplant

Original Articles: General Thoracic
Effect of ischemic time on survival in clinical lung transplantation