- Email: [email protected]
Early Outcomes Comparing Perfadex, Euro-Collins, and Papworth Solutions in Lung Transplantation
GENERAL THORACIC
Early Outcomes Comparing Perfadex, Euro-Collins, and Papworth Solutions in Lung Transplantation Takahiro Oto, MD, Anne P. Griffiths, FRCNA, Franklin Rosenfeldt, MD, Bronwyn J. Levvey, RN, Trevor J. Williams, MD, and Gregory I. Snell, MD Heart and Lung Transplant Unit, The Alfred Hospital, Melbourne, Australia
Background. Despite improved surgical techniques and medical management, primary graft dysfunction (PGD) remains a major cause of early morbidity and mortality after lung transplantation. Different types of lung preservation solutions have been developed and applied to clinical use; however, the relative clinical efficacy of these solutions to prevent PGD remains controversial. This study aimed to investigate the effect of the three solutions most commonly used (Perfadex [Vitrolife, Göteborg, Sweden], Papworth, and EuroCollins [Baxter Healthcare, Old Toongabbie NSW, Australia]) on posttransplant outcomes. 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 ⴝ 0.57), pulmonary vascular resistance (p ⴝ 0.34), intubation hours (p ⴝ 0.66), intensive care unit days (p ⴝ 0.34), severe PGD (grade 3) (p ⴝ 0.70), 30-day mortality (p ⴝ 0.87), and
3-month % predicted forced expiratory volume in 1 second (p ⴝ 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 ⴝ 0.26 [0.10 to 0.72], p < 0.01) compared with Papworth (odds ratio ⴝ 0.75 [0.32 to 1.75], p ⴝ 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.
D
mercially 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 EuroCollins [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
espite improved surgical techniques and medical management, primary graft dysfunction (PGD) remains a major cause of early morbidity and mortality after lung transplantation [1– 4]. Lung preservation techniques and solutions have an important role in determining the incidence and severity of PGD. 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 EuroCollins (intracellular type solution) was originally developed for kidney preservation. More recently lowpotassium 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 EuroCollins solution [7–12]. One particular type of low-potassium dextran glucose solution (Perfadex; Vitrolife, Göteborg, Sweden) is comAccepted 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; e-mail: [email protected].
© 2006 by The Society of Thoracic Surgeons Published by Elsevier Inc
(Ann Thorac Surg 2006;82:1842– 8) © 2006 by The Society of Thoracic Surgeons
0003-4975/06/$32.00 doi:10.1016/j.athoracsur.2006.05.088
Ann Thorac Surg 2006;82:1842– 8
Patients and Methods From January 2002 to February 2006, 157 consecutive lung transplants (113 bilateral and 44 single) performed at The Alfred Hospital were included in this study. Heart-lung transplants were excluded from this study to avoid any confusion related to the variable effects of the transplanted heart on cardiac pulmonary edema. Institutional Ethics Committee advice was sought and ethical exemption without the necessity for consent was confirmed as this was deemed a clinical audit activity.
Study Groups All patients were divided into those who received lungs preserved with Perfadex (Perfadex group), or EuroCollins (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 donorrecipient 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.
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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 g/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 (Pao2/Fio2) 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 Pao2/Fio2 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.
GENERAL THORACIC
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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Table 1. Demographics of the Donor and Recipient Total Lung Transplants (n ⫽ 157) GENERAL THORACIC
Variables Donor factor Age (years) Sex (M/F) Smoking history ⬎ 20 pack-years Cause of death CVA Trauma Anoxia Others Intubation (hours) Pao2/Fio2 ratio Unexpected donor lung pulmonary embolism (yes/no) Recipient factor Age (years) Sex (M/F) Diagnosis COPD CF ILD PH Operative factor Procurement team (Alfred/others) Type of transplant (bilateral/single) Transplant era 2002–2003/2004–2006 Cardiopulmonary bypass use Ischemic time (minutes)
Perfadex (n ⫽ 40)
Papworth (n ⫽ 38)
Euro-Collins (n ⫽ 79)
40 ⫾ 2 24/16 4
33 ⫾ 2 26/12 4
38 ⫾ 2 53/26 14
24 6 9 1 68 ⫾ 8 438 ⫾ 17 9/30
12 22 3 1 42 ⫾ 4 459 ⫾ 13 12/10
38 25 12 4 64 ⫾ 6 472 ⫾ 10 16/27
47 ⫾ 2 22/17
49 ⫾ 2 26/12
46 ⫾ 2 51/28
19 11 9 1
17 10 7 4
33 26 14 6
40/0 34/6
0/38 24/14
76/3 55/24
⬍0.0001 0.08
0/40 8 325 ⫾ 20
21/17 10 465 ⫾ 14
59/20 13 346 ⫾ 15
⬍0.0001 ⬎0.2 ⬍0.0001
p 0.09 ⬎0.2 ⬎0.2 0.007
0.007 0.16 0.05 ⬎0.2 ⬎0.2 ⬎0.2
Continuous data are expressed as mean ⫾ SEM. p values for donor cause of death and underlying disease were given by overall comparison. CF ⫽ cystic fibrosis; COPD ⫽ chronic obstructive pulmonary disease; CPB ⫽ cardiopulmonary bypass; ILD ⫽ interstitial lung disease; Pao2/Fio2 ⫽ ratio of arterial oxygen tension and inspired oxygen consumption;
CVA ⫽ cerebrovascular accident; PH ⫽ pulmonary hypertension.
Primary Graft Dysfunction Grading
Statistical Analysis
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 Pao2/Fio2. The Pao2/ Fio2 ratio greater than 300 without radiographic infiltrates is considered as grade 0, Pao2/Fio2 greater than 300 with radiographic infiltrates is considered as grade 1, Pao2/Fio2 between 200 and 300 with radiographic infiltrates is considered as grade 2, Pao2/Fio2 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 Fio2 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 Pao2/Fio2 ratio is less than 300, any patients mechanically ventilated with Fio2 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.
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
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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.
Primary Graft Dysfunction Grading Fig 1. Percentage utilization of three preservation solutions in each year. (e ⫽ Perfadex; ; ⫽ Papworth, ⫽ Euro-Collins.)
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.
The incidence of severe PGD (grade 3) in the Perfadex, Papworth, and Euro-Collins groups was 29%, 44%, and 34% (p ⫽ 0.36) at T0, 13%, 11%, and 23% (p ⫽ 0.26) at T24, 11%, 14%, and 18% (p ⫽ 0.70) at T48, respectively. The incidence of severe PGD (grade 3) in the Perfadex group tended to be lower than that in the Papworth and Euro-Collins groups. However, these differences among the three groups did not reach statistical significance because the number of severe PGD (grade 3) patients was small.
Results Lung Preservation Solution The percentage utilization of the three preservation solutions in each year is shown in Figure 1. After 2004, Euro-Collins solution was completely replaced by Perfadex solution, although Papworth solution has continued to be used into 2006.
Donor and Recipient Demographics Detailed demographics, including donor, recipient, and operative factors, are shown in Table 1. Significant differences among the three groups were seen in some of the donor factors (cause of death and duration of intubation) and operative factors (organ procurement team, transplant era, and graft ischemic time). All of the recipient factors were similar among the three groups.
Posttransplant Oxygenation and Pulmonary Vascular Resistance The Pao2/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.
Fig 2. (A) Percentage of patients remaining intubated versus time (hours) after transplant. (B) Percentage of patients remaining in intensive care unit (ICU) versus time (days) after transplant. (Œ ⫽ Perfadex; ‚ ⫽ Papworth; ● ⫽ Euro-Collins.)
GENERAL THORACIC
Duration of Intubation and Length of ICU Stay
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GENERAL THORACIC Fig 3. Incidence of moderate to severe primary graft dysfunction (PGD) (grade 2–3) at 48 hours after transplant (T48). (e ⫽ PGD grade 0 –1; ⫽ PGD grade 2–3.)
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comparison with intracellular type solutions [13–19, 22– 25]. However, we have found no study that has directly compared the effect of three different and clinically most commonly used solutions including Perfadex, Papworth, and Euro-Collins on posttransplant outcomes. The current study showed that Perfadex was significantly associated with prevention of moderate to severe PGD (grade 2–3) at T48. Early posttransplant outcomes, including oxygenation, PVR, duration of intubation and ICU stay, severe PGD (grade 3), 30-day mortality, and 3-month %predFEV1, were comparable. However, for most of these parameters, Perfadex trended toward superiority among the three solutions. In addition, this translated to 27% of Papworth and Euro-Collins patients being still in ICU at 7 days compared with 13% of Perfadex patients. 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
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).
Table 2. Logistic Regression Analysis for Moderate to Severe Primary Graft Dysfunction (Grade 2–3) at 48 Hours After Transplantation
Thirty-Day Mortality
Comment
Univariate analysis Lung preservation solutions Perfadex Papworth Euro-Collins Diagnosis of pulmonary hypertension Unexpected donor pulmonary emboli Recipient age Type of Transplant (single) Cardiopulmonary bypass use Donor smoking history ⬎ 20 pack-years Transplant era Recipient gender (male) Ischemic time Procurement team (Alfred) Donor Pao2/Fio2 ratio Multivariate analysis Lung preservation solutions Perfadex Papworth Euro-Collins Type of transplant (single) Diagnosis of pulmonary hypertension
Many clinical articles have described the advantage of using extracellular type lung preservation solutions in
CI ⫽ confidence interval; Pao2/Fio2 ⫽ partial pressure of arterial oxygen/fraction of inspired oxygen.
Seven of 157 (4.5%) patients died within 30 days after transplantation and the cause of these deaths was nonspecific graft failure (n ⫽ 2), Aspergillus infection (n ⫽ 2), pulmonary embolism, liver failure, and multisystem organ failure (n ⫽ 1 each). The numbers of deaths in each group was 1 in the Perfadex, 2 in the Papworth, and 4 in the Euro-Collins groups and there was no significant difference among the groups (p ⫽ 0.87).
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).
Variable
Odds ratio
95% CI
p
0.22 0.85 1.00 8.81
0.08–0.60 0.39–1.89 Reference 1.83–42.41
⬍0.01 0.70
3.96
1.64–9.55
⬍0.01
1.03 2.08
1.00–1.05 1.01–4.30
⬍0.05 ⬍0.05
2.46
1.10–5.49
⬍0.05
2.29
0.92–5.72
0.08
0.56 0.64 1.00 0.81
0.29–1.08 0.33–1.26 0.99–1.01 0.38–1.70
0.08 0.19 0.32 0.57
0.99
0.99–1.00
0.74
0.26 0.75 1.00 4.03
0.10–0.72 0.32–1.75 Reference 2.12–54.99
⬍0.01 0.51
10.80
1.57–133.57
⬍0.05
⬍0.01
⬍0.01
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 syndromefree 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
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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 EuroCollins 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 EuroCollins 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 braindead 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
GENERAL THORACIC
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to contribute to a strategy that reduces clinically significant PGD in lung transplantation. GENERAL THORACIC
We gratefully acknowledge lung transplant surgeons, physicians, and anesthesiologists for technical assistance and Sharon Daly for assembling and verifying the clinical data. We also wish to extend our appreciation to members of the Heart and Lung Transplant Service, The Alfred Hospital, for their assistance.
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19. 20.
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34. 35.
36. 37.
tion injury. Munich Lung Transplant Group. Transplantation 1999;68:1139 – 43. Rega F, Verleden G, Vanhaecke J, et al. Switch from EuroCollins to Perfadex for pulmonary graft preservation resulted in superior outcome in transplant recipients. J Heart Lung Transplant 2003;22:S111. Rabanal JM, Ibanez AM, Mons R, et al. Influence of preservation solution on early lung function (Euro-Collins versus Perfadex). Transplant Proc 2003;35:1938 –9. Aziz TM, Pillay TM, Corris PA, et al. Perfadex for clinical lung procurement: is it an advance? Ann Thorac Surg 2003;75:990 –5. Nath DS, Walter AR, Johnson AC, et al. Does Perfadex affect outcomes in clinical lung transplantation? J Heart Lung Transplant 2005;24:2243– 8. Hooper TL, Locke TJ, Fetherston G, Flecknell PA, McGregor CG. Comparison of cold flush perfusion with modified blood versus modified Euro-Collins solution for lung preservation. J Heart Transplant 1990;9:429 –34. Hakim M, Higenbottam T, Bethune D, et al. Selection and procurement of combined heart and lung grafts for transplantation. J Thorac Cardiovasc Surg 1988;95:474 –9. Parry A, Higgins R, Wheeldon D, Bethune D, Wallwork J. The contribution of donor management and modified blood lung perfusate to post-transplant lung function. J Heart Lung Transplant 1999;18:121– 6. Locke TJ, Hooper TL, Flecknell PA, McGregor CG. Preservation of the lung: comparison of flush perfusion with cold modified blood and core cooling with cardiopulmonary bypass. J Heart Lung Transplant 1991;10:1– 8. Gabbay E, Williams TJ, Griffiths AP, et al. Maximizing the utilization of donor organs offered for lung transplantation. Am J Respir Crit Care Med. 1999;160:265–71. Williams TJ, Snell GI. Organ procurement--strategies to optimize donor availability. Semin Respir Crit Care Med 2001;22:541–50. Parekh K, Patterson A. Technical considerations in adult lung transplantation. Semin Thorac Cardiovasc Surg 2005; 16:322–31. Oto T, Rabinov, M, Negri J, et al. Techniques of reconstruction for inadequate donor left atrial cuff in lung transplantation. Ann Thorac Surg 2006;81:1199 –204. Snell GI, Griffiths A, Macfarlane L, et al. Maximizing thoracic organ transplant opportunities: the importance of efficient coordination. J Heart Lung Transplant 2000;19:401–7. Esmore DS, Brown R, Buckland M, et al. Techniques and results in bilateral sequential single lung transplantation. J Cardiac Surg 1994;9:1–14. Oto T, Rabinov M, Rosenfeldt F, Esmore DS. Extended pericardiotomy avoids cardiopulmonary bypass during bilateral sequential lung transplantation. J Thorac Cardiovasc Surg 2005;129:466 –7. Christie JD, Carby M, Bag R, Corris P, Hertz M, Well D. Report of the ISHLT working group on primary lung graft dysfunction part II: definition. A consensus statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2005;24:1454 –9. Date H, Matsumura A, Manchester JK, et al. Evaluation of lung metabolism during successful twenty-four hour canine lung preservation. J Thorac Cardiovasc Surg 1993;105:480 –91. Lucas BA, Vaughn WK, Spees EK, et al. Identification of donor factors predisposing to high discard rates of cadaver kidneys and increased graft loss within one year posttransplantation-SEOPF 1977-1982. South-Eastern Organ Procurement Foundation. Transplantation 1987;43:253– 8. Busuttil RW, Goldstein LI, Danovitch GM, et al. Liver transplantation today. Ann Intern Med 1986;104:377– 89. Tremblay LN, Yamashiro T, DeCampos KN, et al. Effect of hypotension preceding death on the function of lungs from donors with nonbeating hearts. J Heart Lung Transplant 1996;15:260 – 8.
Early Outcomes Comparing Perfadex, Euro-Collins, and Papworth Solutions in Lung Transplantation Takahiro Oto, MD, Anne P. Griffiths, FRCNA, Franklin Rosenfeldt, MD, Bronwyn J. Levvey, RN, Trevor J. Williams, MD, and Gregory I. Snell, MD Heart and Lung Transplant Unit, The Alfred Hospital, Melbourne, Australia
Background. Despite improved surgical techniques and medical management, primary graft dysfunction (PGD) remains a major cause of early morbidity and mortality after lung transplantation. Different types of lung preservation solutions have been developed and applied to clinical use; however, the relative clinical efficacy of these solutions to prevent PGD remains controversial. This study aimed to investigate the effect of the three solutions most commonly used (Perfadex [Vitrolife, Göteborg, Sweden], Papworth, and EuroCollins [Baxter Healthcare, Old Toongabbie NSW, Australia]) on posttransplant outcomes. 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 ⴝ 0.57), pulmonary vascular resistance (p ⴝ 0.34), intubation hours (p ⴝ 0.66), intensive care unit days (p ⴝ 0.34), severe PGD (grade 3) (p ⴝ 0.70), 30-day mortality (p ⴝ 0.87), and
3-month % predicted forced expiratory volume in 1 second (p ⴝ 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 ⴝ 0.26 [0.10 to 0.72], p < 0.01) compared with Papworth (odds ratio ⴝ 0.75 [0.32 to 1.75], p ⴝ 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.
D
mercially 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 EuroCollins [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
espite improved surgical techniques and medical management, primary graft dysfunction (PGD) remains a major cause of early morbidity and mortality after lung transplantation [1– 4]. Lung preservation techniques and solutions have an important role in determining the incidence and severity of PGD. 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 EuroCollins (intracellular type solution) was originally developed for kidney preservation. More recently lowpotassium 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 EuroCollins solution [7–12]. One particular type of low-potassium dextran glucose solution (Perfadex; Vitrolife, Göteborg, Sweden) is comAccepted 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; e-mail: [email protected].
© 2006 by The Society of Thoracic Surgeons Published by Elsevier Inc
(Ann Thorac Surg 2006;82:1842– 8) © 2006 by The Society of Thoracic Surgeons
0003-4975/06/$32.00 doi:10.1016/j.athoracsur.2006.05.088
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Patients and Methods From January 2002 to February 2006, 157 consecutive lung transplants (113 bilateral and 44 single) performed at The Alfred Hospital were included in this study. Heart-lung transplants were excluded from this study to avoid any confusion related to the variable effects of the transplanted heart on cardiac pulmonary edema. Institutional Ethics Committee advice was sought and ethical exemption without the necessity for consent was confirmed as this was deemed a clinical audit activity.
Study Groups All patients were divided into those who received lungs preserved with Perfadex (Perfadex group), or EuroCollins (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 donorrecipient 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.
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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 g/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 (Pao2/Fio2) 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 Pao2/Fio2 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.
GENERAL THORACIC
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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Table 1. Demographics of the Donor and Recipient Total Lung Transplants (n ⫽ 157) GENERAL THORACIC
Variables Donor factor Age (years) Sex (M/F) Smoking history ⬎ 20 pack-years Cause of death CVA Trauma Anoxia Others Intubation (hours) Pao2/Fio2 ratio Unexpected donor lung pulmonary embolism (yes/no) Recipient factor Age (years) Sex (M/F) Diagnosis COPD CF ILD PH Operative factor Procurement team (Alfred/others) Type of transplant (bilateral/single) Transplant era 2002–2003/2004–2006 Cardiopulmonary bypass use Ischemic time (minutes)
Perfadex (n ⫽ 40)
Papworth (n ⫽ 38)
Euro-Collins (n ⫽ 79)
40 ⫾ 2 24/16 4
33 ⫾ 2 26/12 4
38 ⫾ 2 53/26 14
24 6 9 1 68 ⫾ 8 438 ⫾ 17 9/30
12 22 3 1 42 ⫾ 4 459 ⫾ 13 12/10
38 25 12 4 64 ⫾ 6 472 ⫾ 10 16/27
47 ⫾ 2 22/17
49 ⫾ 2 26/12
46 ⫾ 2 51/28
19 11 9 1
17 10 7 4
33 26 14 6
40/0 34/6
0/38 24/14
76/3 55/24
⬍0.0001 0.08
0/40 8 325 ⫾ 20
21/17 10 465 ⫾ 14
59/20 13 346 ⫾ 15
⬍0.0001 ⬎0.2 ⬍0.0001
p 0.09 ⬎0.2 ⬎0.2 0.007
0.007 0.16 0.05 ⬎0.2 ⬎0.2 ⬎0.2
Continuous data are expressed as mean ⫾ SEM. p values for donor cause of death and underlying disease were given by overall comparison. CF ⫽ cystic fibrosis; COPD ⫽ chronic obstructive pulmonary disease; CPB ⫽ cardiopulmonary bypass; ILD ⫽ interstitial lung disease; Pao2/Fio2 ⫽ ratio of arterial oxygen tension and inspired oxygen consumption;
CVA ⫽ cerebrovascular accident; PH ⫽ pulmonary hypertension.
Primary Graft Dysfunction Grading
Statistical Analysis
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 Pao2/Fio2. The Pao2/ Fio2 ratio greater than 300 without radiographic infiltrates is considered as grade 0, Pao2/Fio2 greater than 300 with radiographic infiltrates is considered as grade 1, Pao2/Fio2 between 200 and 300 with radiographic infiltrates is considered as grade 2, Pao2/Fio2 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 Fio2 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 Pao2/Fio2 ratio is less than 300, any patients mechanically ventilated with Fio2 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.
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
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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.
Primary Graft Dysfunction Grading Fig 1. Percentage utilization of three preservation solutions in each year. (e ⫽ Perfadex; ; ⫽ Papworth, ⫽ Euro-Collins.)
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.
The incidence of severe PGD (grade 3) in the Perfadex, Papworth, and Euro-Collins groups was 29%, 44%, and 34% (p ⫽ 0.36) at T0, 13%, 11%, and 23% (p ⫽ 0.26) at T24, 11%, 14%, and 18% (p ⫽ 0.70) at T48, respectively. The incidence of severe PGD (grade 3) in the Perfadex group tended to be lower than that in the Papworth and Euro-Collins groups. However, these differences among the three groups did not reach statistical significance because the number of severe PGD (grade 3) patients was small.
Results Lung Preservation Solution The percentage utilization of the three preservation solutions in each year is shown in Figure 1. After 2004, Euro-Collins solution was completely replaced by Perfadex solution, although Papworth solution has continued to be used into 2006.
Donor and Recipient Demographics Detailed demographics, including donor, recipient, and operative factors, are shown in Table 1. Significant differences among the three groups were seen in some of the donor factors (cause of death and duration of intubation) and operative factors (organ procurement team, transplant era, and graft ischemic time). All of the recipient factors were similar among the three groups.
Posttransplant Oxygenation and Pulmonary Vascular Resistance The Pao2/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.
Fig 2. (A) Percentage of patients remaining intubated versus time (hours) after transplant. (B) Percentage of patients remaining in intensive care unit (ICU) versus time (days) after transplant. (Œ ⫽ Perfadex; ‚ ⫽ Papworth; ● ⫽ Euro-Collins.)
GENERAL THORACIC
Duration of Intubation and Length of ICU Stay
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GENERAL THORACIC Fig 3. Incidence of moderate to severe primary graft dysfunction (PGD) (grade 2–3) at 48 hours after transplant (T48). (e ⫽ PGD grade 0 –1; ⫽ PGD grade 2–3.)
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comparison with intracellular type solutions [13–19, 22– 25]. However, we have found no study that has directly compared the effect of three different and clinically most commonly used solutions including Perfadex, Papworth, and Euro-Collins on posttransplant outcomes. The current study showed that Perfadex was significantly associated with prevention of moderate to severe PGD (grade 2–3) at T48. Early posttransplant outcomes, including oxygenation, PVR, duration of intubation and ICU stay, severe PGD (grade 3), 30-day mortality, and 3-month %predFEV1, were comparable. However, for most of these parameters, Perfadex trended toward superiority among the three solutions. In addition, this translated to 27% of Papworth and Euro-Collins patients being still in ICU at 7 days compared with 13% of Perfadex patients. 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
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).
Table 2. Logistic Regression Analysis for Moderate to Severe Primary Graft Dysfunction (Grade 2–3) at 48 Hours After Transplantation
Thirty-Day Mortality
Comment
Univariate analysis Lung preservation solutions Perfadex Papworth Euro-Collins Diagnosis of pulmonary hypertension Unexpected donor pulmonary emboli Recipient age Type of Transplant (single) Cardiopulmonary bypass use Donor smoking history ⬎ 20 pack-years Transplant era Recipient gender (male) Ischemic time Procurement team (Alfred) Donor Pao2/Fio2 ratio Multivariate analysis Lung preservation solutions Perfadex Papworth Euro-Collins Type of transplant (single) Diagnosis of pulmonary hypertension
Many clinical articles have described the advantage of using extracellular type lung preservation solutions in
CI ⫽ confidence interval; Pao2/Fio2 ⫽ partial pressure of arterial oxygen/fraction of inspired oxygen.
Seven of 157 (4.5%) patients died within 30 days after transplantation and the cause of these deaths was nonspecific graft failure (n ⫽ 2), Aspergillus infection (n ⫽ 2), pulmonary embolism, liver failure, and multisystem organ failure (n ⫽ 1 each). The numbers of deaths in each group was 1 in the Perfadex, 2 in the Papworth, and 4 in the Euro-Collins groups and there was no significant difference among the groups (p ⫽ 0.87).
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).
Variable
Odds ratio
95% CI
p
0.22 0.85 1.00 8.81
0.08–0.60 0.39–1.89 Reference 1.83–42.41
⬍0.01 0.70
3.96
1.64–9.55
⬍0.01
1.03 2.08
1.00–1.05 1.01–4.30
⬍0.05 ⬍0.05
2.46
1.10–5.49
⬍0.05
2.29
0.92–5.72
0.08
0.56 0.64 1.00 0.81
0.29–1.08 0.33–1.26 0.99–1.01 0.38–1.70
0.08 0.19 0.32 0.57
0.99
0.99–1.00
0.74
0.26 0.75 1.00 4.03
0.10–0.72 0.32–1.75 Reference 2.12–54.99
⬍0.01 0.51
10.80
1.57–133.57
⬍0.05
⬍0.01
⬍0.01
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 syndromefree 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
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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 EuroCollins 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 EuroCollins 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 braindead 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
GENERAL THORACIC
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to contribute to a strategy that reduces clinically significant PGD in lung transplantation. GENERAL THORACIC
We gratefully acknowledge lung transplant surgeons, physicians, and anesthesiologists for technical assistance and Sharon Daly for assembling and verifying the clinical data. We also wish to extend our appreciation to members of the Heart and Lung Transplant Service, The Alfred Hospital, for their assistance.
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18.
19. 20.
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