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Ann Thorac Surg 1999;68:2015-2019
© 1999 The Society of Thoracic Surgeons
a Division of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
Address reprint requests to Dr Gammie, Division of Cardiothoracic Surgery, University of Massachusetts Medical Center, 55 Lake Ave N, Worcester, MA 01655-0304
e-mail: gammiej{at}ummhc.org
Presented at the Thirty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 25–27, 1999.
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.
Prolonged cold ischemic times are unequivocally associated with reduced posttransplantation survival in cardiac transplantation [1]. Although it is generally accepted that the upper limit for safe ischemic time in lung transplantation is 4 to 6 hours [2, 3], there is surprisingly little data to support this conclusion. We performed this review to assess the effect of ischemic time on outcomes in lung transplantation.
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.
Donor selection and organ preservation
Donor selection criteria have been previously published [4–6]. Briefly, pulmonary preservation was accomplished with infusion of 50 to 100 mL/kg of cold (4°C) crystalloid solution (pulmoplegia) into the pulmonary artery after aortic cross-clamping. Euro-Collins solution was used through April 1991, after which University of Wisconsin solution was utilized. Details of the harvesting and preservation techniques were previously published. Alprostadil (prostaglandin E1; 500 µg) was administered before infusion of preservation solution, as well as in the first liter of pulmoplegia. Lungs were transported on ice. Ischemic time was defined as the interval from application of the aortic cross-clamp during harvesting until reperfusion of the graft in the recipient. For double-lung transplants, ischemic time was defined as the mean ischemic time for both lungs.
Allograft function and survival
Acute rejection was defined by histologic criteria [7], with grade II or higher considered important. The number of acute rejection episodes in the first 100 days after transplantation was calculated for those patients surviving more than 30 days. Obliterative bronchiolitis (OB) was diagnosed based on histologic criteria [7]. The diagnosis of diffuse alveolar damage (DAD) was assigned based on histologic findings from autopsy or biopsy specimens [8]. Survival is defined as graft survival.
Statistical analysis
Statistical computations were performed using JMP software (SAS Institute, Cary, NC). Actuarial survivals between groups were estimated by means of the Kaplan-Meier method, and significance was tested using the log-rank test. Comparisons between the incidence of DAD, OB, acute rejection, and duration of intubation for the different groups were done with the use of the unpaired t test, the Mann-Whitney U test, or 
2 test where appropriate. Multivariate regression analysis performed with the Cox proportional-hazards model was used to assess the influence of various donor variables on survival.
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 significant difference in the duration of postoperative intubation (median 3, 4, 3 days), episodes of acute rejection in the first 100 days after transplantation (1.9, 1.8, 1.7), or incidence of obliterative bronchiolitis (23%, 28%, 26%) between the three groups (0 to 4 hours, 4 to 6 hours, > 6 hours, respectively) (Table 1).
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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 ischemic time on both 1- and 5-year mortality [9]. The experience gained in cardiac transplantation has been extrapolated to lung transplantation. Although it is generally accepted that the upper limit for safe ischemia in pulmonary transplantation is in the range of 4 to 6 hours [10], there are little data to support this notion. We reviewed our experience at a single established center and found no effect of cold allograft ischemic time on posttransplantation survival. Early graft function, measured indirectly as the duration of postoperative intubation, was similar among groups. The histologic correlate of early graft injury, diffuse alveolar damage, occurred with a similar frequency in each of the three ischemic time groups. Finally, both acute and chronic (OB) rejection were equally common in each of the groups.
Two single-center experiences published in 1996 reached opposite conclusions. Snell and associates reviewed their experience with 106 lung and heart-lung transplantations, and found graft ischemic time to be an independent predictor of survival on multivariate analysis [11]. They concluded that ischemic times in excess of 5 hours were associated with poorer outcomes and therefore should be avoided. In contrast, Kshettry and colleagues analyzed results of 83 lung transplantations and found graft ischemic time to have no influence on postoperative survival [12]. They also demonstrated a lack of effect of ischemic time on incidence of postoperative rejection episodes, intensive care unit length of stay, and postoperative pulmonary function. More recently, Bund and associates examined postreperfusion intraoperative oxygenation in 23 lung transplant recipients, and found that prolonged ischemic times exerted a negative influence on oxygenation, although no effect on duration of postoperative intubation was observed [13]. They extrapolated their results and suggested that ischemic times in excess of 6 hours would likely result in severe early graft dysfunction. In the International Society for Heart and Lung Transplantation (ISHLT) registry report, lung allograft cold ischemic time is not an independent predictor of survival at either 1 or 5 years after transplantation [9]. Novick and colleagues recently examined 5,052 lung transplant recipients in the United Network for Organ Sharing (UNOS)/International Society for Heart and Lung Transplantation (ISHLT) registry using multivariate analysis and confirmed that ischemic time did not predict early survival after transplantation [14]. When the interaction between donor age and ischemic time was considered, patients at the extremes of donor age (> 55 years) and ischemic times (> 6 to 7 hours) were found to have an increased 1-year mortality after lung transplantation.
Additional evidence that ischemic time constraints may be substantially less stringent in lung transplantation exists in the form of several anecdotal reports of excellent clinical outcomes despite markedly prolonged pulmonary graft ischemic times, in some cases longer than 11 hours [10, 12, 15–17]. In our review, the longest ischemic time was 8 hours, 58 minutes for a double-lung graft that was implanted in a 31-year-old woman with Eisenmenger’s syndrome resulting from an atrial septal defect. She was transferred out of the intensive care unit 1 week after transplantation, and was discharged from the hospital 3 weeks later. She remains alive and well more than 6.5 years posttransplantation. Animal models of lung transplantation in which cold graft ischemic times far in excess of those experienced in clinical lung transplantation populate the literature, suggesting that conventional limits of ischemic time using standard cold preservation techniques have not been adequately tested in the clinical practice of lung transplantation [18–23] (Table 3).
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In our review, we identified the diagnosis of diffuse alveolar damage to be associated with substantially reduced graft survival. DAD, or acute alveolar injury, is the histologic correlate of the adult respiratory distress syndrome. DAD is a pattern of lung injury that can arise from numerous and diverse conditions, including both direct injuries to the lung as well as systemic disorders. On examination, DAD is characterized by interstitial and intraalveolar edema, with dense eosinophilic hyaline membranes composed of fibrin, cell debris, and hemorrhage coating denuded alveolar septae and ducts. In lung transplantation, DAD has been identified early after transplantation and is considered to be the histologic correlate of preservation injury. Sibley and associates found DAD in 10% of their lung transplant population within the first 3 weeks after transplantation [25]. Chapparro and associates identified DAD in 31% of 137 lung transplant recipients, with 80% of cases occurring within 4 months of transplantation. In their experience, DAD was most commonly associated with infection (52% of biopsies), followed by perioperative ischemia-reperfusion injury (19%). In our review, DAD was a common histologic diagnosis seen in 40% of recipients a median of 12 days after transplantation. However, the incidence of DAD was not related to ischemic time. Similar to our previously published experience in double-lung transplantation, DAD was seen more commonly in patients placed on cardiopulmonary bypass during the lung transplant operation. In an earlier report from our institution, Pham and associates demonstrated that a histologic diagnosis of DAD early after lung transplantation was highly correlated with clinical ischemia-reperfusion injury as well as elevated levels of interleukin-6 (IL-6) [26]. However, DAD did not correlate with ischemia time. In that study, among 5 patients with DAD, the 30-day mortality was 80%, in contrast to no mortality among 10 patients without DAD. Our current study extends and confirms these observations and clearly demonstrates that a diagnosis of DAD early after lung transplantation has no relationship with prolonged cold ischemic times, but is a histologic correlate of early graft dysfunction that is more common among patients transplanted on CPB, and is associated with significant early graft loss.
Our report provides solid evidence that prolonged pulmonary graft ischemic time does not have a negative impact on survival or on other measures of posttransplantation outcome, including duration of mechanical ventilation, and the incidence of acute and chronic rejection in clinical lung transplantation using conventional single-flush preservation techniques and cold storage. There are several important implications of this finding. Increasing the threshold for tolerable ischemia beyond the traditionally accepted 4 to 6 hours would significantly improve the logistics of pulmonary transplantation. The donor pool would be expanded by allowing retrieval of lungs from greater distances. More time would be available for optimal donor-recipient matching (although the value of improved immunologic matching in lung transplantation is unclear) [27, 28]. Single-flush preservation techniques that are currently used in clinical lung transplantation may be adequate. Research into improved lung preservation should focus on altering the pathophysiologic state of the donor and recipient, rather than extending the duration of ischemia of previously healthy lungs, as is commonly done in the laboratory [24]. Finally, in the future, longer periods of safe ischemia might allow immunomodulation/tolerance induction of the recipient.
References
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