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Flush perfusion with low potassium dextran solution improves early graft function in clinical lung transplantation

Flush perfusion with low potassium dextran solution improves early graft function in clinical... Abstract Objectives: We have previously demonstrated experimentally an amelioration of reperfusion injury of the lung after preservation using low potassium dextran (LPD) solution compared to Euro–Collins (EC) solution. Now we report on early graft function in 106 lung transplant recipients of LPD or EC preserved grafts. Methods: Initial graft function was assessed by measurement of lung compliance and oxygenation index 2 h after transplantation. Length of stay on the intensive care unit and hours of mechanical ventilation were compared. Correlation of donor oxygenation, ischemic time, type of transplant, recipient age and sex as well as initial lung compliance and oxygenation with early postoperative course were calculated. Results: Dynamic lung compliance was significantly (P < 0.05) improved in the LPD group. PO2/fiO2 was comparable in both groups (303±122 mmHg LPD, 282±118 mmHg EC). Mechanical ventilation was used for 321±500 h in the EC group and 189±365 h in the LPD group (P = 0.006). Intensive care therapy was required for 17.2±23.7 days in the EC group and 10.4±16 days in the LPD group (P = 0.012). Significantly higher lung function parameters were obtained in extubated recipients of LPD preserved grafts 2 weeks after TX. Thirty day graft survival was improved in the LPD group (P = 0.045). In the EC group, 30 day mortality was 14.2 and 8% in the LPD group. Conclusions: A reduction of perioperative mortality and morbidity suggests that LPD solution has superior early graft function compared to lung preservation using EC solution. Lung transplantation, Surfactant, Reperfusion injury, Preservation solution, Low potassium dextran solution 1 Introduction Pulmonary allograft reperfusion injury remains a significant and common problem in clinical lung transplantation. Perioperative mortality still is in the range of 10–20%. Reperfusion injury is one of the most frequent causes of early death after lung transplantation [1]. The incidence of reperfusion injury has been reported to range from 20 to 40% in different lung transplant programs [2]. Clinical symptoms range from mild reduction of compliance to edema and failure of the graft. The requirement of extracorporeal support due to graft failure of the lung was reported in 7.4% of 215 recipients [3]. Therefore, numerous studies were conducted to elucidate the pathophysiology of reperfusion injury of the lung and to improve early graft function. It was shown that the integrity of endothelial cells and of alveolar type II cells is of importance for the initial graft function [4]. Euro–Collins (EC) solution, which is the most commonly used clinical lung preservation solution, is of intracellular ion composition (Table 1) . This solution as well as other high potassium containing perfusates was shown to impair pulmonary arterial endothelial cell function [5]. Solutions with extracellular ion composition, such as low potassium dextran (LPD) solution, were found to be superior to EC with regard to preservation of endothelial function [6]. In addition, preservation of type II pneumocytes with LPD solution revealed less cytotoxicity and improved cellular metabolic activity when compared to EC solution [7]. In an experimental study using minipigs we found an amelioration of reperfusion injury of lungs preserved with LPD solution compared to EC. In addition, surfactant activity was severely impaired in the EC group, but well preserved in LPD perfused lungs [8]. Table 1 Open in new tabDownload slide Composition of EC and LPD solution Table 1 Open in new tabDownload slide Composition of EC and LPD solution Because of these findings LPD solution was used for clinical lung preservation. Early graft function of 57 consecutive lung transplant recipients was compared to a historic control group of patients who received EC perfused grafts. 2 Patients and methods From April 1996 to October 1999 lung transplants were performed in 120 recipients at our institution. LPD solution for preservation of the lung was used in 57 grafts from April 1998 to October 1999. The remaining 63 lungs were perfused with EC solution and transplanted from April 1996 to April 1998. This group serves as a historic control group. Recipients who were on mechanical ventilation or extracorporeal support prior to transplantation were excluded from the study (six patients in the LPD group and eight patients in the EC group). Fifty-one recipients of LPD perfused grafts were included in the analysis and 55 patients with EC perfusion were included. The mean recipient age in the EC group was 42±12 years (range 16–62 years) and in the LPD group 38.9±11 years (range 19–59 years). Twenty-nine patients of the EC group were female and 26 were male. In the LPD group 21 recipients were female and 30 were male. EC perfused grafts were used for 11 single lung transplantations and for 44 cases of bilateral grafting. In the LPD group, nine single lungs were transplanted and 42 bilateral transplants were performed. The diagnoses of the recipients are shown in Fig. 1 . Fig. 1 Open in new tabDownload slide Diagnosis of recipients of LPD or EC preserved lung transplants. Fig. 1 Open in new tabDownload slide Diagnosis of recipients of LPD or EC preserved lung transplants. Donor lungs were harvested after careful evaluation of blood gas parameters and bronchoscopic findings. Lungs were perfused either with cold (4°C) EC or LPD solution (8°C, Perfadex®, Medisan, Uppsala, Sweden). Prostacyclin (250 μg; Flolan®, Wellcome) was infused prior to cross-clamping of the aorta in all harvesting procedures. Thereafter, flush perfusion with 4 l of EC or LPD solution was started via the pulmonary artery. The perfusate was drained through an incision of the left auricle. Usually 10 min were required to complete the flush procedure. Lungs were ventilated at a fiO2 of 1.0. After removal of the heart the lungs were excised as a double lung block and stored in a mild inflated state in cold perfusion solution. The PO2/fiO2 value prior to harvesting was 475±15 mmHg in the EC group and 477±14 mmHg in the LPD group. The mean ischemic time for EC perfused grafts was 280±41 min. After LPD perfusion the mean ischemic time was 320±54 min. Lung transplants were performed as single lung grafting in patients with fibrosis and an absence of bronchiectasis. In all other cases bilateral sequential transplantation was carried out. All patients with a diagnosis of PPHT were electively planned for use of extracorporeal circulation (ECC) (15% EC, 10% LPD). In addition, an inability to place a double lumen tracheal tube for malformation of the trachea (10% in both groups) led to elective use of ECC. In all other cases an indication for ECC was impairment of right heart function after clamping of the right pulmonary artery or inadequate gas exchange after transplantation of the first lung in double lung procedures. ECC was required in 53% of procedures with EC perfused grafts and in 58% of procedures with LPD preserved lungs. For assessment of initial graft function PO2/fiO2 was determined 2 h after the procedure. In addition, pulmonary vascular resistance was calculated after measurement of cardiac output by thermodilution methods using a Swan-Ganz catheter. Dynamic compliance was computed by the mechanical ventilator (Evita 4, Dräger, Lübeck, Germany). Patients were ventilated in a pressure controlled mode with a positive end-expiratory pressure of 10 mmHg and an inspiration/expiration time ratio of 1:1. Other indicators of postoperative graft function were time of extubation and time of transfer to a regular ward. Additional end-point parameters for this study were 30 day mortality, 30 day graft survival and spirometry parameters (FeV1 and vital capacity (VC)) 1 and 4 weeks after transplantation for extubated patients. A long-term intensive care unit (ICU) requirement was proposed as a mechanical ventilation for more than 100 h or a length of stay in an ICU of more than 10 days. Correlations of recipient age, diagnosis, sex, donor PO2/fiO2, ischemic time, type of preservation solution and initial compliance after TX were calculated with postoperative compliance, PO2/fiO2, duration of intensive care and mechanical ventilation as well as spirometry data 1 and 4 weeks after TX and the 30 day graft survival. 2.1 Statistics and data analysis All data are presented as the mean±SD. To compare the effects of the preservation solution the Mann–Whitney U-test was performed. Bivariate correlations were calculated using Spearman rank correlations. The SPSS statistical program for the PC was used for all calculations and statistical analysis. A P value of less than 5% was considered as statistically significant. 3 Results Compliance of the lung 2 h after transplantation was 30±10 ml/mmHg in the EC group and 34±11 ml/mmHg in LPD preserved grafts (P = 0.04). PO2/fiO2 was comparable at this time (303±122 mmHg for LPD and 282±120 mmHg for EC). Mechanical ventilation was required for 321±500 h in the EC group (median 57 h) and 189±365 h (P = 0.006) in patients with LPD perfused grafts (median 45 h) (Fig. 2) . Intensive care therapy (Fig. 3) was shorter in the LPD group (10.4±16 days) compared to EC graft recipients (17.2±23.4 days, P = 0.012). Long-term ICU therapy was required in 47% of patients with EC preserved lungs. In contrast, 20% of recipients in the LPD group needed long-term ICU support (mechanical ventilation for more than 100 h or ICU stay of more than 10 days). The perioperative mortality (30 days) was higher (14.2%) in the EC group compared to recipients of LPD preserved grafts (8.0%). Fig. 2 Open in new tabDownload slide ICU therapy requirements in days are shown for patients with LPD and EC preserved lungs and diagnosis prior to transplantation. Data are expressed as mean values. Fig. 2 Open in new tabDownload slide ICU therapy requirements in days are shown for patients with LPD and EC preserved lungs and diagnosis prior to transplantation. Data are expressed as mean values. Fig. 3 Open in new tabDownload slide Time of mechanical ventilation after lung transplantation shown for patients with LPD and EC preserved lungs and diagnosis prior to transplantation. Data are expressed as mean values. Fig. 3 Open in new tabDownload slide Time of mechanical ventilation after lung transplantation shown for patients with LPD and EC preserved lungs and diagnosis prior to transplantation. Data are expressed as mean values. No differences were found between both groups in post-TX pulmonary artery pressure or pulmonary vascular resistance. Spirometry data 2 and 4 weeks after transplantation were only available from extubated patients (n = 75, 38 EC and 37 LPD). Two weeks after lung transplantation spirometry of recipients of LPD perfused grafts revealed significantly higher VC (P = 0.033) and FeV1 values (P = 0.031) compared to patients with EC preserved lungs (Fig. 4) . An increase of FeV1 and VC was found 4 weeks after transplantation in both groups. FeV1 was 2.1±0.6 l in the EC group and 2.4±0.6 l in the LPD group (P = 0.06). In addition, the corresponding VC of LPD recipients was significantly higher compared to the EC group (P = 0.029). Fig. 4 Open in new tabDownload slide Spirometry data of extubated patients 2 and 4 weeks after lung transplantation. Data are expressed as mean values. Fig. 4 Open in new tabDownload slide Spirometry data of extubated patients 2 and 4 weeks after lung transplantation. Data are expressed as mean values. The female gender correlated significantly with a lower postoperative compliance (P = 0.007), longer ICU requirements (P = 0.009), mechanical ventilation (P = 0.001) and reduced spirometry values 2 (P = 0.000) and 4 weeks (P = 0.000) after transplant. The diagnosis of lung fibrosis led to a significant reduction of postoperative compliance (P = 0.01) and reduced VC after 4 weeks (P = 0.03). No significant correlation was found between diagnosis and intensive care requirements, mechanical ventilation or survival. Donor PO2/fiO2 did not correlate with postoperative graft function. Length of ischemic time had an adverse effect on graft FeV1 4 weeks after TX (P = 0.036). Early dynamic compliance of the graft correlated with a reduction of ICU (P = 0.003) and mechanical ventilation requirements (P = 0.001), and an improvement of graft survival (P = 0.04) and spirometry values 2 (FeV1, P = 0.026; VC, P = 0.029) and 4 weeks (FeV1, P = 0.011; VC, P = 0.013) after transplantation. 4 Discussion This study represents a retrospective clinical analysis on the impact of a different preservation solution on the early results after lung transplantation. It shares the disadvantages of such study designs in that both groups do not match exactly in terms of patient selection and type of procedures. In addition, a general learning curve leading to an improvement of results can not be excluded by statistical methods. Recipients of EC preserved grafts were transplanted from 1996 to 1998 and served as a historic control group. LPD perfused grafts were used from 1998 to 1999. However, there are no multicenter prospective trials on the effect of different preservation solutions in lung transplantation. This may be because the number of lung transplants is quite low and the patients are different not only in age and gender, but also in their diagnosis, which may have an influence on the postoperative course. Preservation procedures, transplantation and postoperative care may be standardized for a single center, but are of high variance at different centers. During this study the criteria for acceptance of donor lungs, standards for procurement of the grafts, surgical procedure, anesthesia, postoperative care and immunosuppressive protocol remained unchanged, since they were developed in the earlier experience of the program from 1989 to 1996. With the above-mentioned limitations of the study, a significant improvement of the perioperative graft with cold EC or University of Wisconsin solution function and survival was found in the LPD preserved group, leading to a reduction of the intensive care requirement which was measured by hours of mechanical ventilation and stay at the ICU. The length of mechanical ventilation shows high standard deviations in both groups. It is determined by the group of patients who need long-term ICU treatment after lung transplantation. This group was defined as requiring more than 100 h of mechanical ventilation or an ICU stay of more than 10 days. An incidence of 47% of those patients in the EC group has to be attributed in part to postoperative graft function and in part to patient selection. The waiting list of a large European lung transplant center is characterized by a high number of patients waiting for more than 2 years until a donor organ is available, while becoming a ‘borderline’ transplant candidate due to deteriorated physical status, a high incidence of prior thoracic surgery and a 10% incidence of retransplant procedures for bronchiolitis obliterans syndrome. These recipients were not excluded from the study. Since the selection criteria were unchanged for the recipients in this study, a reduction of long-term ICU requirements to 20% in the LPD group seems to indicate that LPD perfused grafts are more adequate for this patient population. A likely explanation is the amelioration of reperfusion injury LPD perfused grafts. The most common preservation method of the lung is flush perfusion. Reperfusion injury is a common complication after lung TX. In approximately 15% of cases it leads to graft failure [9], and in an even higher percentage the amelioration of reperfusion injury leads to a less severe disturbed graft function. Therefore, many experimental studies were conducted to modify both solutions in order to improve the quality of the graft and to extend the ischemic time. None of the modifications were accepted generally for clinical practice with the exception of prostacyclin for flush perfusion with EC solution. LPD solution is significantly different to EC and University of Wisconsin solution, because the ion composition is of extracellular composition. In numerous experimental studies a protective effect of LPD solution on endothelial function and type II pneumocytes was found [6,7]. Endothelial dysfunction may cause pulmonary hypertension and leukocyte sequestration. Impairment of type II cells may lead to a reduction of surfactant function. A capillary leakage due to leukocyte sequestration may further aggravate surfactant dysfunction by inactivation of surfactant due to plasma proteins [10] leaking into the alveolar space. Although this study was not designed to highlight the pathophysiology of lung reperfusion injury, it is already known that pulmonary hypertension and surfactant dysfunction [11] are features of graft dysfunction after lung transplantation [12]. Treatment strategies include the use of nitric oxide which may counteract endothelial dysfunction and surfactant replacement [13]. Therefore, it may be speculated that beneficial effects of the preservation of endothelial cells and pneumocytes are possible mechanisms for the improvement of perioperative graft function. In 1999, the lung transplant group from Munich published similar favorable clinical results with the use of LPD solution. A reduction of reperfusion injury was described in the LPD group. The higher number of single lung transplants and the use of relatively old data in the EC group weaken this study [14] but it is supportive to our findings. In addition, an improvement in lung compliance was found after transplantation as well as higher spirometry values in the first month after the procedure in patients with LPD preserved grafts. In part this may be due to differences between the study groups. There was a higher number of women in the EC group which may have caused a bias towards transplantation of smaller lungs in this group. However, this difference was not of statistical significance (P = 0.11). An intragroup comparison of the postoperative courses revealed a high variation in terms of mechanical ventilation and intensive care requirement. Patients with emphysema seemed to have a more favorable postoperative course in both groups, although the differences were not of statistical significance. In the LPD group there were more recipients with cystic fibrosis and fibrosis and less patients with a diagnosis of primary pulmonary hypertension and emphysema. Since patients with cystic fibrosis had a comparable postoperative course to patients with fibrosis or PPHT, the differences in the diagnosis cannot explain the generally more favorable course of recipients of the LPD group. In this study it was shown that initial dynamic lung compliance is predictive of the length of stay in intensive care, mechanical ventilation as well as graft survival and spirometry values. This parameter may reflect graft quality at a very early postoperative phase. It can be speculated that improved initial graft compliance is associated with proper surfactant function. Further clinical studies have to verify this hypothesis. In addition, donor PO2/fiO2 which is often used for assessment of graft quality did not correlate with early graft function and should not be overestimated for this purpose. In conclusion, this retrospective analysis of more than 100 lung transplants revealed an improvement of perioperative mortality and morbidity with the change of the preservation protocol from flush perfusion with EC to LPD solution. Clinical use of LPD solution is encouraged. A multicenter prospective randomized trial is required to verify these results. In addition, long-term results of graft function after preservation with LPD solution are pending. References [1] Cooper J.D. , Patterson G.A. , Trulock E.P. , Washington University Lung Transplant Group . Results of 131 consecutive single and bilateral lung transplant recipients , J Thorac Cardiovasc Surg , 1994 , vol. 107 (pg. 460 - 471 ) Google Scholar PubMed OpenURL Placeholder Text WorldCat [2] Colquhoun I.W. , Kirk A.J.B. , Au J. , Conacher I.D. , Corris P.A. , Hilton C.J. , Dark J.H. . Single flush perfusion with modified Euro-Collins solution: experience in clinical lung preservation , J Heart Lung Transplant , 1992 , vol. 11 (pg. S209 - S214 ) Google Scholar PubMed OpenURL Placeholder Text WorldCat [3] Glassman L.R. , Keenan R.J. , Fabrizio M.C. , Sonett J.R. , Bierman M.I. , Pham S.M. , Griffith B.P. . Extracorporeal membrane oxygenation as an adjunct for primary graft failure in adult lung transplant recipients , J Thorac Cardiovasc Surg , 1995 , vol. 110 (pg. 723 - 727 ) Google Scholar Crossref Search ADS PubMed WorldCat [4] Novick R.J. , Gehman K.E. , Ali I.S. , Lee J. . Lung preservation: the importance of endothelial and alveolar type II cell integrity , Ann Thorac Surg , 1996 , vol. 62 (pg. 302 - 314 ) Google Scholar Crossref Search ADS PubMed WorldCat [5] Strüber M. , Ehlers K.A. , Nielsson F.N. , Miller V.M. , McGregor C.G.A. , Haverich A. . Effect of lung preservation with Euro-Collins and University of Wisconsin solution on endothelium dependent relaxations , Ann Thorac Surg , 1997 , vol. 63 (pg. 1428 - 1435 ) Google Scholar Crossref Search ADS PubMed WorldCat [6] Ingemansson R. , Massa G. , Pandita R.K. , Sjöberg T. , Steen S. . Perfadex is superior to Euro-Collins solution regarding 24 hour preservation of vascular function , Ann Thorac Surg , 1995 , vol. 60 (pg. 1210 - 1214 ) Google Scholar Crossref Search ADS PubMed WorldCat [7] Maccherini M. , Keshavjee S.H. , Slutsky A.S. , Patterson G.A. , Edelson J.D. . The effect of low-potassium dextran versus Euro-Collins solution for preservation of isolated type II pneumocytes , Transplantation , 1991 , vol. 52 (pg. 621 - 626 ) Google Scholar Crossref Search ADS PubMed WorldCat [8] Strüber M. , Hohlfeld J.M. , 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 , vol. 120 (pg. 566 - 572 ) Google Scholar Crossref Search ADS PubMed WorldCat [9] Arcasoy S.M. , Kotloff R.M. . Lung transplantation , N Engl J Med , 1999 , vol. 340 (pg. 1081 - 1091 ) Google Scholar Crossref Search ADS PubMed WorldCat [10] Fuchimukai T. , Fujiwara T. , Takahashi A. , Enhorning G. . Artificial pulmonary surfactant inhibited by proteins , Appl J Physiol , 1987 , vol. 62 (pg. 429 - 437 ) Google Scholar Crossref Search ADS WorldCat [11] Novick R.J. , MacDonald J. , Veldhuizen R.A. , Wan F. , Duplan J. , Denning L. , Posmayer F. , Gilpin A.A. , Yao L.J. , Bjarneson D. , Lewis J.F. . Evaluation of surfactant replacement treatment strategies after prolonged graft storage in lung transplantation , Am J Respir Crit Care Med , 1996 , vol. 154 (pg. 98 - 104 ) Google Scholar Crossref Search ADS PubMed WorldCat [12] Hohlfeld J.M. , Tiryaki E. , Hamm H. , Hoymann H.G. , Krug N. , Haverich A. , Fabel H. . Pulmonary surfactant activity is impaired in lung transplant recipients , Am J Respir Crit Care Med , 1998 , vol. 158 3 (pg. 706 - 712 ) Google Scholar Crossref Search ADS PubMed WorldCat [13] Strüber M. , Brandt M. , Cremer J. , Harringer W. , Hirt S.W. , Haverich A. . Therapy for lung failure using nitric oxide and surfactant replacement , Ann Thorac Surg , 1996 , vol. 61 (pg. 1543 - 1545 ) Google Scholar Crossref Search ADS PubMed WorldCat [14] Müller C. , Fürst H. , Reichenspurner H. , Briegel J. , Groh J. , Reichart B. . Lung procurement by low-potassium dextran and the effect on preservation injury , Transplantation , 1999 , vol. 68 (pg. 1139 - 1143 ) Google Scholar Crossref Search ADS PubMed WorldCat © 2001 Elsevier Science B.V. All rights reserved. Elsevier Science B.V. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Cardio-Thoracic Surgery Oxford University Press

Flush perfusion with low potassium dextran solution improves early graft function in clinical lung transplantation

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Oxford University Press
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© 2001 Elsevier Science B.V. All rights reserved.
Subject
Articles
ISSN
1010-7940
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1873-734X
DOI
10.1016/S1010-7940(00)00631-X
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Abstract

Abstract Objectives: We have previously demonstrated experimentally an amelioration of reperfusion injury of the lung after preservation using low potassium dextran (LPD) solution compared to Euro–Collins (EC) solution. Now we report on early graft function in 106 lung transplant recipients of LPD or EC preserved grafts. Methods: Initial graft function was assessed by measurement of lung compliance and oxygenation index 2 h after transplantation. Length of stay on the intensive care unit and hours of mechanical ventilation were compared. Correlation of donor oxygenation, ischemic time, type of transplant, recipient age and sex as well as initial lung compliance and oxygenation with early postoperative course were calculated. Results: Dynamic lung compliance was significantly (P < 0.05) improved in the LPD group. PO2/fiO2 was comparable in both groups (303±122 mmHg LPD, 282±118 mmHg EC). Mechanical ventilation was used for 321±500 h in the EC group and 189±365 h in the LPD group (P = 0.006). Intensive care therapy was required for 17.2±23.7 days in the EC group and 10.4±16 days in the LPD group (P = 0.012). Significantly higher lung function parameters were obtained in extubated recipients of LPD preserved grafts 2 weeks after TX. Thirty day graft survival was improved in the LPD group (P = 0.045). In the EC group, 30 day mortality was 14.2 and 8% in the LPD group. Conclusions: A reduction of perioperative mortality and morbidity suggests that LPD solution has superior early graft function compared to lung preservation using EC solution. Lung transplantation, Surfactant, Reperfusion injury, Preservation solution, Low potassium dextran solution 1 Introduction Pulmonary allograft reperfusion injury remains a significant and common problem in clinical lung transplantation. Perioperative mortality still is in the range of 10–20%. Reperfusion injury is one of the most frequent causes of early death after lung transplantation [1]. The incidence of reperfusion injury has been reported to range from 20 to 40% in different lung transplant programs [2]. Clinical symptoms range from mild reduction of compliance to edema and failure of the graft. The requirement of extracorporeal support due to graft failure of the lung was reported in 7.4% of 215 recipients [3]. Therefore, numerous studies were conducted to elucidate the pathophysiology of reperfusion injury of the lung and to improve early graft function. It was shown that the integrity of endothelial cells and of alveolar type II cells is of importance for the initial graft function [4]. Euro–Collins (EC) solution, which is the most commonly used clinical lung preservation solution, is of intracellular ion composition (Table 1) . This solution as well as other high potassium containing perfusates was shown to impair pulmonary arterial endothelial cell function [5]. Solutions with extracellular ion composition, such as low potassium dextran (LPD) solution, were found to be superior to EC with regard to preservation of endothelial function [6]. In addition, preservation of type II pneumocytes with LPD solution revealed less cytotoxicity and improved cellular metabolic activity when compared to EC solution [7]. In an experimental study using minipigs we found an amelioration of reperfusion injury of lungs preserved with LPD solution compared to EC. In addition, surfactant activity was severely impaired in the EC group, but well preserved in LPD perfused lungs [8]. Table 1 Open in new tabDownload slide Composition of EC and LPD solution Table 1 Open in new tabDownload slide Composition of EC and LPD solution Because of these findings LPD solution was used for clinical lung preservation. Early graft function of 57 consecutive lung transplant recipients was compared to a historic control group of patients who received EC perfused grafts. 2 Patients and methods From April 1996 to October 1999 lung transplants were performed in 120 recipients at our institution. LPD solution for preservation of the lung was used in 57 grafts from April 1998 to October 1999. The remaining 63 lungs were perfused with EC solution and transplanted from April 1996 to April 1998. This group serves as a historic control group. Recipients who were on mechanical ventilation or extracorporeal support prior to transplantation were excluded from the study (six patients in the LPD group and eight patients in the EC group). Fifty-one recipients of LPD perfused grafts were included in the analysis and 55 patients with EC perfusion were included. The mean recipient age in the EC group was 42±12 years (range 16–62 years) and in the LPD group 38.9±11 years (range 19–59 years). Twenty-nine patients of the EC group were female and 26 were male. In the LPD group 21 recipients were female and 30 were male. EC perfused grafts were used for 11 single lung transplantations and for 44 cases of bilateral grafting. In the LPD group, nine single lungs were transplanted and 42 bilateral transplants were performed. The diagnoses of the recipients are shown in Fig. 1 . Fig. 1 Open in new tabDownload slide Diagnosis of recipients of LPD or EC preserved lung transplants. Fig. 1 Open in new tabDownload slide Diagnosis of recipients of LPD or EC preserved lung transplants. Donor lungs were harvested after careful evaluation of blood gas parameters and bronchoscopic findings. Lungs were perfused either with cold (4°C) EC or LPD solution (8°C, Perfadex®, Medisan, Uppsala, Sweden). Prostacyclin (250 μg; Flolan®, Wellcome) was infused prior to cross-clamping of the aorta in all harvesting procedures. Thereafter, flush perfusion with 4 l of EC or LPD solution was started via the pulmonary artery. The perfusate was drained through an incision of the left auricle. Usually 10 min were required to complete the flush procedure. Lungs were ventilated at a fiO2 of 1.0. After removal of the heart the lungs were excised as a double lung block and stored in a mild inflated state in cold perfusion solution. The PO2/fiO2 value prior to harvesting was 475±15 mmHg in the EC group and 477±14 mmHg in the LPD group. The mean ischemic time for EC perfused grafts was 280±41 min. After LPD perfusion the mean ischemic time was 320±54 min. Lung transplants were performed as single lung grafting in patients with fibrosis and an absence of bronchiectasis. In all other cases bilateral sequential transplantation was carried out. All patients with a diagnosis of PPHT were electively planned for use of extracorporeal circulation (ECC) (15% EC, 10% LPD). In addition, an inability to place a double lumen tracheal tube for malformation of the trachea (10% in both groups) led to elective use of ECC. In all other cases an indication for ECC was impairment of right heart function after clamping of the right pulmonary artery or inadequate gas exchange after transplantation of the first lung in double lung procedures. ECC was required in 53% of procedures with EC perfused grafts and in 58% of procedures with LPD preserved lungs. For assessment of initial graft function PO2/fiO2 was determined 2 h after the procedure. In addition, pulmonary vascular resistance was calculated after measurement of cardiac output by thermodilution methods using a Swan-Ganz catheter. Dynamic compliance was computed by the mechanical ventilator (Evita 4, Dräger, Lübeck, Germany). Patients were ventilated in a pressure controlled mode with a positive end-expiratory pressure of 10 mmHg and an inspiration/expiration time ratio of 1:1. Other indicators of postoperative graft function were time of extubation and time of transfer to a regular ward. Additional end-point parameters for this study were 30 day mortality, 30 day graft survival and spirometry parameters (FeV1 and vital capacity (VC)) 1 and 4 weeks after transplantation for extubated patients. A long-term intensive care unit (ICU) requirement was proposed as a mechanical ventilation for more than 100 h or a length of stay in an ICU of more than 10 days. Correlations of recipient age, diagnosis, sex, donor PO2/fiO2, ischemic time, type of preservation solution and initial compliance after TX were calculated with postoperative compliance, PO2/fiO2, duration of intensive care and mechanical ventilation as well as spirometry data 1 and 4 weeks after TX and the 30 day graft survival. 2.1 Statistics and data analysis All data are presented as the mean±SD. To compare the effects of the preservation solution the Mann–Whitney U-test was performed. Bivariate correlations were calculated using Spearman rank correlations. The SPSS statistical program for the PC was used for all calculations and statistical analysis. A P value of less than 5% was considered as statistically significant. 3 Results Compliance of the lung 2 h after transplantation was 30±10 ml/mmHg in the EC group and 34±11 ml/mmHg in LPD preserved grafts (P = 0.04). PO2/fiO2 was comparable at this time (303±122 mmHg for LPD and 282±120 mmHg for EC). Mechanical ventilation was required for 321±500 h in the EC group (median 57 h) and 189±365 h (P = 0.006) in patients with LPD perfused grafts (median 45 h) (Fig. 2) . Intensive care therapy (Fig. 3) was shorter in the LPD group (10.4±16 days) compared to EC graft recipients (17.2±23.4 days, P = 0.012). Long-term ICU therapy was required in 47% of patients with EC preserved lungs. In contrast, 20% of recipients in the LPD group needed long-term ICU support (mechanical ventilation for more than 100 h or ICU stay of more than 10 days). The perioperative mortality (30 days) was higher (14.2%) in the EC group compared to recipients of LPD preserved grafts (8.0%). Fig. 2 Open in new tabDownload slide ICU therapy requirements in days are shown for patients with LPD and EC preserved lungs and diagnosis prior to transplantation. Data are expressed as mean values. Fig. 2 Open in new tabDownload slide ICU therapy requirements in days are shown for patients with LPD and EC preserved lungs and diagnosis prior to transplantation. Data are expressed as mean values. Fig. 3 Open in new tabDownload slide Time of mechanical ventilation after lung transplantation shown for patients with LPD and EC preserved lungs and diagnosis prior to transplantation. Data are expressed as mean values. Fig. 3 Open in new tabDownload slide Time of mechanical ventilation after lung transplantation shown for patients with LPD and EC preserved lungs and diagnosis prior to transplantation. Data are expressed as mean values. No differences were found between both groups in post-TX pulmonary artery pressure or pulmonary vascular resistance. Spirometry data 2 and 4 weeks after transplantation were only available from extubated patients (n = 75, 38 EC and 37 LPD). Two weeks after lung transplantation spirometry of recipients of LPD perfused grafts revealed significantly higher VC (P = 0.033) and FeV1 values (P = 0.031) compared to patients with EC preserved lungs (Fig. 4) . An increase of FeV1 and VC was found 4 weeks after transplantation in both groups. FeV1 was 2.1±0.6 l in the EC group and 2.4±0.6 l in the LPD group (P = 0.06). In addition, the corresponding VC of LPD recipients was significantly higher compared to the EC group (P = 0.029). Fig. 4 Open in new tabDownload slide Spirometry data of extubated patients 2 and 4 weeks after lung transplantation. Data are expressed as mean values. Fig. 4 Open in new tabDownload slide Spirometry data of extubated patients 2 and 4 weeks after lung transplantation. Data are expressed as mean values. The female gender correlated significantly with a lower postoperative compliance (P = 0.007), longer ICU requirements (P = 0.009), mechanical ventilation (P = 0.001) and reduced spirometry values 2 (P = 0.000) and 4 weeks (P = 0.000) after transplant. The diagnosis of lung fibrosis led to a significant reduction of postoperative compliance (P = 0.01) and reduced VC after 4 weeks (P = 0.03). No significant correlation was found between diagnosis and intensive care requirements, mechanical ventilation or survival. Donor PO2/fiO2 did not correlate with postoperative graft function. Length of ischemic time had an adverse effect on graft FeV1 4 weeks after TX (P = 0.036). Early dynamic compliance of the graft correlated with a reduction of ICU (P = 0.003) and mechanical ventilation requirements (P = 0.001), and an improvement of graft survival (P = 0.04) and spirometry values 2 (FeV1, P = 0.026; VC, P = 0.029) and 4 weeks (FeV1, P = 0.011; VC, P = 0.013) after transplantation. 4 Discussion This study represents a retrospective clinical analysis on the impact of a different preservation solution on the early results after lung transplantation. It shares the disadvantages of such study designs in that both groups do not match exactly in terms of patient selection and type of procedures. In addition, a general learning curve leading to an improvement of results can not be excluded by statistical methods. Recipients of EC preserved grafts were transplanted from 1996 to 1998 and served as a historic control group. LPD perfused grafts were used from 1998 to 1999. However, there are no multicenter prospective trials on the effect of different preservation solutions in lung transplantation. This may be because the number of lung transplants is quite low and the patients are different not only in age and gender, but also in their diagnosis, which may have an influence on the postoperative course. Preservation procedures, transplantation and postoperative care may be standardized for a single center, but are of high variance at different centers. During this study the criteria for acceptance of donor lungs, standards for procurement of the grafts, surgical procedure, anesthesia, postoperative care and immunosuppressive protocol remained unchanged, since they were developed in the earlier experience of the program from 1989 to 1996. With the above-mentioned limitations of the study, a significant improvement of the perioperative graft with cold EC or University of Wisconsin solution function and survival was found in the LPD preserved group, leading to a reduction of the intensive care requirement which was measured by hours of mechanical ventilation and stay at the ICU. The length of mechanical ventilation shows high standard deviations in both groups. It is determined by the group of patients who need long-term ICU treatment after lung transplantation. This group was defined as requiring more than 100 h of mechanical ventilation or an ICU stay of more than 10 days. An incidence of 47% of those patients in the EC group has to be attributed in part to postoperative graft function and in part to patient selection. The waiting list of a large European lung transplant center is characterized by a high number of patients waiting for more than 2 years until a donor organ is available, while becoming a ‘borderline’ transplant candidate due to deteriorated physical status, a high incidence of prior thoracic surgery and a 10% incidence of retransplant procedures for bronchiolitis obliterans syndrome. These recipients were not excluded from the study. Since the selection criteria were unchanged for the recipients in this study, a reduction of long-term ICU requirements to 20% in the LPD group seems to indicate that LPD perfused grafts are more adequate for this patient population. A likely explanation is the amelioration of reperfusion injury LPD perfused grafts. The most common preservation method of the lung is flush perfusion. Reperfusion injury is a common complication after lung TX. In approximately 15% of cases it leads to graft failure [9], and in an even higher percentage the amelioration of reperfusion injury leads to a less severe disturbed graft function. Therefore, many experimental studies were conducted to modify both solutions in order to improve the quality of the graft and to extend the ischemic time. None of the modifications were accepted generally for clinical practice with the exception of prostacyclin for flush perfusion with EC solution. LPD solution is significantly different to EC and University of Wisconsin solution, because the ion composition is of extracellular composition. In numerous experimental studies a protective effect of LPD solution on endothelial function and type II pneumocytes was found [6,7]. Endothelial dysfunction may cause pulmonary hypertension and leukocyte sequestration. Impairment of type II cells may lead to a reduction of surfactant function. A capillary leakage due to leukocyte sequestration may further aggravate surfactant dysfunction by inactivation of surfactant due to plasma proteins [10] leaking into the alveolar space. Although this study was not designed to highlight the pathophysiology of lung reperfusion injury, it is already known that pulmonary hypertension and surfactant dysfunction [11] are features of graft dysfunction after lung transplantation [12]. Treatment strategies include the use of nitric oxide which may counteract endothelial dysfunction and surfactant replacement [13]. Therefore, it may be speculated that beneficial effects of the preservation of endothelial cells and pneumocytes are possible mechanisms for the improvement of perioperative graft function. In 1999, the lung transplant group from Munich published similar favorable clinical results with the use of LPD solution. A reduction of reperfusion injury was described in the LPD group. The higher number of single lung transplants and the use of relatively old data in the EC group weaken this study [14] but it is supportive to our findings. In addition, an improvement in lung compliance was found after transplantation as well as higher spirometry values in the first month after the procedure in patients with LPD preserved grafts. In part this may be due to differences between the study groups. There was a higher number of women in the EC group which may have caused a bias towards transplantation of smaller lungs in this group. However, this difference was not of statistical significance (P = 0.11). An intragroup comparison of the postoperative courses revealed a high variation in terms of mechanical ventilation and intensive care requirement. Patients with emphysema seemed to have a more favorable postoperative course in both groups, although the differences were not of statistical significance. In the LPD group there were more recipients with cystic fibrosis and fibrosis and less patients with a diagnosis of primary pulmonary hypertension and emphysema. Since patients with cystic fibrosis had a comparable postoperative course to patients with fibrosis or PPHT, the differences in the diagnosis cannot explain the generally more favorable course of recipients of the LPD group. In this study it was shown that initial dynamic lung compliance is predictive of the length of stay in intensive care, mechanical ventilation as well as graft survival and spirometry values. This parameter may reflect graft quality at a very early postoperative phase. It can be speculated that improved initial graft compliance is associated with proper surfactant function. Further clinical studies have to verify this hypothesis. In addition, donor PO2/fiO2 which is often used for assessment of graft quality did not correlate with early graft function and should not be overestimated for this purpose. In conclusion, this retrospective analysis of more than 100 lung transplants revealed an improvement of perioperative mortality and morbidity with the change of the preservation protocol from flush perfusion with EC to LPD solution. Clinical use of LPD solution is encouraged. A multicenter prospective randomized trial is required to verify these results. In addition, long-term results of graft function after preservation with LPD solution are pending. References [1] Cooper J.D. , Patterson G.A. , Trulock E.P. , Washington University Lung Transplant Group . Results of 131 consecutive single and bilateral lung transplant recipients , J Thorac Cardiovasc Surg , 1994 , vol. 107 (pg. 460 - 471 ) Google Scholar PubMed OpenURL Placeholder Text WorldCat [2] Colquhoun I.W. , Kirk A.J.B. , Au J. , Conacher I.D. , Corris P.A. , Hilton C.J. , Dark J.H. . Single flush perfusion with modified Euro-Collins solution: experience in clinical lung preservation , J Heart Lung Transplant , 1992 , vol. 11 (pg. S209 - S214 ) Google Scholar PubMed OpenURL Placeholder Text WorldCat [3] Glassman L.R. , Keenan R.J. , Fabrizio M.C. , Sonett J.R. , Bierman M.I. , Pham S.M. , Griffith B.P. . Extracorporeal membrane oxygenation as an adjunct for primary graft failure in adult lung transplant recipients , J Thorac Cardiovasc Surg , 1995 , vol. 110 (pg. 723 - 727 ) Google Scholar Crossref Search ADS PubMed WorldCat [4] Novick R.J. , Gehman K.E. , Ali I.S. , Lee J. . Lung preservation: the importance of endothelial and alveolar type II cell integrity , Ann Thorac Surg , 1996 , vol. 62 (pg. 302 - 314 ) Google Scholar Crossref Search ADS PubMed WorldCat [5] Strüber M. , Ehlers K.A. , Nielsson F.N. , Miller V.M. , McGregor C.G.A. , Haverich A. . Effect of lung preservation with Euro-Collins and University of Wisconsin solution on endothelium dependent relaxations , Ann Thorac Surg , 1997 , vol. 63 (pg. 1428 - 1435 ) Google Scholar Crossref Search ADS PubMed WorldCat [6] Ingemansson R. , Massa G. , Pandita R.K. , Sjöberg T. , Steen S. . Perfadex is superior to Euro-Collins solution regarding 24 hour preservation of vascular function , Ann Thorac Surg , 1995 , vol. 60 (pg. 1210 - 1214 ) Google Scholar Crossref Search ADS PubMed WorldCat [7] Maccherini M. , Keshavjee S.H. , Slutsky A.S. , Patterson G.A. , Edelson J.D. . The effect of low-potassium dextran versus Euro-Collins solution for preservation of isolated type II pneumocytes , Transplantation , 1991 , vol. 52 (pg. 621 - 626 ) Google Scholar Crossref Search ADS PubMed WorldCat [8] Strüber M. , Hohlfeld J.M. , 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 , vol. 120 (pg. 566 - 572 ) Google Scholar Crossref Search ADS PubMed WorldCat [9] Arcasoy S.M. , Kotloff R.M. . Lung transplantation , N Engl J Med , 1999 , vol. 340 (pg. 1081 - 1091 ) Google Scholar Crossref Search ADS PubMed WorldCat [10] Fuchimukai T. , Fujiwara T. , Takahashi A. , Enhorning G. . Artificial pulmonary surfactant inhibited by proteins , Appl J Physiol , 1987 , vol. 62 (pg. 429 - 437 ) Google Scholar Crossref Search ADS WorldCat [11] Novick R.J. , MacDonald J. , Veldhuizen R.A. , Wan F. , Duplan J. , Denning L. , Posmayer F. , Gilpin A.A. , Yao L.J. , Bjarneson D. , Lewis J.F. . Evaluation of surfactant replacement treatment strategies after prolonged graft storage in lung transplantation , Am J Respir Crit Care Med , 1996 , vol. 154 (pg. 98 - 104 ) Google Scholar Crossref Search ADS PubMed WorldCat [12] Hohlfeld J.M. , Tiryaki E. , Hamm H. , Hoymann H.G. , Krug N. , Haverich A. , Fabel H. . Pulmonary surfactant activity is impaired in lung transplant recipients , Am J Respir Crit Care Med , 1998 , vol. 158 3 (pg. 706 - 712 ) Google Scholar Crossref Search ADS PubMed WorldCat [13] Strüber M. , Brandt M. , Cremer J. , Harringer W. , Hirt S.W. , Haverich A. . Therapy for lung failure using nitric oxide and surfactant replacement , Ann Thorac Surg , 1996 , vol. 61 (pg. 1543 - 1545 ) Google Scholar Crossref Search ADS PubMed WorldCat [14] Müller C. , Fürst H. , Reichenspurner H. , Briegel J. , Groh J. , Reichart B. . Lung procurement by low-potassium dextran and the effect on preservation injury , Transplantation , 1999 , vol. 68 (pg. 1139 - 1143 ) Google Scholar Crossref Search ADS PubMed WorldCat © 2001 Elsevier Science B.V. All rights reserved. Elsevier Science B.V.

Journal

European Journal of Cardio-Thoracic SurgeryOxford University Press

Published: Feb 1, 2001

Keywords: Lung transplantation Surfactant Reperfusion injury Preservation solution Low potassium dextran solution

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