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Ann Thorac Surg 2006;82:1842-1848
© 2006 The Society of Thoracic Surgeons
Heart and Lung Transplant Unit, The Alfred Hospital, Melbourne, Australia
Accepted for publication May 18, 2006.
* Address correspondence to Dr Snell, Department of Allergy, Immunology, and Respiratory Medicine, The Alfred Hospital, Commercial Road, Melbourne, Victoria 3004, Australia (Email: g.snell{at}alfred.org.au).
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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METHODS: Early outcomes from 157 consecutive lung transplants (113 bilateral and 44 single) performed at The Alfred Hospital were compared across three preservation solutions.
RESULTS: Posttransplant oxygenation (p = 0.57), pulmonary vascular resistance (p = 0.34), intubation hours (p = 0.66), intensive care unit days (p = 0.34), severe PGD (grade 3) (p = 0.70), 30-day mortality (p = 0.87), and 3-month % predicted forced expiratory volume in 1 second (p = 0.58) were not statistically different; however, Perfadex trended toward superiority among the three solutions. After adjustment of donor, recipient, and operative factors in multivariate analysis, Perfadex was significantly associated with the prevention of moderate to severe PGD (grade 2 to 3) at 48 hours posttransplant (odds ratio = 0.26 [0.10 to 0.72], p < 0.01) compared with Papworth (odds ratio = 0.75 [0.32 to 1.75], p = 0.51) and Euro-Collins (reference) solutions.
CONCLUSIONS: Although any advantageous effects of Perfadex on early posttransplant outcomes were generally subtle and statistically nonsignificant, Perfadex prevented moderate to severe PGD. Switching preservation solution from Euro-Collins (or Papworth) to Perfadex would appear to usefully contribute to a strategy to reduce PGD in lung transplantation.
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Introduction |
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Since its introduction 18 years ago, flush perfusion of pulmonary grafts with cold modified Euro-Collins solution (Baxter Healthcare, Old Toongabbie NSW, Australia) has been the gold standard for clinical lung transplantation in the majority of transplant centers around the world [5, 6]. This was despite the fact that Euro-Collins (intracellular type solution) was originally developed for kidney preservation. More recently low-potassium dextran solutions (extracellular type solution) have been specifically developed for lung preservation [7–12]. Many experimental studies have shown their superior effects on lung preservation compared to Euro-Collins solution [7–12].
One particular type of low-potassium dextran glucose solution (Perfadex; Vitrolife, Göteborg, Sweden) is commercially available and many centers now routinely use this agent for lung preservation [13–20]. However, the superiority of Perfadex in comparison with Euro-Collins in clinical lung transplantation remains controversial. The first seven clinical studies concluded that the use of Perfadex (or other extracellular type solutions) improved posttransplant lung functional parameters compared with an historic control group preserved with Euro-Collins [13–19]. In contrast, two recent studies conducted in a retrospective manner found no difference in the clinical results of Perfadex compared with Euro-Collins [20, 21].
Papworth solution, an extracellular type solution containing mannitol, albumin and donor blood, has been used in approximately 8% of all lung transplant centers with satisfactory outcomes [5, 22–25]. However, few studies have described its efficacy in comparison with other preservation solutions [16].
In Australia, Euro-Collins and Papworth solutions had been used for lung preservation. Perfadex was introduced in September 2004, replacing Euro-Collins in our institution. In recent years, therefore, lungs transplanted in our institution have been preserved with Euro-Collins, Papworth, or Perfadex solutions depending on the time frame and which donor team procured the organs. This study aims to describe our unique experience in lung preservation and to compare the clinical efficacy of the three different solutions in lung transplantation.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Study Groups
All patients were divided into those who received lungs preserved with Perfadex (Perfadex group), or Euro-Collins (Euro-Collins group), or Papworth (Papworth group) solution.
Donor Assessment and Management
The lung donor assessment and management have been described elsewhere [26, 27]. Preoperative donor-recipient lymphocytotoxic cross-matching was routinely performed. Donor management, including repeated suctioning, physiotherapy, revision of antibiotic therapy, and fluid management, was encouraged to optimize the donor for transplantation where appropriate. Repeated assessments, including serial chest X-rays and arterial blood gases, were also undertaken after donor management before a final decision was made to accept or decline donor organs.
Donor Lung Procurement and Preservation
Lung procurement and preservation followed standard procedures [2, 28, 29]. In Australia the home state of the donor has priority to receive the donor referral; however, any organs not utilized in the donor state are offered on to interstate transplant programs in rotation [30]. Normally, organ procurement teams from the state transplant center where the organs are to be implanted perform the donor procurement. Occasionally, lungs not utilized in the donor-state are procured by the local team and transported to other centers [29]. In our institution, Perfadex replaced Euro-Collins solution in September 2004 and these two were the only preservation solutions used. Papworth solution was used in other institutions throughout the study period. An intravenous infusion of prostacyclin (Flolan, Wellcome, Sydney, Australia) (at 40 to 80 ng/kg/minute) for approximately 10 minutes before cross-clamp was performed when the intracellular type solution (Euro-Collins) was used for lung preservation. Papworth solution contained 100 to 200 mL/L of donor blood along the protocols of each transplant center. A single antegrade flush with cold preservation solution, followed by heart-lung en bloc procurement, was routinely performed.
Lung Transplant Surgical Technique and Perioperative Management
Lung transplant procedures have been described elsewhere [6, 31, 32]. Cardiopulmonary bypass was not routinely performed in our institution and only considered when intolerance of single lung ventilation due to hemodynamic instability was seen. As a part of pulmonary graft preparation, retrograde exploratory flush was performed to detect any unexpected pulmonary embolism in the donor pulmonary artery prior to implantation [4]. Before the completion of implantation, retrograde followed by antegrade reperfusion and removal of air were performed by the untied pulmonary vascular anastomotic suture lines. Postoperative management in the intensive care unit (ICU) was performed to ensure satisfactory end organ perfusion while maintaining a relatively low filling pressure (cardiac index > 2.4, pulmonary capillary wedge pressure < 10 mm Hg, and central venous pressure < 7 mm Hg). Patients with PGD received standardized evaluation and therapy, with increasing complexity depending on degree of ventilatory and hemodynamic compromise.
Immunosuppression and Surveillance of Transbronchial Lung Biopsy
Immunosuppression was based on triple therapy with cyclosporine (trough levels of 300 to 450 µg/L assayed by an enzyme-multiplied immunoassay technique with the ETS analyzer, [Syva, Palo Alto, CA]), azathioprine (1.5 to 2.0 mg/kg/day), and prednisolone (0.15 mg/kg/day). Prophylaxis for infection with Pneumocystis carinii or cytomegalovirus was undertaken with low dose oral trimethaprim-sulfamethoxazole and intravenous and oral ganciclovir, respectively. Surveillance bronchoscopy and transbronchial lung biopsy was performed at 0.5, 1, 2, 3, 6, 9, 12, 18, and 24 months, as well as yearly thereafter [26].
Data Collection
Data were retrieved retrospectively from the transplant database and a review of ICU and donor records. Pulmonary vascular resistance (PVR) and partial pressure of oxygen, arterial to fraction of inspired oxygen (PaO
2/FIO
2) ratio were collected 6 hourly within the first 24 hours after operation. Arterial blood gas analysis data and the existence of infiltrates on chest X-ray at the time points of 0 hour (T0), 24 hours (T24), 48 hours (T48), and 72 hours (T72) after operation were used to define PGD grade. The graft ischemic time of a bilateral lung transplant was defined as the ischemic time for the second transplanted lung.
Assessment of Outcome
The PaO
2/FIO
2 ratio, PVR, duration of intubation, length of ICU stay, PGD grade, percent of predicted forced expiratory volume in 1 second (%predFEV1) 3 months after transplantation, and 90-day survival were used as indicators of outcome.
Primary Graft Dysfunction Grading
Grading of PGD severity was undertaken according to International Society for Heart and Lung Transplantation criteria [33]. Briefly, the classification scheme is based on two clinical and Lung Transplantation parameters including the chest radiograph and PaO
2/FIO
2. The PaO
2/FIO
2 ratio greater than 300 without radiographic infiltrates is considered as grade 0, PaO
2/FIO
2 greater than 300 with radiographic infiltrates is considered as grade 1, PaO
2/FIO
2 between 200 and 300 with radiographic infiltrates is considered as grade 2, PaO
2/FIO
2 less than 200 with radiographic infiltrates is considered as grade 3. There are other specific inclusion-exclusion criteria, such as any patients on nasal cannula for oxygen or FIO
2 less than 0.3 are graded as 0 or 1 based on chest radiograph, absence of radiographic infiltrates is sufficient for grade 0 even if the PaO
2/FIO
2 ratio is less than 300, any patients mechanically ventilated with FIO
2 greater than 0.5 on nitric oxide beyond 48 hours after transplant is graded grade 3, and any patients on extracorporeal membrane oxygenation are automatically considered as grade 3.
Statistical Analysis
Continuous data were reported as mean ± standard error of the mean or median (interquartile range), while categoric data were reported as count and proportions. Comparison among groups was performed using the Kruskal-Wallis test for nonparametric continuous variables, or one-way analysis of variance or repeated measurements analysis of variance for parametric continuous variables, and the 
2 test or Fisher exact test for categoric variables. Logistic regression analysis was used to estimate the relationship of individual factors with the occurrence of PGD. All variables (Table 1) suggested by the univariate analysis with a level of significance defined as p less than 0.2 or those judged to be clinically important were included in the multivariate model. Multivariate models were constructed using a stepwise selection technique and validated using a backward elimination technique and further assessed for biological and clinical plausibility. For 34% of the patients, data regarding the existence of donor pulmonary emboli were not available as an exploratory preimplantation retrograde pulmonary arterial flush was not routinely performed over the early period of this study. However, unexpected donor pulmonary embolism was a significant risk factor for development of PGD [6]. Therefore, unexpected donor pulmonary embolism was included in a separate multivariate model and the association of the solutions and the subsequent development of PGD was assessed by two separated multivariate models with and without donor pulmonary emboli. Analysis was performed using the Statview 5.0 software package (SAS Institute Inc, Cary, NC). A two-sided p value of 0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Posttransplant Oxygenation and Pulmonary Vascular Resistance
The PaO
2/FIO2 ratio in the Perfadex and Papworth groups tended to be greater than that in the Euro-Collins group (p = 0.53), and PVR in the Perfadex group tended to be lower than that in the Papworth and Euro-Collins groups (p = 0.34). However, these differences among the three groups are not statistically significant.
Duration of Intubation and Length of ICU Stay
The percentages of the patients remaining intubated and remaining in ICU are shown in Figure 2. The percentages of the patients remaining intubated 24 hours after transplantation in the Perfadex, Papworth, and Euro-Collins groups are 23%, 45%, and 38%, respectively (Fig 2A). The percentages of the patients remaining in ICU 7 days after transplant in the Perfadex, Papworth, and Euro-Collins groups are 13%, 26%, and 27%, respectively (Figure 2B). Patients in the Perfadex group tended to be extubated (p = 0.66) and discharged from ICU (p = 0.34) earlier than those in the Papworth and Euro-Collins groups, however, these differences among the three groups are not statistically significant.
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The incidence of moderate to severe PGD (grade 2–3) at T48 is shown in Figure 3. The incidence of PGD (grade 2–3) was 16% in the Perfadex, 42% in the Papworth and 46% in the Euro-Collins groups, and the difference among groups is statistically significant (p < 0.01).
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Three-Month Pulmonary Function
Three-month posttransplant %predFEV1 was 74 ± 4% in the Perfadex, 76 ± 3% in the Papworth, and 71 ± 3% in the Euro-Collins groups and there was no significant difference among the groups (p = 0.58).
Multivariate Risk Factor Analysis for Primary Graft Dysfunction
Univariate and multivariate logistic regression analysis for moderate to severe PGD (grade 2–3) at T48 is shown in Table 2. In the multivariate analysis, the use of Perfadex, single lung transplant, and diagnosis of pulmonary hypertension were significantly associated with development of moderate to severe PGD (grade 2–3). Perfadex was a negative risk factor for PGD (grade 2–3) (odds ratio = 0.26 [0.10 to 0.72], p < 0.01). A similar association was seen in a second multivariate model that included unexpected donor pulmonary embolism (odds ratio = 0.22 [0.06 to 0.75], p < 0.05).
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Perfadex has been introduced for clinical lung preservation because of its superior effects on lung preservation as supported by many experimental studies [7–12]. A low potassium extracellular type solution (Perfadex) avoids the severe vasoconstriction seen in a high potassium intracellular type solution (Euro-Collins) and provides better preservation of endothelial function [12]. Theoretically, the dextran in Perfadex retains water in the intravascular compartment resulting in decreased interstitial edema formation. This leads to a reduction in the aggregation of erythrocytes and circulating thrombocytes, thereby improving the microcirculation and reducing cellular activation. Preservation of type II pneumocytes with Perfadex contributes less cytotoxicity and improved cellular metabolism compared with Euro-Collins [8, 9, 12]. Additionally, Perfadex reduces lipid peroxidation [10] and ischemia-reperfusion injury [9, 10] and achieves better graft function in an experimental transplant model [12, 13].
In clinical lung transplantation, initial studies demonstrated that Perfadex improves posttransplant lung functional parameters when compared with a historic control group preserved with Euro-Collins [13–15, 17–19]. However, the superiority in utilization of Perfadex in comparison with Euro-Collins in clinical lung transplantation remains controversial, as two recent studies did not confirm the superior effects of Perfadex as previously reported [20, 21].
Aziz and colleagues [20] investigated 69 patients and found no differences on posttransplant chest X-ray score at 1 and 48 hours, oxygenation ratio at 12 and 48 hours, intubation hours, ICU days, and 30-day mortality between Perfadex and Euro-Collins. The authors pointed out that the previous studies had limitations regarding group matching including patient selection, type and era of transplant, and lack of radiographic assessment. Nath and colleagues [21], in a cohort study including the largest number of patients (n = 231) comparing Perfadex and Euro-Collins found that both groups had similar extubation rates at 48 hours, similar ICU and hospital days, and similar survival rates (30-day, 90-day, 1-year survival, and 1-year bronchiolitis obliterans syndrome-free survival). They also investigated the incidence of severe PGD (grade 3) at 0, 24, and 48 hours and found that PGD (grade 3) at 24 hours was lower in Perfadex compared with Euro-Collins. Unfortunately, the authors used a nonstandard [33], locally modified, PGD grading system in which chest X-ray data were not incorporated. The current study used multivariate analysis and adjusted for potential donor, recipient, and operative variables to compare the effect of three different solutions. Perfadex was significantly associated with a decreased incidence of moderate to severe PGD (grade 2–3) and trended towards significance in other important outcomes. The results from the current study support the findings of the studies by Aziz and colleagues [20] and Nath and colleagues [21].
Regarding the discrepancy between the experimental evidence and clinical results, Aziz and colleagues [20] pointed out that this discrepancy could be due to the lack of brainstem death models used in the experimental studies. Nath and colleagues [21] pointed out that many of the superior effects of Perfadex in experimental studies were realized when the ischemic time was significantly longer than in the clinical setting. The inflated lungs have ability to take oxygen and the addition of glucose in Perfadex supports aerobic metabolism and maintains cell integrity during prolonged storage period [34]. Perfadex might have enhanced effects when used for extended donor lungs with longer ischemic time. When analyzed for ischemic time more than 6 hours, our data do not support this hypothesis; however, numbers of patients in the current study with extended graft ischemic time are small.
There are other issues to be noted. The first issue is the cost regarding the solution and patient care. The cost of each solution including additives (ie, specific minerals, buffers, albumin, mannitol, and vasodilators) is different. The cost of administering Perfadex, Papworth, and Euro-Collins per lung transplant are approximately US$900, $600, and $700, respectively. The resultant cost for patient care (ie, ICU costs) among the three solutions may also be different. The percentage of the patients remaining in ICU 7 days after transplant was 13% with Perfadex and 27% with Papworth and Euro-Collins solutions. In our institution, the ICU care for postlung transplant patient costs approximately US$800 per day per patient and around 35 transplants were performed annually, therefore the utilization of Perfadex may contribute to a significant cost saving. The second issue is the standardization of the quality of the solution. Perfadex and Euro-Collins are commercially based products, therefore the quality of these two is well-controlled all over the world. In contrast, Papworth is a self-made solution that requires addition of donor blood. Moreover, the recipe of the blood concentration varies between centers, ranging from 100 to 200 mL blood per liter. It might therefore be harder to justify "quality" in the administration of Papworth solution. It can also be argued that taking 200 to 400 mL of blood from hemodynamically unstable brain-dead multiorgan donors should be avoided as hemodynamic instability with persistent low blood pressure can increase the risk of posttransplant graft dysfunction after lung, liver, and kidney transplantation [35–37].
The retrospective and observational nature of the analysis represents the main limitation in the current study. Historic controls from different eras and different procurement teams were used. Although potential confounding variables were considered and adjusted by multivariate analysis, the number of patients in each group limited the statistical power of the study. However, with a robust PGD grading system [33] now available, a randomized study is now required to investigate definitively the role of Perfadex in clinical lung preservation for ideal and extended donor lungs.
This study compares three different preservation solutions including Perfadex, Papworth, and Euro-Collins in clinical lung transplantation. Factors influencing posttransplant outcomes were numerous and complex. Although the early posttransplant outcomes of these three solutions were not significantly different, Perfadex was significantly associated with the prevention of moderate to severe PGD (grade 2–3) at T48. Overall, switching preservation solution from Euro-Collins (or Papworth) to Perfadex would appear to contribute to a strategy that reduces clinically significant PGD in lung transplantation.
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Acknowledgments |
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TopAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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References |
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TopAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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This article has been cited by other articles:
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  P. A. Corris and J. D. Christie Update in Transplantation 2006 Am. J. Respir. Crit. Care Med., March 1, 2007; 175(5): 432 - 435. [Full Text] [PDF]
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 T. Oto, B. J. Levvey, H. Whitford, A. P. Griffiths, T. Kotsimbos, T. J. Williams, and G. I. Snell Feasibility and Utility of a Lung Donor Score: Correlation With Early Post-Transplant Outcomes Ann. Thorac. Surg., January 1, 2007; 83(1): 257 - 263. [Abstract] [Full Text] [PDF]
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= Perfadex; 
; = Papworth, 
= Euro-Collins.)
= Perfadex; 
= Papworth; • = Euro-Collins.)