- Email: [email protected]
Does Perfadex Affect Outcomes In Clinical Lung Transplantation?
Does Perfadex Affect Outcomes In Clinical Lung Transplantation? Dilip S. Nath, MD, Adam R. Walter, MD, Adam C. Johnson, MD, David M. Radosevich, RN, PhD, Mark E. Prekker, MD, Cynthia S. Herrington, MD, Peter S. Dahlberg, MD, PhD, and Rosemary F. Kelly, MD Background: The use of a low-potassium– based preservation solution improves gas exchange in experimental models of lung transplantation. However, its efficacy in reducing the incidence of primary graft dysfunction (PGD) and improving patient outcomes in the clinical setting is controversial. Methods: In this study we measured: oxygenation index (OI); International Society of Heart and Lung Transplantation (ISHLT) PGD grades; extubation times; intensive care unit (ICU) and hospital length of stay; 30-day, 90-day and 1-year survival rates; and bronchiolitis obliterans syndrome (BOS)-free survival. We compared 115 consecutive (2001 to 2004) lung recipients who received allografts preserved with Perfadex, a low-potassium dextran (LPD) solution, and compared the results with the previous 116 consecutive (1999 to 2001) lung recipients who received allografts preserved with modified Euro-Collins (MEC) solution. Recipients were classified as having severe PGD (ISHLT Grade III) if the lowest arterial oxygenation (P) to fraction of inspired oxygen (F) (P/F ratio) within 48 hours post-transplantation was ⬍200. Results: Baseline characteristics of the 2 cohorts were similar except for recipient age (LPD 53.5 vs MEC 49.9 years; p ⫽ 0.03). There were no differences in donor age, gender, category of transplant, indication for transplant, use of cardiopulmonary bypass or pre-operative pulmonary artery pressures. When gas-exchange parameters were measured upon arrival to the ICU (T0), at 24 hours post-transplant (T24) and at 48 hours post-transplant (T48), the only significant finding was that the incidence of ISHLT Grade III PGD at T24 was lower in the LPD group compared with the MEC group (8% vs 20%, p ⫽ 0.03). The incidence of severe PGD at other timepoints was not statistically different (LPD vs MEC: T0, 17% vs 26%; T0 to T48, 25% vs 31%). Both groups had similar extubation rates at 48 hours post-transplant (LPD 64% vs MEC 67%). The 30-day survival (LPD 93% vs MEC 95%), 90-day survival (LPD 89% vs MEC 89%), 1-year patient survival (LPD 80% vs MEC 77%) and 1-year BOS-free survival (LPD 70% vs MEC 74%) were not statistically different. Conclusions: Lung preservation with LPD as compared with MEC does not improve early gas exchange or impact 90-day and 1-year mortality. Continued investigation into lung preservation solution composition is necessary to reduce the incidence of PGD. J Heart Lung Transplant 2005;24:2243– 8. Copyright © 2005 by the International Society for Heart and Lung Transplantation.
Lung transplantation is an accepted therapeutic option for patients with end-stage pulmonary disease who are otherwise refractory to medical therapy.1 An ongoing challenge is to effectively reduce the incidence of primary graft dysfunction (PGD), which leads to significant early morbidity and mortality in the post-transplant period.2,3 Ischemia and subsequent reperfusion injury are considered to be the principal mechanisms underlying early graft dysfunction and, hence, there is From the Division of Cardiovascular and Thoracic Surgery, University of Minnesota, Minneapolis, Minnesota. Submitted April 18, 2005; revised June 3, 2005; accepted June 21, 2005. Reprint requests: Rosemary Kelly, MD, Division of Cardiovascular and Thoracic Surgery, Veterans Administration Medical Center, 1 Veterans Drive, Minneapolis, MN 55417. Telephone: 612-725-2148. Fax: 612-7251920. E-mail: [email protected] Copyright © 2005 by the International Society for Heart and Lung Transplantation. 1053-2498/05/$–see front matter. doi:10.1016/ j.healun.2005.06.019
considerable interest in developing a lung preservation solution that leads to improved functional outcomes. There is considerable evidence from laboratory studies that Perfadex, a low-potassium dextran (LPD) solution, provides excellent lung preservation for up to 24 hours and limits the extent of ischemia–reperfusion injury, especially when compared with modified Euro-Collins (MEC) solution.4,5 The utility of LPD in improving clinical outcomes in lung transplant recipients has not been clearly demonstrated. Four recent studies have suggested that the use of LPD leads to improved lung function parameters and higher survival rates compared with historic controls where MEC was used.6 –9 These reviews have typically been limited by one of the following: small sample sizes; unmatched cohorts; the use of controls from a different transplantation era; or limited data regarding post-transplant lung function parameters. One study did address many of these concerns but failed to demonstrate a significant 2243
2244
Nath et al.
difference between LPD and MEC in clinical lung preservation.10 Given the discrepancy between this study and the reduction in PGD reported by others, we compared matched cohorts in the largest study to date to determine if there were any advantages to using LPD as opposed to MEC with respect to gas exchange or 90-day and 1-year patient survival. METHODS Patients The institutional review board at the University of Minnesota approved the study protocol. We retrospectively examined the medical records of patients who underwent lung transplantation at the Fairview University Medical Center between November 8, 1997 and December 31, 2004. After July 15, 2001, LPD was used exclusively as the preservation solution for lung allografts. One hundred fifteen consecutive recipients for whom LPD (Vitrolife, Göteborg, Sweden) was used were identified and matched with a cohort of the previous 116 patients for whom MEC (Baxter Healthcare, Deerfield, IL) was used. Patients receiving lungs from living donors (n ⫽ 8) were excluded from this analysis. Oxygenation index (OI) and International Society of Heart and Lung Transplantation (ISHLT) PGD grades were the 2 primary end-points used to assess early gas exchange in recipients. OI is defined as (MAP · F)/P, where MAP is mean airway pressure, F is fraction of inspired oxygen and P is arterial oxygenation. Using an ISHLT working group definition, we classified recipients as having ISHLT Grade III (severe) PGD if the lowest P/F ratio within 48 hours post-transplant was ⬍200.11–13 These parameters were measured upon arrival to the ICU (T0), at 24 hours post-transplant (T24) and at 48 hours post-transplant (T48). As chest X-rays for all patients were not consistently available to be read and compared, these data were not incorporated into the ISHLT classification. Data collected regarding the donor included: (1) age; (2) gender; (3) mechanism of death; and (4) allograft ischemic time. Data collected regarding the recipient in the peri-transplant period included: (1) age; (2) gender; (3) indication for transplant; (4) category of transplant; (5) use of cardiopulmonary bypass (CPB); and (6) pulmonary artery pressures. Data obtained in the posttransplant period included: (1) duration of mechanical ventilatory support; (2) OI; (3) ISHLT PGD grade; (4) length of ICU stay; (5) length of hospital stay; (6) bronchiolitis obliterans syndrome (BOS)-free survival; and (7) patient survival. BOS was defined as a decline of ⬎20% of forced expiratory volume in 1 second (FEV1) in the post-transplant period compared with the baseline value. The baseline value was established by the 2
The Journal of Heart and Lung Transplantation December 2005
highest FEV1 measurements obtained at least 3 weeks apart soon after transplantation.14 Donor and Recipient Surgery We used well-established criteria for accepting donor lungs, including objective evidence of adequate gas exchange and bronchoscopic evaluation, to exclude aspiration or purulent secretions.15 A cold preservation solution (LPD or MEC) was infused via the donor pulmonary artery at low pressure in an antegrade fashion. Table 1 shows the composition of LPD and MEC used by our center. In addition, 500 g of prostaglandin E1 (PGE1) was administered via the pulmonary artery to diminish vasoconstriction.16 During procurement, the vascular structures were divided in situ and the trachea dissected well proximal to the carina. With the lungs partially inflated, the trachea was divided between staple lines and the organ transported to our center immersed in either LPD or MEC. We do not utilize corticosteroids as part of our procurement protocol. The most common recipient operation performed was a single-lung transplant using a standard technique that we have described elsewhere.17 In the case of a single-lung transplant, a posterolateral thoracotomy was performed and the need for CPB determined based on trial occlusion of the pulmonary artery with 1-lung ventilation. CPB was utilized for bilateral single-lung transplants, as indicated by pulmonary pressures, and was routinely utilized for patients with a diagnosis of primary pulmonary hypertension. Once the donor lung was present in the operating room, the recipient pneumonectomy was completed. We completed the recipient vascular anastomoses and used a modified telescoping technique to perform the bronchial anastomoses. Statistics Statistical computations were carried out using JMP 4 software (SAS Institute). Results are expressed as mean ⫾ standard deviation. The unpaired Student’s t-test, analysis Table 1. Composition of Preservation Solutions Component Na (mmol/liter) K (mmol/liter) Cl (mmol/liter) PO4 (mmol/liter) HCO3 (mmol/liter) SO4 (mmol/liter) Glucose (g/liter) Dextran-40 (g/liter) Penta-fraction (g/liter) Osmolality pH
LPD solution 168 4 103 37 2 2 0 20 0 335 7.4
LPD, low-potassium dextran; MEC, modified Euro-Collins.
MEC solution 10 108 14 93 8 8 35 0 8 355 7.4
The Journal of Heart and Lung Transplantation Volume 24, Number 12
Nath et al.
of variance (ANOVA) and chi-square analysis were used to determine significant (p ⬍ 0.05) differences between groups. The end-point of patient survival was analyzed using the Kaplan–Meier (KM) actuarial method. RESULTS Patient Demographics During the study period from November 8, 1997 to December 31, 2004, we performed 239 lung transplants at our institution. The donor characteristics of the LPD and MEC groups are detailed in Table 2. The groups had donors of similar age (LPD 31.6 vs MEC 34.2 years), gender (LPD 49% vs MEC 53% male), mechanisms of death (LPD vs MEC: blunt trauma, 49% vs 42%; penetrating trauma, 10% vs 6%; atraumatic, 42% vs 52%), and intubation time before procurement (LPD 3.0 vs MEC 2.2 days). The average allograft ischemic time was nearly 5 hours in both groups. Table 3 details the recipient characteristics in both groups. The patients in the LPD group were older than those in the MEC group (53.5 vs 49.9 years, p ⫽ 0.03). Other recipient characteristics were similar including: gender (LPD 50% vs MEC 51% male); category of transplant (LPD vs MEC: single lung [SL], 66% vs 61%; bilateral single lung [BSL], 34% vs 39%); indications for transplant (LPD vs MEC: idiopathic pulmonary fibrosis [IPF], 12% vs 13%; primary pulmonary hypertension [PPH], 4% vs 7%; cystic fibrosis [CF], 9% vs 14%; chronic obstructive pulmonary disease [COPD], 68% vs 58%; other [sarcoidosis, histiocystosis X, Eisenmenger’s syndrome, lymphangioleiomyomatosis], 8% vs 9%); use of cardiopulmonary bypass (LPD 33% vs MEC 41%); and pre-operative mean pulmonary artery pressures (LPD 23.9 vs MEC 24.5 mm Hg). All patients with PPH in both groups received BSL transplants. All patients with CF received a BSL except for one patient in the LPD group and one patient in the MEC group who received an SLT. Thirty-four patients with a diagnosis of COPD under-
Table 2. Donor Characteristics of Both Groupsa Variablea Age (years) Male gender Mechanism of death Blunt trauma Penetrating trauma Atraumatic Intubation time (days) Total allograft ischemic time (minutes)
LPD solution (n ⫽ 115) 31.6 ⫾ 13.6 56
MEC solution (n ⫽ 116) 34.2 ⫾ 14.1 61
56 11 48 3.0 ⫾ 2.8 298.3 ⫾ 97.3
47 7 59 2.2 ⫾ 1.4 298.3 ⫾ 72.6
p-value 0.20 0.59 0.22
0.24 0.81
LPD, low-potassium dextran; MEC, modified Euro-Collins. a Nominal/ordinal variables specified as number of patients. Continuous variables specified as mean ⫾ SD.
2245
Table 3. Recipient Characteristics of Both Groups LPD solution MEC solution (n ⫽ 115) (n ⫽ 116) p-value Age (years) 53.5 ⫾ 9.6 49.9 ⫾ 12.4 0.03 Male gender 58 59 0.95 Category of transplant 0.44 Single lung 76 71 Bilateral single lung 39 45 Cardiopulmonary bypass used 38 47 0.22 23.9 ⫾ 9.1 24.5 ⫾ 11.5 0.99 Mean pulmonary artery pressure (mm Hg) (cardiac catheterization during transplant evaluation) Recipient diagnosis 0.43 Idiopathic pulmonary 14 15 fibrosis Primary pulmonary 4 8 hypertension Cystic fibrosis 10 16 Chronic obstructive 78 67 pulmonary disease Other 9 10 Variable
LPD, low-potassium dextran; MEC, modified Euro-Collins. a Nominal/ordinal variables specified as number of patients. Continuous variables specified as mean ⫾ SD.
went BSL transplants and these were distributed equally between the 2 groups. Allograft Function We examined OI and severe PGD (ISHLT Grade III) as parameters of gas exchange. As Table 4 depicts, these measurements were taken at various timepoints during the post-operative course, including on arrival to the ICU (T0), 24 hours post-transplant (T24) and 48 hours post-transplant (T48). In addition, the lowest OI during the first 48 hours (T0 to T48), as well as the incidence of any Grade III PGD during T0 to T48, was also noted. The oxygenation indices were similar in both groups at all timepoints measured. This finding was also consistent when the number of patients extubated in the first 12, 24 and 48 hours post-transplant were compared. At 48 hours post-transplant, the percentage of patients extubated in the LPD group was 64% compared with 68% in the MEC cohort. Severe PGD was noted in a significant number of recipients in both groups at T0 (LPD 18% vs MEC 26%), T24 (LPD 8% vs MEC 20%, p ⫽ 0.03) and at any timepoint during T0 to T48 (LPD 25% vs MEC 31%). The only significant difference was noted at T24, where the incidence of severe PGD was lower in the LPD group. Hospital Course and Patient Survival The mean length of ICU stay post-transplant was 7.2 days in both groups and there was no significant
2246
Nath et al.
The Journal of Heart and Lung Transplantation December 2005
Table 4. Post-operative Characteristics of Allograft Function Variablea Oxygenation index
ISHLT Grade III PGD
Extubation
Timepoint T0 T24 Worst T0–T48 T0 T24 T0–T48 T48
LPD solution (n ⫽ 115) 3.8 ⫾ 3.4 3.6 ⫾ 2.2 4.8 ⫾ 4.7 20 9 29 74
MEC solution (n ⫽ 116) 4.8 ⫾ 5.5 4.7 ⫾ 3.4 5.6 ⫾ 5.7 30 23 36 78
p-value 0.11 0.14 0.45 0.13 0.03 0.33 0.64
LPD, low-potassium dextran; MEC, modified Euro-Collins. a Nominal/ordinal variables expressed as number of patients. Continuous variables specified as mean ⫾ SD.
difference in hospital length of stay (LPD 16.4 vs MEC 19.4 days). Table 5 reveals no statistically significant differences in the groups when 30-day, 90-day and 1-year survival and 1-year BOS-free survival are compared. The Kaplan–Meier survival curves for both groups are shown in Figure 1. Thirteen patients in each group died in the first 90 days post-transplant. In the PFD group, the causes of death included: acute graft failure (4); multisystem organ failure (2); sepsis (2); heart failure (2); acute rejection episode (1); and gastrointestinal bleeding (1). The cause of death in 1 case could not be identified. In the MEC group, the causes of death included: acute graft failure (4); multisystem organ failure (2); heart failure (2); diffuse bronchoalveolar damage (1); dissecting aortic aneurysm (1); and sepsis (1). The cause of death in 2 cases could not be identified. DISCUSSION Preservation solution is an important variable in affecting outcomes in lung transplantation. During the earliest clinical attempts, the donor and recipient operations were performed at the same institution to ensure that ischemic time could be minimized by implanting the lung as soon as it was retrieved from the donor.18,19 Laboratory studies, later confirmed by clinical experience, showed that prolonged ischemia time could be tolerated if the donor lung underwent uniform pulmonary cooling, was ventilated after cessation of circulation, was transported in an inflated state, and was Table 5. Length of Stay and Patient Survival Variablea ICU days Hospital days 30-day survival 90-day survival 1-year survival 1-year BOS-free survival
LPD solution (n ⫽ 115) 7.2 ⫾ 11.7 16.4 ⫾ 14.6 93.0% 88.5% 79.9% 70.4%
MEC solution (n ⫽ 116) 7.2 ⫾ 10.0 19.4 ⫾ 18.2 94.8% 88.8% 76.7% 73.9%
preserved at 10°C to maintain cellular membrane integrity.20 –22 The ideal perfusate for lung preservation has changed over the years. Initially, a fluid similar in ionic composition to Ringer’s lactate or normal saline was used. Later, agents such as Euro-Collins and University of Wisconsin solution were utilized in experimental and clinical settings.23 Over time, MEC, a high-potassium– based ionic solution that duplicates the intracellular ionic environment, became the preservation solution of choice for the majority of transplant programs.1 The high potassium concentration in MEC causes severe pulmonary vasoconstriction that can be ameliorated by the vasodilatory properties of prostaglandins.24 However, experimental and clinical studies were never able to demonstrate tolerance to prolonged ischemia time nor improved clinical outcomes based on prostaglandin infusion during donor procurement.25,26 Laboratory evidence suggests that LPD is superior to MEC in significantly reducing ischemia–reperfusion injury and providing good functional results with respect to post-ischemic oxygenation in animals.10 In contrast to MEC, LPD is a low- potassium dextran solution that reflects the extracellular ionic composition and is better equipped to address oxygen free radical–mediated reperfusion injury.5,27,28 Animal studies have shown that using LPD is less cytotoxic to Type II pneumocytes and enables preservation of surfactant activity and 1.0 MEC LPD
0.9
p-value 0.83 0.13 0.55 0.94 0.80 0.57
LPD, low-potassium dextran; MEC, modified Euro-Collins. a Continuous variables specified as mean ⫾ SD. Kaplan–Meier curves results expressed as percent.
0.8 Surviving 0.7
0.6 0.5 0
90
180
270
Days
Figure 1. Survival curve of PFD and MEC groups.
360
The Journal of Heart and Lung Transplantation Volume 24, Number 12
endothelial vascular function.5,29 –31 One important mechanism of graft rejection is binding of complement to damaged endothelium, but LPD may reduce this risk given that it is more protective of endothelial cells.32 These critical factors in maintaining initial graft function substantiated the basis for the use of LPD in clinical lung transplants.33 In an effort to reduce PGD, our institution altered the preservation method to replace MEC. Despite the experimental evidence that favors the use of LPD, we were not able to demonstrate any significant improvement clinically. There was no statistically significant benefit of LPD compared with MEC in early gas-exchange parameters, incidence of severe PGD, patient survival or BOS-free survival when we compared 115 LPD recipients to 116 MEC recipients. The cohorts were well matched with the slightly older recipient age in the LPD group being the only significant difference. Although there was a lower incidence of severe PGD noted 24 hours post-transplant in the LPD group, the clinical significance is unclear, especially given that this effect dissipates when looking at the 48-hour post-transplant period as a whole. It appears that lung function is most significantly influenced by preservation solution early in the post-operative course. Yet the impact of preservation solution alone may be less critical over time as many other factors impacting graft function predominate. There are several limitations to this study. It is a retrospective, non-randomized analysis that used historic controls from different eras. Also, the number of patients in each cohort limited the statistical power of the study. Despite these limitations, this is the largest clinical study comparing LPD to MEC with wellmatched study cohorts using clearly defined criteria for PGD. Aziz et al recently reported that they could not demonstrate a difference between LPD and MEC cohorts at their institution with respect to gas-exchange parameters or patient survival.10 They pointed out an important variable that could explain the discrepancy between the experimental evidence and clinical experience—that is, brain-stem death models are not used in the laboratory.10 In addition, much of the experimental evidence supporting the use of LPD was seen in small animal models. These advantages may not be evident in larger animal models.34 Furthermore, factors such as improved endothelial contractility and relaxation with LPD in the experimental forum are short-lived and allografts preserved in MEC do recover these functions over a longer period of time.5 Many benefits of LPD in the laboratory setting were realized as allografts were preserved for significantly longer periods than in the clinical setting. In donor allografts with long preservation times or marginal donor characteristics, it is possible that LPD may be superior to MEC. A randomized,
Nath et al.
2247
multicenter study with a large sample of this type of patient population is necessary to assess the role of LPD in determining patient outcome and gas-exchange parameters. The conflicting data from both the laboratory and clinical realm regarding benefits of LPD indicate that the factors influencing post-transplant allograft function are numerous and complex. Although we were unable to show a significant clinical difference between LPD and MEC, there remains much work to be done to further elucidate the factors that influence allograft function. Translating additional research findings into the clinical arena will be critical for the continued efforts toward reducing the incidence of PGD in lung transplantation. It is possible that the preferential use of LPD over MEC could be substantiated upon further study, particularly among recipients with much longer ischemia times than those in this investigation. REFERENCES 1. Arcasoy SM, Kotloff RM. Lung transplantation. N Engl J Med 1999;340:1081–91. 2. Colquhoun IW, Kirk AJB, Au J, et al. Single flush perfusion with modified Euro-Collins solution: experience in clinical lung preservation. J Heart Lung Transplant 1992; 11(suppl):S209 –14. 3. Cooper JD, Patterson GA, Trulock EP. Results of 131 consecutive single and bilateral lung transplant recipients. Washington University Lung Transplant Group. J Thorac Cardiovasc Surg 1994;107:460 –71. 4. Steen S, Kimblad PO, Sjoberg T, Lindberg L, Ingemasson R, Massa G. Safe lung preservation for twenty-four hours with Perfadex. Ann Thorac Surg 1994;57:450 –7. 5. Ingemansson R, Massa G, Pandita RK, Sjobert T, Steen S. Perfadex is superior to Euro-Collins solution regarding 24-hour preservation of vascular function. Ann Thorac Surg 1995;60:1210 – 4. 6. Struber M, Wilhelmi M, Harringer W, et al. Flush perfusion with low potassium dextran solution improves early graft function in clinical lung transplantation. Eur J Cardiothorac Surg 2001;19:190 – 4. 7. Rabanal JM, Ibanez AM, Mons R, et al. Influence of preservation solution on early lung function (Euro-Collins vs Perfadex). Transplant Proc 2003;35:1938 –9. 8. Fischer S, Matte-Martyn A, de Perrot M, et al. Lowpotassium dextran preservation solution improves lung function after human lung transplantation. J Thorac Cardiovasc Surg 2001;121:594 – 6. 9. Muller C, Furst H, Reichenspurner H, et al. Lung procurement by low-potassium dextran and the effect on preservation injury. Transplantation 1999;68:1139 – 43. 10. Aziz TM, Pillay TM, Corris PA, et al. Perfadex for clinical lung procurement: is it an advance? Ann Thorac Surg 2003;75:990 –5. 11. Thabut G, Vinatier I, Stern JB, et al. Primary graft failure following lung transplantation: predictive factors of mortality. Chest 2002;121:1876 – 82.
2248
Nath et al.
12. Sekine Y, Waddell TK, Matte-Martyn A, et al. Risk quantification of early outcome after lung transplantation: donor, recipient, operative, and post-transplant parameters. J Heart Lung Transplant 2004;21:297–310. 13. Prekker ME, Nath DS, Johnson AC, Walker AR, Hertz M, Dahlberg PS. Validation of the proposed ISHLT grading system for primary graft dysfunction following lung transplantation. J Heart Lung Transplant 2005;24(suppl 1):S72. 14. Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002;21:297–310. 15. Egan TM, Kaiser LR, Cooper JD. Lung Transplantation. Curr Probl Sur 1989;26:675–751. 16. Mulvin D, Jone K, Howard R, Grosso M, Repine J, Johnston M. The effect of prostacyclin as a constituent of a preservation solution in protecting lungs from ischemic injury because of its vasodilatory properties. Transplantation 1990;49:828 –30. 17. Kshettry VR, Shumway SJ, Gauthier RL, Bolman RM III. Technique of single-lung transplantation. Ann Thorac Surg 1993;55:1019 –21. 18. Hardy JD, Eraslan S, Dalton ML Jr, Walker GR Jr. Lung homotransplantation in man: report of the initial case. JAMA 1963;186:1065–74. 19. The Toronto Lung Transplant Group. Unilateral lung transplantation for pulmonary fibrosis. N Engl J Med 1986;314:1140 –5. 20. Ulichny KS Jr, Eagan TM, Lambert CJ Jr, Wilcox BR. Postmortem nitrogen ventilation improves function of transplantated canine cadaver lungs. Chest 1991;100(suppl):63S. 21. Puskas JD, Hirai T, Christie N, Mayer E, Slutsky AS, Patterson GA. Reliable 30-hour lung preservation by donor hyperinflation. J Thorac Cardiovasc Surg 1992;104:1075– 83. 22. Wang LS, Yoshikawa K, Miyoshi S, et al. The effect of ischemic time and temperature on lung preservation in a simple ex vivo rabbit model used for functional assessment. J Thorac Cardiovasc Surg 1989;98:333– 42. 23. Haverich A, Scott WC, Jamieson SW. Twenty years of lung preservation: a review. Heart Transplant 1985;4:234 – 40.
The Journal of Heart and Lung Transplantation December 2005
24. Unruh H, Hoppensack M, Oppenheimer L. Vascular properties of canine lungs perfused with Eurocollins solution and prostacyclin. Ann Thorac Surg 1990;49:292– 8. 25. Ueno T, Yokomise H, Oka T, et al. The effect of PGE1 and temperature on lung function following preservation. Transplantation 1991;52:626 –30. 26. Kukkonen S, Heikkila LJ, Verkkala K, Mattila SP, Toivonen H. Prostaglandin E1 or prostacyclin in Euro-Collins solution fails to improve lung preservation. Ann Thorac Surg 1995;60:1617–22. 27. Detterbeck FC, Keagy BA, Paull DE, Wilcox BR. Oxygen free radical scavengers decrease reperfusion injury in lung transplantation. Ann Thorac Surg 1990;50:204 –9. 28. Kelly RF, Murar J, Hong Z, et al. Low potassium dextran lung preservation solution reduces reactive oxygen species production. Ann Thorac Surg 2003;75:1705–10. 29. Maccherini M, Keshavjee SH, Slutsky AS, Patterson GA, Edelson JD. The effect of low-potassium– dextran versus Euro-Collins solution for preservation of isolated type II pneumocytes. Transplantation 1991;52:621– 6. 30. Struber M, Hohlfeld JM, Fraund S, Kim P, Warnecke G, Haverich A. Low-potassium dextran solution ameliorates reperfusion injury of the lung and protects surfactant function. J Thorac Cardiovasc Surg 2000;120: 566 –72. 31. Fehrenbach A, Pufe T, Wittwer T, et al. Reduced vascular endothelial growth factor correlates with alveolar epithelial damage after experimental ischemia and reperfusion. J Heart Lung Transplant 2003;22:967–78. 32. Ryan US. The endothelial cell surface and response to injury. Fed Proc 1986;45:101– 8. 33. Novick RJ, Gehman KE, Ali IS, Lee J. Lung preservation: the importance of endothelial and alveolar type II cell integrity. Ann Thorac Surg 1996;62:302–14. 34. Wierup P, Liao Q, Bolys R, Trygve, Rippe B, Steen S. Lung edema formation during cold perfusion: important differences between rat and porcine lung. J Heart Lung Transplant 2005;24:379 – 85.
Lung transplantation is an accepted therapeutic option for patients with end-stage pulmonary disease who are otherwise refractory to medical therapy.1 An ongoing challenge is to effectively reduce the incidence of primary graft dysfunction (PGD), which leads to significant early morbidity and mortality in the post-transplant period.2,3 Ischemia and subsequent reperfusion injury are considered to be the principal mechanisms underlying early graft dysfunction and, hence, there is From the Division of Cardiovascular and Thoracic Surgery, University of Minnesota, Minneapolis, Minnesota. Submitted April 18, 2005; revised June 3, 2005; accepted June 21, 2005. Reprint requests: Rosemary Kelly, MD, Division of Cardiovascular and Thoracic Surgery, Veterans Administration Medical Center, 1 Veterans Drive, Minneapolis, MN 55417. Telephone: 612-725-2148. Fax: 612-7251920. E-mail: [email protected] Copyright © 2005 by the International Society for Heart and Lung Transplantation. 1053-2498/05/$–see front matter. doi:10.1016/ j.healun.2005.06.019
considerable interest in developing a lung preservation solution that leads to improved functional outcomes. There is considerable evidence from laboratory studies that Perfadex, a low-potassium dextran (LPD) solution, provides excellent lung preservation for up to 24 hours and limits the extent of ischemia–reperfusion injury, especially when compared with modified Euro-Collins (MEC) solution.4,5 The utility of LPD in improving clinical outcomes in lung transplant recipients has not been clearly demonstrated. Four recent studies have suggested that the use of LPD leads to improved lung function parameters and higher survival rates compared with historic controls where MEC was used.6 –9 These reviews have typically been limited by one of the following: small sample sizes; unmatched cohorts; the use of controls from a different transplantation era; or limited data regarding post-transplant lung function parameters. One study did address many of these concerns but failed to demonstrate a significant 2243
2244
Nath et al.
difference between LPD and MEC in clinical lung preservation.10 Given the discrepancy between this study and the reduction in PGD reported by others, we compared matched cohorts in the largest study to date to determine if there were any advantages to using LPD as opposed to MEC with respect to gas exchange or 90-day and 1-year patient survival. METHODS Patients The institutional review board at the University of Minnesota approved the study protocol. We retrospectively examined the medical records of patients who underwent lung transplantation at the Fairview University Medical Center between November 8, 1997 and December 31, 2004. After July 15, 2001, LPD was used exclusively as the preservation solution for lung allografts. One hundred fifteen consecutive recipients for whom LPD (Vitrolife, Göteborg, Sweden) was used were identified and matched with a cohort of the previous 116 patients for whom MEC (Baxter Healthcare, Deerfield, IL) was used. Patients receiving lungs from living donors (n ⫽ 8) were excluded from this analysis. Oxygenation index (OI) and International Society of Heart and Lung Transplantation (ISHLT) PGD grades were the 2 primary end-points used to assess early gas exchange in recipients. OI is defined as (MAP · F)/P, where MAP is mean airway pressure, F is fraction of inspired oxygen and P is arterial oxygenation. Using an ISHLT working group definition, we classified recipients as having ISHLT Grade III (severe) PGD if the lowest P/F ratio within 48 hours post-transplant was ⬍200.11–13 These parameters were measured upon arrival to the ICU (T0), at 24 hours post-transplant (T24) and at 48 hours post-transplant (T48). As chest X-rays for all patients were not consistently available to be read and compared, these data were not incorporated into the ISHLT classification. Data collected regarding the donor included: (1) age; (2) gender; (3) mechanism of death; and (4) allograft ischemic time. Data collected regarding the recipient in the peri-transplant period included: (1) age; (2) gender; (3) indication for transplant; (4) category of transplant; (5) use of cardiopulmonary bypass (CPB); and (6) pulmonary artery pressures. Data obtained in the posttransplant period included: (1) duration of mechanical ventilatory support; (2) OI; (3) ISHLT PGD grade; (4) length of ICU stay; (5) length of hospital stay; (6) bronchiolitis obliterans syndrome (BOS)-free survival; and (7) patient survival. BOS was defined as a decline of ⬎20% of forced expiratory volume in 1 second (FEV1) in the post-transplant period compared with the baseline value. The baseline value was established by the 2
The Journal of Heart and Lung Transplantation December 2005
highest FEV1 measurements obtained at least 3 weeks apart soon after transplantation.14 Donor and Recipient Surgery We used well-established criteria for accepting donor lungs, including objective evidence of adequate gas exchange and bronchoscopic evaluation, to exclude aspiration or purulent secretions.15 A cold preservation solution (LPD or MEC) was infused via the donor pulmonary artery at low pressure in an antegrade fashion. Table 1 shows the composition of LPD and MEC used by our center. In addition, 500 g of prostaglandin E1 (PGE1) was administered via the pulmonary artery to diminish vasoconstriction.16 During procurement, the vascular structures were divided in situ and the trachea dissected well proximal to the carina. With the lungs partially inflated, the trachea was divided between staple lines and the organ transported to our center immersed in either LPD or MEC. We do not utilize corticosteroids as part of our procurement protocol. The most common recipient operation performed was a single-lung transplant using a standard technique that we have described elsewhere.17 In the case of a single-lung transplant, a posterolateral thoracotomy was performed and the need for CPB determined based on trial occlusion of the pulmonary artery with 1-lung ventilation. CPB was utilized for bilateral single-lung transplants, as indicated by pulmonary pressures, and was routinely utilized for patients with a diagnosis of primary pulmonary hypertension. Once the donor lung was present in the operating room, the recipient pneumonectomy was completed. We completed the recipient vascular anastomoses and used a modified telescoping technique to perform the bronchial anastomoses. Statistics Statistical computations were carried out using JMP 4 software (SAS Institute). Results are expressed as mean ⫾ standard deviation. The unpaired Student’s t-test, analysis Table 1. Composition of Preservation Solutions Component Na (mmol/liter) K (mmol/liter) Cl (mmol/liter) PO4 (mmol/liter) HCO3 (mmol/liter) SO4 (mmol/liter) Glucose (g/liter) Dextran-40 (g/liter) Penta-fraction (g/liter) Osmolality pH
LPD solution 168 4 103 37 2 2 0 20 0 335 7.4
LPD, low-potassium dextran; MEC, modified Euro-Collins.
MEC solution 10 108 14 93 8 8 35 0 8 355 7.4
The Journal of Heart and Lung Transplantation Volume 24, Number 12
Nath et al.
of variance (ANOVA) and chi-square analysis were used to determine significant (p ⬍ 0.05) differences between groups. The end-point of patient survival was analyzed using the Kaplan–Meier (KM) actuarial method. RESULTS Patient Demographics During the study period from November 8, 1997 to December 31, 2004, we performed 239 lung transplants at our institution. The donor characteristics of the LPD and MEC groups are detailed in Table 2. The groups had donors of similar age (LPD 31.6 vs MEC 34.2 years), gender (LPD 49% vs MEC 53% male), mechanisms of death (LPD vs MEC: blunt trauma, 49% vs 42%; penetrating trauma, 10% vs 6%; atraumatic, 42% vs 52%), and intubation time before procurement (LPD 3.0 vs MEC 2.2 days). The average allograft ischemic time was nearly 5 hours in both groups. Table 3 details the recipient characteristics in both groups. The patients in the LPD group were older than those in the MEC group (53.5 vs 49.9 years, p ⫽ 0.03). Other recipient characteristics were similar including: gender (LPD 50% vs MEC 51% male); category of transplant (LPD vs MEC: single lung [SL], 66% vs 61%; bilateral single lung [BSL], 34% vs 39%); indications for transplant (LPD vs MEC: idiopathic pulmonary fibrosis [IPF], 12% vs 13%; primary pulmonary hypertension [PPH], 4% vs 7%; cystic fibrosis [CF], 9% vs 14%; chronic obstructive pulmonary disease [COPD], 68% vs 58%; other [sarcoidosis, histiocystosis X, Eisenmenger’s syndrome, lymphangioleiomyomatosis], 8% vs 9%); use of cardiopulmonary bypass (LPD 33% vs MEC 41%); and pre-operative mean pulmonary artery pressures (LPD 23.9 vs MEC 24.5 mm Hg). All patients with PPH in both groups received BSL transplants. All patients with CF received a BSL except for one patient in the LPD group and one patient in the MEC group who received an SLT. Thirty-four patients with a diagnosis of COPD under-
Table 2. Donor Characteristics of Both Groupsa Variablea Age (years) Male gender Mechanism of death Blunt trauma Penetrating trauma Atraumatic Intubation time (days) Total allograft ischemic time (minutes)
LPD solution (n ⫽ 115) 31.6 ⫾ 13.6 56
MEC solution (n ⫽ 116) 34.2 ⫾ 14.1 61
56 11 48 3.0 ⫾ 2.8 298.3 ⫾ 97.3
47 7 59 2.2 ⫾ 1.4 298.3 ⫾ 72.6
p-value 0.20 0.59 0.22
0.24 0.81
LPD, low-potassium dextran; MEC, modified Euro-Collins. a Nominal/ordinal variables specified as number of patients. Continuous variables specified as mean ⫾ SD.
2245
Table 3. Recipient Characteristics of Both Groups LPD solution MEC solution (n ⫽ 115) (n ⫽ 116) p-value Age (years) 53.5 ⫾ 9.6 49.9 ⫾ 12.4 0.03 Male gender 58 59 0.95 Category of transplant 0.44 Single lung 76 71 Bilateral single lung 39 45 Cardiopulmonary bypass used 38 47 0.22 23.9 ⫾ 9.1 24.5 ⫾ 11.5 0.99 Mean pulmonary artery pressure (mm Hg) (cardiac catheterization during transplant evaluation) Recipient diagnosis 0.43 Idiopathic pulmonary 14 15 fibrosis Primary pulmonary 4 8 hypertension Cystic fibrosis 10 16 Chronic obstructive 78 67 pulmonary disease Other 9 10 Variable
LPD, low-potassium dextran; MEC, modified Euro-Collins. a Nominal/ordinal variables specified as number of patients. Continuous variables specified as mean ⫾ SD.
went BSL transplants and these were distributed equally between the 2 groups. Allograft Function We examined OI and severe PGD (ISHLT Grade III) as parameters of gas exchange. As Table 4 depicts, these measurements were taken at various timepoints during the post-operative course, including on arrival to the ICU (T0), 24 hours post-transplant (T24) and 48 hours post-transplant (T48). In addition, the lowest OI during the first 48 hours (T0 to T48), as well as the incidence of any Grade III PGD during T0 to T48, was also noted. The oxygenation indices were similar in both groups at all timepoints measured. This finding was also consistent when the number of patients extubated in the first 12, 24 and 48 hours post-transplant were compared. At 48 hours post-transplant, the percentage of patients extubated in the LPD group was 64% compared with 68% in the MEC cohort. Severe PGD was noted in a significant number of recipients in both groups at T0 (LPD 18% vs MEC 26%), T24 (LPD 8% vs MEC 20%, p ⫽ 0.03) and at any timepoint during T0 to T48 (LPD 25% vs MEC 31%). The only significant difference was noted at T24, where the incidence of severe PGD was lower in the LPD group. Hospital Course and Patient Survival The mean length of ICU stay post-transplant was 7.2 days in both groups and there was no significant
2246
Nath et al.
The Journal of Heart and Lung Transplantation December 2005
Table 4. Post-operative Characteristics of Allograft Function Variablea Oxygenation index
ISHLT Grade III PGD
Extubation
Timepoint T0 T24 Worst T0–T48 T0 T24 T0–T48 T48
LPD solution (n ⫽ 115) 3.8 ⫾ 3.4 3.6 ⫾ 2.2 4.8 ⫾ 4.7 20 9 29 74
MEC solution (n ⫽ 116) 4.8 ⫾ 5.5 4.7 ⫾ 3.4 5.6 ⫾ 5.7 30 23 36 78
p-value 0.11 0.14 0.45 0.13 0.03 0.33 0.64
LPD, low-potassium dextran; MEC, modified Euro-Collins. a Nominal/ordinal variables expressed as number of patients. Continuous variables specified as mean ⫾ SD.
difference in hospital length of stay (LPD 16.4 vs MEC 19.4 days). Table 5 reveals no statistically significant differences in the groups when 30-day, 90-day and 1-year survival and 1-year BOS-free survival are compared. The Kaplan–Meier survival curves for both groups are shown in Figure 1. Thirteen patients in each group died in the first 90 days post-transplant. In the PFD group, the causes of death included: acute graft failure (4); multisystem organ failure (2); sepsis (2); heart failure (2); acute rejection episode (1); and gastrointestinal bleeding (1). The cause of death in 1 case could not be identified. In the MEC group, the causes of death included: acute graft failure (4); multisystem organ failure (2); heart failure (2); diffuse bronchoalveolar damage (1); dissecting aortic aneurysm (1); and sepsis (1). The cause of death in 2 cases could not be identified. DISCUSSION Preservation solution is an important variable in affecting outcomes in lung transplantation. During the earliest clinical attempts, the donor and recipient operations were performed at the same institution to ensure that ischemic time could be minimized by implanting the lung as soon as it was retrieved from the donor.18,19 Laboratory studies, later confirmed by clinical experience, showed that prolonged ischemia time could be tolerated if the donor lung underwent uniform pulmonary cooling, was ventilated after cessation of circulation, was transported in an inflated state, and was Table 5. Length of Stay and Patient Survival Variablea ICU days Hospital days 30-day survival 90-day survival 1-year survival 1-year BOS-free survival
LPD solution (n ⫽ 115) 7.2 ⫾ 11.7 16.4 ⫾ 14.6 93.0% 88.5% 79.9% 70.4%
MEC solution (n ⫽ 116) 7.2 ⫾ 10.0 19.4 ⫾ 18.2 94.8% 88.8% 76.7% 73.9%
preserved at 10°C to maintain cellular membrane integrity.20 –22 The ideal perfusate for lung preservation has changed over the years. Initially, a fluid similar in ionic composition to Ringer’s lactate or normal saline was used. Later, agents such as Euro-Collins and University of Wisconsin solution were utilized in experimental and clinical settings.23 Over time, MEC, a high-potassium– based ionic solution that duplicates the intracellular ionic environment, became the preservation solution of choice for the majority of transplant programs.1 The high potassium concentration in MEC causes severe pulmonary vasoconstriction that can be ameliorated by the vasodilatory properties of prostaglandins.24 However, experimental and clinical studies were never able to demonstrate tolerance to prolonged ischemia time nor improved clinical outcomes based on prostaglandin infusion during donor procurement.25,26 Laboratory evidence suggests that LPD is superior to MEC in significantly reducing ischemia–reperfusion injury and providing good functional results with respect to post-ischemic oxygenation in animals.10 In contrast to MEC, LPD is a low- potassium dextran solution that reflects the extracellular ionic composition and is better equipped to address oxygen free radical–mediated reperfusion injury.5,27,28 Animal studies have shown that using LPD is less cytotoxic to Type II pneumocytes and enables preservation of surfactant activity and 1.0 MEC LPD
0.9
p-value 0.83 0.13 0.55 0.94 0.80 0.57
LPD, low-potassium dextran; MEC, modified Euro-Collins. a Continuous variables specified as mean ⫾ SD. Kaplan–Meier curves results expressed as percent.
0.8 Surviving 0.7
0.6 0.5 0
90
180
270
Days
Figure 1. Survival curve of PFD and MEC groups.
360
The Journal of Heart and Lung Transplantation Volume 24, Number 12
endothelial vascular function.5,29 –31 One important mechanism of graft rejection is binding of complement to damaged endothelium, but LPD may reduce this risk given that it is more protective of endothelial cells.32 These critical factors in maintaining initial graft function substantiated the basis for the use of LPD in clinical lung transplants.33 In an effort to reduce PGD, our institution altered the preservation method to replace MEC. Despite the experimental evidence that favors the use of LPD, we were not able to demonstrate any significant improvement clinically. There was no statistically significant benefit of LPD compared with MEC in early gas-exchange parameters, incidence of severe PGD, patient survival or BOS-free survival when we compared 115 LPD recipients to 116 MEC recipients. The cohorts were well matched with the slightly older recipient age in the LPD group being the only significant difference. Although there was a lower incidence of severe PGD noted 24 hours post-transplant in the LPD group, the clinical significance is unclear, especially given that this effect dissipates when looking at the 48-hour post-transplant period as a whole. It appears that lung function is most significantly influenced by preservation solution early in the post-operative course. Yet the impact of preservation solution alone may be less critical over time as many other factors impacting graft function predominate. There are several limitations to this study. It is a retrospective, non-randomized analysis that used historic controls from different eras. Also, the number of patients in each cohort limited the statistical power of the study. Despite these limitations, this is the largest clinical study comparing LPD to MEC with wellmatched study cohorts using clearly defined criteria for PGD. Aziz et al recently reported that they could not demonstrate a difference between LPD and MEC cohorts at their institution with respect to gas-exchange parameters or patient survival.10 They pointed out an important variable that could explain the discrepancy between the experimental evidence and clinical experience—that is, brain-stem death models are not used in the laboratory.10 In addition, much of the experimental evidence supporting the use of LPD was seen in small animal models. These advantages may not be evident in larger animal models.34 Furthermore, factors such as improved endothelial contractility and relaxation with LPD in the experimental forum are short-lived and allografts preserved in MEC do recover these functions over a longer period of time.5 Many benefits of LPD in the laboratory setting were realized as allografts were preserved for significantly longer periods than in the clinical setting. In donor allografts with long preservation times or marginal donor characteristics, it is possible that LPD may be superior to MEC. A randomized,
Nath et al.
2247
multicenter study with a large sample of this type of patient population is necessary to assess the role of LPD in determining patient outcome and gas-exchange parameters. The conflicting data from both the laboratory and clinical realm regarding benefits of LPD indicate that the factors influencing post-transplant allograft function are numerous and complex. Although we were unable to show a significant clinical difference between LPD and MEC, there remains much work to be done to further elucidate the factors that influence allograft function. Translating additional research findings into the clinical arena will be critical for the continued efforts toward reducing the incidence of PGD in lung transplantation. It is possible that the preferential use of LPD over MEC could be substantiated upon further study, particularly among recipients with much longer ischemia times than those in this investigation. REFERENCES 1. Arcasoy SM, Kotloff RM. Lung transplantation. N Engl J Med 1999;340:1081–91. 2. Colquhoun IW, Kirk AJB, Au J, et al. Single flush perfusion with modified Euro-Collins solution: experience in clinical lung preservation. J Heart Lung Transplant 1992; 11(suppl):S209 –14. 3. Cooper JD, Patterson GA, Trulock EP. Results of 131 consecutive single and bilateral lung transplant recipients. Washington University Lung Transplant Group. J Thorac Cardiovasc Surg 1994;107:460 –71. 4. Steen S, Kimblad PO, Sjoberg T, Lindberg L, Ingemasson R, Massa G. Safe lung preservation for twenty-four hours with Perfadex. Ann Thorac Surg 1994;57:450 –7. 5. Ingemansson R, Massa G, Pandita RK, Sjobert T, Steen S. Perfadex is superior to Euro-Collins solution regarding 24-hour preservation of vascular function. Ann Thorac Surg 1995;60:1210 – 4. 6. Struber M, Wilhelmi M, Harringer W, et al. Flush perfusion with low potassium dextran solution improves early graft function in clinical lung transplantation. Eur J Cardiothorac Surg 2001;19:190 – 4. 7. Rabanal JM, Ibanez AM, Mons R, et al. Influence of preservation solution on early lung function (Euro-Collins vs Perfadex). Transplant Proc 2003;35:1938 –9. 8. Fischer S, Matte-Martyn A, de Perrot M, et al. Lowpotassium dextran preservation solution improves lung function after human lung transplantation. J Thorac Cardiovasc Surg 2001;121:594 – 6. 9. Muller C, Furst H, Reichenspurner H, et al. Lung procurement by low-potassium dextran and the effect on preservation injury. Transplantation 1999;68:1139 – 43. 10. Aziz TM, Pillay TM, Corris PA, et al. Perfadex for clinical lung procurement: is it an advance? Ann Thorac Surg 2003;75:990 –5. 11. Thabut G, Vinatier I, Stern JB, et al. Primary graft failure following lung transplantation: predictive factors of mortality. Chest 2002;121:1876 – 82.
2248
Nath et al.
12. Sekine Y, Waddell TK, Matte-Martyn A, et al. Risk quantification of early outcome after lung transplantation: donor, recipient, operative, and post-transplant parameters. J Heart Lung Transplant 2004;21:297–310. 13. Prekker ME, Nath DS, Johnson AC, Walker AR, Hertz M, Dahlberg PS. Validation of the proposed ISHLT grading system for primary graft dysfunction following lung transplantation. J Heart Lung Transplant 2005;24(suppl 1):S72. 14. Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002;21:297–310. 15. Egan TM, Kaiser LR, Cooper JD. Lung Transplantation. Curr Probl Sur 1989;26:675–751. 16. Mulvin D, Jone K, Howard R, Grosso M, Repine J, Johnston M. The effect of prostacyclin as a constituent of a preservation solution in protecting lungs from ischemic injury because of its vasodilatory properties. Transplantation 1990;49:828 –30. 17. Kshettry VR, Shumway SJ, Gauthier RL, Bolman RM III. Technique of single-lung transplantation. Ann Thorac Surg 1993;55:1019 –21. 18. Hardy JD, Eraslan S, Dalton ML Jr, Walker GR Jr. Lung homotransplantation in man: report of the initial case. JAMA 1963;186:1065–74. 19. The Toronto Lung Transplant Group. Unilateral lung transplantation for pulmonary fibrosis. N Engl J Med 1986;314:1140 –5. 20. Ulichny KS Jr, Eagan TM, Lambert CJ Jr, Wilcox BR. Postmortem nitrogen ventilation improves function of transplantated canine cadaver lungs. Chest 1991;100(suppl):63S. 21. Puskas JD, Hirai T, Christie N, Mayer E, Slutsky AS, Patterson GA. Reliable 30-hour lung preservation by donor hyperinflation. J Thorac Cardiovasc Surg 1992;104:1075– 83. 22. Wang LS, Yoshikawa K, Miyoshi S, et al. The effect of ischemic time and temperature on lung preservation in a simple ex vivo rabbit model used for functional assessment. J Thorac Cardiovasc Surg 1989;98:333– 42. 23. Haverich A, Scott WC, Jamieson SW. Twenty years of lung preservation: a review. Heart Transplant 1985;4:234 – 40.
The Journal of Heart and Lung Transplantation December 2005
24. Unruh H, Hoppensack M, Oppenheimer L. Vascular properties of canine lungs perfused with Eurocollins solution and prostacyclin. Ann Thorac Surg 1990;49:292– 8. 25. Ueno T, Yokomise H, Oka T, et al. The effect of PGE1 and temperature on lung function following preservation. Transplantation 1991;52:626 –30. 26. Kukkonen S, Heikkila LJ, Verkkala K, Mattila SP, Toivonen H. Prostaglandin E1 or prostacyclin in Euro-Collins solution fails to improve lung preservation. Ann Thorac Surg 1995;60:1617–22. 27. Detterbeck FC, Keagy BA, Paull DE, Wilcox BR. Oxygen free radical scavengers decrease reperfusion injury in lung transplantation. Ann Thorac Surg 1990;50:204 –9. 28. Kelly RF, Murar J, Hong Z, et al. Low potassium dextran lung preservation solution reduces reactive oxygen species production. Ann Thorac Surg 2003;75:1705–10. 29. Maccherini M, Keshavjee SH, Slutsky AS, Patterson GA, Edelson JD. The effect of low-potassium– dextran versus Euro-Collins solution for preservation of isolated type II pneumocytes. Transplantation 1991;52:621– 6. 30. Struber M, Hohlfeld JM, Fraund S, Kim P, Warnecke G, Haverich A. Low-potassium dextran solution ameliorates reperfusion injury of the lung and protects surfactant function. J Thorac Cardiovasc Surg 2000;120: 566 –72. 31. Fehrenbach A, Pufe T, Wittwer T, et al. Reduced vascular endothelial growth factor correlates with alveolar epithelial damage after experimental ischemia and reperfusion. J Heart Lung Transplant 2003;22:967–78. 32. Ryan US. The endothelial cell surface and response to injury. Fed Proc 1986;45:101– 8. 33. Novick RJ, Gehman KE, Ali IS, Lee J. Lung preservation: the importance of endothelial and alveolar type II cell integrity. Ann Thorac Surg 1996;62:302–14. 34. Wierup P, Liao Q, Bolys R, Trygve, Rippe B, Steen S. Lung edema formation during cold perfusion: important differences between rat and porcine lung. J Heart Lung Transplant 2005;24:379 – 85.