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Low-potassium dextran preservation solution improves lung function after human lung transplantation
Abstract
J Thorac Cardiovasc Surg 2001;120:594-6
... Our research group introduced the first preservation solution specifically tailored for clinical lung SCS, low potassium dextran solution, in 1989 [4]. Since its clinical adoption as Perfadex ® solution, several studies have shown that its overall efficacy can be improved with the inclusion of additional buffering components and cytoprotective agents [5][6][7]. ...
Background
Cellular stress associated with static-cold storage (SCS) and warm reperfusion of donor lungs can contribute to ischemia–reperfusion (IR) injury during transplantation. Adding cytoprotective agents to the preservation solution may be conducive to reducing graft deterioration and improving post-transplant outcomes.
Methods
SCS and warm reperfusion were simulated in human lung epithelial cells (BEAS-2B) by exposing cells to low potassium dextran glucose solution at 4 °C for different periods and then switching back to serum-containing culture medium at 37 °C. Transcriptomic analysis was used to explore potential cytoprotective agents. Based on its results, cell viability, caspase activity, cell morphology, mitochondrial function, and inflammatory gene expression were examined under simulated IR conditions with or without thyroid hormones (THs).
Results
After 18 h SCS followed by 2 h warm reperfusion, genes related to inflammation and cell death were upregulated, and genes related to protein synthesis and metabolism were downregulated in BEAS-2B cells, which closely mirrored gene profiles found in thyroid glands of mice with congenital hypothyroidism. The addition of THs (T3 or T4) to the preservation solution increases cell viability, inhibits activation of caspase 3, 8 and 9, preserves cell morphology, enhances mitochondrial membrane potential, reduces mitochondrial superoxide production, and suppresses inflammatory gene expression.
Conclusion
Adding THs to lung preservation solutions may protect lung cells during SCS by promoting mitochondrial function, reducing apoptosis, and inhibiting pro-inflammatory pathways. Further in vivo testing is warranted to determine the potential clinical application of adding THs as therapeutics in lung preservation solutions.
... Low-potassium dextran glucose (LPDG) solution is the lung preservation solution we developed. 12,13 LPDG limits reactive oxygen species by inhibiting voltage-gated potassium channels. 14 The low-potassium context has been shown to preserve the functional and structural integrity of endothelial cells. ...
Formalin, a common laboratory fixative, is a type 1 carcinogen, a biohazard with risks, environmental, disposal and legal costs, and a chemical modifier of protein epitopes in tissue. A less toxic tissue preservation method is therefore badly needed. We have developed a novel tissue preservation media, Amber, composed of Low Potassium Dextran Glucose (LPDG), 10% honey and 1% coconut oil. This work investigates Amber as compared to formalin with respect to: (1) histological preservation, (2) epitope integrity with immunohistochemistry (IHC) and immunofluorescence (IF), and (3) integrity of tissue RNA. Rat and human lung, liver, kidney and heart tissues were collected and stored for 24 h at 4 °C in Amber or formalin. Tissues were evaluated with: Hematoxylin and Eosin (H&E); IHC: Thyroid Transcription Factor (TTF-1), Muscle Specific Actin (MSA), Hepatocyte Specific Antigen (HepPar1) and Common Acute Lymphoblastic Leukemia Antigen (CD10); and IF: VE-cadherin, vimentin (VIM) and muscle specific actin (MSA). RNA quality upon extraction was also assessed. Amber demonstrated superior and/or non-inferior performance in rat and human tissue evaluation with respect to standard techniques of histology, immunohistochemistry, immunofluorescence, and extracted RNA quality. Amber maintains high quality morphology without compromising the ability to perform IHC and nucleic acid extraction. As such, Amber could be a safer and superior substitute to formalin for clinical tissue preservation for contemporary pathological examination.
... The current clinical practice for donor lung preservation is cold static preservation (17,18). The induced hypothermia protects lung grafts by reducing cell metabolism, oxygen requirement and nutrient consumption. ...
Lung transplantation is a life-saving treatment for patients with end stage lung disease. The imbalance between lung graft supply and recipients has been a serious issue and barrier to successful lung transplantation. Ex vivo lung perfusion is a strategy wherein lungs are perfused and ventilated outside of the body. This technology has emerged as a safe preservation method that also enables the reassessment and reconditioning of marginal lung grafts. Ex vivo lung perfusion has successfully expanded the donor pool and led to greater lung transplant activity worldwide. Furthermore, ex vivo lung perfusion can be used as a platform for advanced diagnostics that enable specific targeted or personalized treatments that can be developed along a bench to bedside pathway leading to safe ex vivo intervention. Recent findings have shown that ex vivo lung perfusion could significantly and safely extend the preservation period, which enables transplant programs further optimization of the logistics around transplantation surgeries, and create a new paradigm whereby donor lungs are assessed at a centralized ex vivo lung perfusion center prior to delivery to a transplant clinic in need. The introduction of ex vivo lung perfusion to clinical lung transplantation has been a major step in the evolution and practice of lung transplantation.
... Low-potassium dextran has consistently been associated with less PGD. [58][59][60] Celsior is a more recent solution to be studied. A singlecohort, retrospective study of 417 patients evaluated the difference in PGD between grafts preserved with Celsior versus low-potassium dextran. ...
Primary graft dysfunction (PGD) is a form of acute lung injury that develops within the first 72 hours after lung transplantation. The overall incidence of PGD is estimated to be around 30%, and the 30-day mortality for grade 3 PGD around 36%. PGD is also associated with the development of bronchiolitis obliterans syndrome, a specific form of chronic lung allograft dysfunction. In this article, we will discuss perioperative strategies for PGD prevention as well as possible future avenues for prevention and treatment.
... Increased formation of ROS is involved in the development of lung injury through the activation of nuclear factor-kappa B (NF-κB) which precedes the release of proinflammatory cytokines [35]. Accordingly, lung preservation solutions that reduce ROS production (i.e., low-potassium dextran) are of choice because they have shown to decrease the incidence of PGD [36,37]. In this study, we demonstrated that the administration of HUCPVCs during the warm ischemia period prevents the development of oxidative stress and, hence, better preserves donor lung function. ...
Lung transplantation is a lifesaving therapy for people living with severe, life-threatening lung disease. The high mortality rate among patients awaiting transplantation is mainly due to the low percentage of lungs that are deemed acceptable for implantation. Thus, the current shortage of lung donors may be significantly reduced by implementing different therapeutic strategies which facilitate both organ preservation and recovery. Here, we studied whether the anti-inflammatory effect of human umbilical cord-derived mesenchymal stem cells (HUCPVCs) increases lung availability by improving organ preservation. We developed a lung preservation rat model that mimics the different stages by which donor organs must undergo before implantation. The therapeutic schema was as follows: cardiac arrest, warm ischemia (2 h at room temperature), cold ischemia (1.5 h at 4°C, with Perfadex), and normothermic lung perfusion with ventilation (Steen solution, 1 h). After 1 h of warm ischemia, HUCPVCs ( 1×106 cells) or vehicle was infused via the pulmonary artery. Physiologic data (pressure-volume curves) were acquired right after the cardiac arrest and at the end of the perfusion. Interestingly, although lung edema did not change among groups, lung compliance dropped to 34% in the HUCPVC-treated group, while the vehicle group showed a stronger reduction (69%, p<0.0001 ). Histologic assessment demonstrated less overall inflammation in the HUCPVC-treated lungs. In addition, MPO activity, a neutrophil marker, was reduced by 41% compared with vehicle ( p<0.01 ). MSC therapy significantly decreased tissue oxidative damage by controlling reactive oxygen species production. Accordingly, catalase and superoxide dismutase enzyme activities remained at baseline levels. In conclusion, these results demonstrate that the anti-inflammatory effect of MSCs protects donor lungs against ischemic injury and postulates MSC therapy as a novel tool for organ preservation.
... There is some evidence to suggest that the type of preservation solution used might play a role. [21][22][23] Others contend that non-COPD recipient diagnoses are a risk factor for the development of PGD. 24 The most commonly supported argument is that the progressive shift toward marginal donors results in a higher incidence of PGD. ...
Objective
Over the past 30 years, lung transplantation has emerged as the definitive treatment for end stage lung disease. In 2005, the lung allocation score (LAS) was introduced as a way by which organs would be allocated based on disease severity. The number of transplants performed annually in the United States continues to increase as centers have become more comfortable expanding donor and recipient criteria and have become more facile with the perioperative and long –term management of these patients. We report a single-center experience with lung transplants, looking at patients before and after the introduction of LAS.
Methods
We retrospectively reviewed 1500 adult lung transplants at a single center performed between 1988 and 2016. Patients were separated into two groups, before and after the introduction of LAS – Group 1 (April 1988 – April 2005; 792 patients) and Group 2 (May 2005 – September 2016; 708 patients).
Results
Differences in demographic data were noted over these periods reflecting changes in allocation of organs. Group 1 patient average age was 48 +/- 13 years and 404 (51%) were men. Disease processes included emphysema (52%; 412), cystic fibrosis (18.2%; 144), pulmonary fibrosis (16.1%; 128) and pulmonary vascular disease (7.2%; 57). Double lung transplant (77.7%; 615) was performed more frequently than single lung transplant (22.3%; 177). Group 2 average age was 50 +/- 14 years and 430 (59%) were men. Disease processes included pulmonary fibrosis (46%; 335), emphysema (25.8%; 188), cystic fibrosis (17.7%; 127) and pulmonary vascular disease (1.6%; 11). Double lung transplant (96.2%; 681) was performed more frequently than single lung transplant (3.8%; 27). Overall incidence of grade 3 primary graft dysfunction (PGD) in Group 1 was significantly lower at 22.1% (175) than in Group 2 at 31.6% (230) (p<.001). Nonetheless, overall hospital mortality was not statistically different between the two groups (4.4% v 3.5%, p<0.4). Most notably, survival at 1 year was statistically different at 646 (81.6%) for Group 1 and 665 (91.4%) for Groups 2 (p<.02).
Conclusions
Patient demographics over the study period have changed with an increased number of fibrotics transplanted. Additionally, more aggressive strategies with donor/recipient selection appear to have resulted in a higher incidence of primary graft dysfunction. This does not, however, appear to impact patient survival on index hospitalization or at 1 year. In fact, we have observed a significant improvement in survival at 1 year in the more recent era. This suggests that continued expansion of possible donors and recipients, coupled with a more sophisticated understanding of primary graft dysfunction and long-term chronic rejection, can lead to increased transplant volume and prolonged survival.
... The current standard clinical practice of organ preservation is cold static preservation (CSP). During donor lung retrieval, a cold pulmonary flush using low-potassium dextran preservation solution is performed with topical cooling and lung ventilation [6,7]. Lungs are then stored and transported at 4°C in a static inflated state. ...
Purpose of the Review
Lung transplantation is a lifesaving therapy for patients suffering from end-stage lung diseases. The number of patients waiting for lung transplantation greatly exceeds the number of donors available. Currently, only 20% of lungs donors are used for transplantation. Ex vivo lung perfusion (EVLP) has been developed as a tool to assess and also potentially repair lungs before transplantation. This article will review the rationale for EVLP and the different EVLP methods including the Toronto EVLP method, describe technical details of EVLP, report on the clinical results of EVLP, and describe the use of EVLP as a platform to deliver different therapies.
Recent Findings
EVLP has been demonstrated to be a safe method of assessing high-risk donor lungs. The long-term survival and graft function of patients that received high-risk donor lungs assessed and treated with EVLP have been shown to be comparable to those receiving conventional donor lungs. Preclinical studies demonstrate that EVLP can serve as a platform for the delivery of specifically targeted therapies to repair injured lungs.
Summary
EVLP has demonstrated to be a promising tool for the assessment and recovery of injured donor lungs using pharmacologic agents as well as gene and cellular therapies.
... preservation solution. Although it is reported to diminish primary graft dysfunction after lung transplantation [6], IR injury still remains a major problem. To reduce IR injury-induced complications, many researchers have taken different approaches, including adding drugs (e.g. ...
... These days, Papworth and Euro-Collins are mostly replaced by Perfadex, a low-potassium-dextran-glucose preservation solution. Although it is reported to diminish primary graft dysfunction after lung transplantation [6], IR injury still remains a major problem. ...
Objectives:
Lung ischaemia-reperfusion (IR) injury is one of the major complications following lung transplantation. The novel peptide GV1001, which is derived from human telomerase reverse transcriptase, has been reported to possess both antitumour and anti-inflammatory effects. In this study, we focused on the anti-inflammatory effects of GV1001 to investigate the IR injury prevention effect of GV1001 in a rat lung transplantation model.
Methods:
An orthotopic left lung transplantation rat model was established using the modified cuff technique. We applied 50 ml of normal saline (control), Perfadex (low-potassium standard dextran containing perfusion solution), Perfadex with 5 mg GV1001 (5-mg GV, low concentration) and Perfadex with 50 mg GV1001 (50-mg GV, high concentration) as both flushing and preservation solutions. The left lung was stored in the same solution as the flushing solution at 4°C for 3 h. After transplantation, the recipient rats were monitored for 3 h. Arterial blood gas analysis (ABGA), bronchoalveolar lavage (BAL) analysis, wet/dry ratio, histological analysis, apoptotic cell analysis and cytokine [tumour necrosis factor alpha (TNF-α) and interleukin 6 (IL-6)] analysis were performed to determine the reduction or prevention effect of GV1001 regarding lung IR injury.
Results:
Compared with the control group, the neutrophil count in BAL, reperfusion oedema and cytokine (TNF-α, IL-6) levels of the transplanted lung were significantly decreased in the 5-mg GV group. Compared with the Perfadex group (16.85 ± 2.43), the neutrophil count in BAL was also significantly decreased in the 5-mg GV group (5.39 ± 0.81) (P< 0.001). In addition, the cytokine (TNF-α, IL-6) levels of the transplanted lung were also significantly decreased in the 5-mg GV group (41.99 ± 12.79, 1069.74 ± 98.48 pg/ml) compared with the Perfadex group (90.73 ± 23.87, 2051.92 ± 243.57 pg/ml) (P < 0.05 and P < 0.001, respectively). However, the 50-mg GV group showed less effect than the 5-mg GV group.
Conclusions:
Adding a low concentration of GV1001 to the lung preservation solution (Perfadex) provided potential protective effects against IR injury after lung transplantation in rats. Therefore, GV1001 should be considered as a promising anti-inflammatory agent for IR injury.
... Since the early years of lung preservation strategies, some advances have emerged in transplant teams, such as adding prostaglandin E2 to prevent counteract temperature and potassium-induced vasoconstriction. The use of low potassium dextran glucose solutions shows better overall lung function, superior early oxygenation, higher lung compliance, lower incidence of severe primary graft dysfunction and 30-day mortality [2]. ...
... The former type solutions are historically used for preservation of solid organs like kidney and liver. On the other hand, based on considerable evidence from laboratory and clinical studies, extracellular-type solutions have been specifically selected in many cases for lung preservation [5][6][7][8][9][10] . However, in some groups, no marked impact on posttransplantation outcomes was reported [11][12][13] . ...
... The former type solutions are historically used for preservation of solid organs like kidney and liver. On the other hand, based on considerable evidence from laboratory and clinical studies, extracellular-type solutions have been specifically selected in many cases for lung preservation [5][6][7][8][9][10] . However, in some groups, no marked impact on posttransplantation outcomes was reported [11][12][13] . ...
BACKGROUND/AIMS:
For lung preservation, one of two types of solutions is commonly employed: Euro-Collins (EC) or low potassium dextran glucose (LPDG). These two solutions have been compared regarding biological, morphometrical and physiological outcomes in many experiments. However, the dynamic mechanics of perfused lung are not well understood because the dynamic characteristics cannot be assessed under static conditions; hence, the primary goal of the present study was to assess this in perfused rat lungs during the preservation period, comparing EC with LPDG at 0 or 9 h at 4°C.
METHODS:
Lung impedance was measured using a forced oscillation technique. Lung resistance and elastance values were obtained by the fast Fourier transform algorithm. The instability of central airways and heterogeneity of ventilation were estimated.
RESULTS:
In the EC group, airway resistance and instability were high after perfusion, and the lung elastance was high and more heterogeneous after cold storage. In contrast, those parameters were stable in the LPDG group during cold storage.
CONCLUSION:
Such dynamic stability might facilitate the handling of lung grafts and eliminate injurious cyclic ventilation stress after reperfusion. Thus, we conclude that the impedance frequency characteristic represents a novel informative parameter for investigating lung preservation techniques.
... [3][4][5] Although diverse animal models of lung preservation were used in these experimental works, since their publication, lowpotassium dextran (Perfadex, Vitrolife, Göteborg, Sweden) has become the standard preservation solution for lung transplantation. 6 Optimal lung inflation techniques before preservation in low-potassium dextran remain undefined, and have not been methodically examined in a rat orthotopic lung transplant model, the most reliable and reproducible model for clinical lung transplantation 3,5,7 (►Table 1). ...
Background:
Most of the experimental work assessing optimal lung inflation during lung graft preservation was performed in the late 1990s. Since that time, lung preservation before transplantation has been more standardized, and the optimal lung inflation techniques used during lung preservation in the current clinical setting remain undefined. Nonetheless, lung inflation during storage may play a pivotal role in optimal lung preservation.
Materials and methods:
Lewis rat lungs were perfused with and stored in cold, low-potassium dextran solution (Perfadex, Vitrolife, Göteborg, Sweden) for 6 hours at different levels of lung inflation (25, 50, 75, or 100% of vital capacity [VC]). Orthotopic left lung transplantation using cuff techniques was performed in syngeneic Lewis rats. Posttransplant allograft function, expression of proinflammatory mediators, and expression of lung surfactants were evaluated.
Results:
Lungs inflated to 75 or 100% VC showed a significantly better oxygenation in blood gas analysis than lungs inflated to 25 or 50% VC. The levels of mRNAs for tumor necrosis factor-α, pro-interleukin-1β, intracellular adhesion molecule 1 were attenuated in lungs inflated to 75 or 100% VC as compared with deflated lungs, suggesting reduced ischemia/reperfusion injury. In addition, transmission electron microscopy demonstrated better preserved lung surfactants in the alveolar space in the lungs inflated to 75 or 100% VC.
Conclusions:
Inflating lungs to 75 or 100% VC during preservation may be beneficial and result in better posttransplant allograft function through attenuated reperfusion injury and better preserved lung surfactants.
... The current clinical practice of organ preservation is cold static preservation (CSP). During retrieval, a cold pulmonary flush using low potassium dextran preservation solution is coupled with topical cooling and lung ventilation [4,5]. Lungs are then transported at 4°C in a static inflated state. ...
The number of patients listed for lung transplantation largely exceeds the number of available transplantable organs because of both a shortage of organ donors and a low utilization rate of lungs from those donors. A novel strategy of donor lung management—ex vivo lung perfusion (EVLP)—that keeps the organ at physiological protective conditions has shown a great promise to increase lung utilization by re-evaluating, treating, and repairing donor lungs prior to transplantation. A clinical trial using EVLP has shown the method to be safe and to allow for reassessment and improvement in function from high-risk donor lungs from both brain death and cardiac death donors prior transplantation. When these lungs were transplanted, low rates of primary graft dysfunction were achieved, and the early outcomes were similar to those with conventionally selected and transplanted lungs. Pre-clinical studies have also shown a great potential of EVLP as a platform for the delivery of novel therapies to repair injured organs ex vivo, and thus further increase the donor lung utilization rate.
... Besides the extracellular potassium concentration, dextran is considered to be the major active component in prevention of cell swelling. 22,23 More recently, Celsior solution has revealed protective effects in pulmonary preservation, although it was originally considered a cardiac preservation solution. Because damage to the alveolocapillary membrane after lung transplantation is believed to be largely attributed to oxygen-derived free radicals, the glutathione contained in Celsior solution could act as a radical scavenger, providing a potential mechanism of improved preservation. ...
Topical in situ cooling of the donor lungs is a prerequisite for procurement of non-heart-beating donor lungs and may be of interest for living related lung donation.
Twenty-four single lung transplants were performed in 4 groups of Landrace pigs (6 per group). Control LPD, control Celsior and topical cooling in situ, followed by LPD (exLPD) or Celsior (exCel) ex situ flush, were employed. All lungs were perfused antegrade with 1 liter of solution at 4°C. Lungs were stored immersed in preservation solution for 24 hours at 4°C. After transplantation of the left lung, the right recipient bronchus and pulmonary artery were clamped.
Four of 6 animals each in the LPD and Celsior groups and all 6 animals in both the exLPD and the exCel groups survived the 7-hour reperfusion. The mean oxygenation index was favorably preserved in the exCel group at 7 hours after reperfusion (417 ± 81) over all other groups (LPD 341 ± 133, Celsior 387 ± 86, exLPD 327 ± 76; p < 0.0001). Pulmonary vascular resistance showed significantly lower values in the Celsior and exCel groups (LPD 1,310 ± 620, Celsior 584 ± 194, exLPD 1,035 ± 361, exCel 650 ± 116 dyn/s/cm(5) at 7 hours after reperfusion; p < 0.0001). Consistently, the wet-to-dry lung weight ratio also indicated beneficial graft protection in the exCel group (LPD 8.1 ± 0.8, Celsior 8.4 ± 0.8, exLPD 7.5 ± 1.0, exCel 3.1 ± 0.9; p < 0.0001).
Initial topical cooling followed by backtable perfusion is a sufficient technique for pulmonary graft preservation providing excellent post-transplant function. Celsior subsequent to in-situ topical cooling revealed the most beneficial results in this setting. This combined technique could advance non-heart-beating, living related lung lobe donation and, potentially, regular heart-beating lung donation.
... 由于供体短缺，相对于其他实体器官移植，心 肺联合移植数量较少，国内既往报道最长生存时间 为 5 年 6 个月 [1] 。中南大学湘雅二医院于 2003 年 9 月 20 日为 1 例艾森曼格综合征患者施行了心肺联合 移植手术 [2] ，现存活超过 8.5 年，是目前国内乃至亚 洲存活时间最长、生活质量最好的患者，现报道如下。 1 临床资料 EC 液、LPD 液、Celsior 液等。Fischer 等 [6] 认为： ...
To summarize the case of combined heart-lung transplantation for a patient who survived for 8.5 years. On September 20, 2003, at Second Xiangya Hospital of Central South University, homologous heartlung transplantation was performed on a male patient who was diagnosed with cardiopulmonary failure secondary to congenital ventricular septal defect with severe pulmonary hypertension. Heart-lung allograft was preserved with 1500 mL modified St.Thomas solution and 3000 mL modified LPD solution. Postoperative immunosuppressive therapies included: methylprednisolone and human anti-lymphocyte globulin protein in the induction period; and combination of ciclosporin A, CellCept and prednisolone in the stable period. In 2007, the treatment was changed to CellCept mg, twice a day+FK506 4 mg, twice a day. The patient lived 8.5 years of normal life with cardiac function of NYHA I-II. Echocardiogram showed left ventricular ejection fraction of 61% to 74%. Heart-lung transplantation proved reliable therapy modality for terminal cardiopulmonary failure. Excellent donor organ preservation and proper perioperative treatment are key factors for long-term survival after heart-lung transplantation.
... [3][4][5] Although static hypothermia is a common and effective means of preserving lung allografts, hypothermia slows metabolism, preventing cellular repair and functional evaluation during allograft storage. [3,6,7] Therefore, an alternative strategy that allows for assessment and potentially repair of injured lungs prior to transplantation could increase the number of transplantable lungs. [2] Normothermic ex vivo lung perfusion (EVLP) is a novel platform for the evaluation and manipulation of potential donor lungs prior to transplantation. ...
Background:
Although ex vivo lung perfusion (EVLP) is increasingly being used to evaluate and manipulate potential donor lungs before lung transplantation (LTx), data on the biochemistry of lungs during EVLP are limited. In this study, we examined the physiology and biochemistry of human lungs on an EVLP circuit.
Methods:
We recovered unallocated double lungs in standard fashion and split them into single lungs. All lungs received a nebulized arginase inhibitor, 2-S-amino-6-boronohexanoic acid (ABH), at either the onset (n = 6) or after 3 h (n = 8) of EVLP. Serial biochemical analysis included levels of arginase, endogenous nitric oxide synthase (eNOS), cyclic guanosine monophosphate, and reactive oxygen species. We considered lungs transplantable if they sustained a PaO2:FiO2 ≥ 350 in addition to stable pulmonary function during EVLP.
Results:
We recovered a total of 14 single lungs. We deemed three single lungs from different donors to be transplantable after EVLP. These lungs had superior oxygenation, lower carbon dioxide, and more stable pulmonary artery pressures. Transplantable lungs had higher baseline levels of eNOS and higher final levels of cyclic guanosine monophosphate than non-transplantable lungs. Early ABH administration was associated with a transient increase in dynamic compliance.
Conclusions:
In this biochemical characterization of lungs deemed unsuitable for LTx, early levels of eNOS and late levels of cyclic guanosine monophosphate appear to be associated with improved allograft function during EVLP. In addition, nebulized ABH is associated with a significant increase in dynamic compliance. These data suggest that biochemical markers during EVLP may predict acceptable allograft function, and that this platform can be used to biochemically manipulate donor lungs before LTx.
Introduction
Some studies have shown increased incidence of Primary Graft Dysfunction (PGD) after heart and lung procurement for heart transplant recipients. There have been limited investigations of the impact of lung procurement on heart procurement and the potential effects of the exposure to the type of lung preservation solution, the volume of the lung preservation solution and adequacy of decompression of the heart during heart and lung procurement and the impact on heart transplant outcomes.
Methods
Adult heart transplant recipients in the UNOS database recorded from January 1, 2000 to June 30, 2022 formed the study cohort. Any heart that was procured with a lung team that utilized Perfadex preservation solution (XVIVO, Gothenburg, Sweden) was classified as exposed to Perfadex and otherwise classified as not exposed to Perfadex. Lung procurements performed with a preservation solution other than Perfadex or unknown were excluded ( n = 2486). Simple comparisons were made with t ‐tests or chi‐squared tests. Logistic regression models were used to predict 30 day and 1 year survival. Accelerated failure time models were employed to analyze time to death and time to rejection.
Results
The cohort consisted of 34 192 heart transplants, of which 21 928 donors were not exposed to Perfadex (64.1%). There were statistically, but not clinically, significant differences in donor characteristics for these groups including in donor age (33.34 ± 11.01 not exposed vs. 30.70 ± 10.69 exposed; p < .001), diabetic donor (4% not exposed vs. 3% exposed; p = .004), and ischemic time (3.28 ± 1.09 h not exposed vs. 3.24 ± 1.05 h exposed; p = .002). In adjusted models, for all included donors, Perfadex exposure was associated with increased short term mortality, but no long term difference (1 year mortality OR 1.10, p = .014).
Conclusion
Perfadex exposure was associated with increased short‐term mortality for heart transplant recipients. Mechanistic investigation is warranted.
Dextran is a biodegradable, nontoxic biological material commonly utilized in drug delivery systems. In this chapter, we brief the effect of dextran on lung diseases, different drug delivery systems with dextran, and their studies on affected lung. With more research and understanding of dextran and its derivatives, people will be able to more precisely control the sequence of dextran using chemical and biosynthetic methods as needed, as well as modify various structures to improve dextran properties such as hydrophilicity, hydrophobicity, temperature sensitivity, pH sensitivity, and ionic strength sensitivity, allowing dextran and its derivatives to be used in more drug delivery systems. Several polymers have been explored to formulate nano and micro-carriers in recent years. Dextran, a polysaccharide produced by bacterial fermentation, and its derivatives have attracted attention of researchers as an advantageous polymer for developing various particulate and other novel drug delivery systems. Critical attributes of dextran include its natural origin, biocompatibility, biodegradability, muco-adhesiveness, non-immunogenicity, safety, and ability to derivatize to a wide range of chemically modified derivatives with thermo- and pH-responsive behaviors to make it a suitable candidate for developing a wide range of drug delivery armamentarium. This chapter will provide a comprehensive understanding of various aspects related to development of dextran-based drug delivery systems with special emphasis on lung disorders. This will make scientists understand the potential of dextran with respect to its advantages, chemical nature, derivatization for specific properties, prior art related to its application in drug delivery systems, deeper understanding of formulation designing, and future prospects to find therapeutically beneficial approaches in treatment of lung diseases.
Die Organisation der Organentnahme obliegt in Deutschland der Deutschen Stiftung Organtransplantation (DSO). Voraussetzung für die Einleitung des postmortale Organspendeprozesses und konsekutiv der Organentnahme ist die zweifelsfreie Feststellung des irreversiblen Hirnfunktionsausfalls (IHA, „Hirntod“) sowie die Einwilligung der Spenderin bzw. des Spenders oder der Angehörigen in den Eingriff. Ziel ist es, Organe schnell, sicher und unversehrt so zu entnehmen, so dass bestmögliche Voraussetzungen für eine technisch einwandfreie Transplantation gegeben sind. Die Entnahme einzelner Organe erfolgt nach einer vorgegebenen Reihenfolge durch speziell geschulte Entnahmechirurginnen und -chirurgen. Die DSO unterstützt diese mit ihren Koordinatorinnen und Koordinatoren sowie – in der Regel – Mitgliedern des Perfusionsdienstes. Für den Transport der Organe in die jeweiligen Empfängerzentren werden die entnommenen Organe gemäß internationalem Standard verpackt.
Vascularized composite allotransplantation represents the final level of the reconstructive ladder, offering treatment options for severe tissue loss and functional deficiencies. Vascularized composite allotransplantation is particularly susceptible to ischemia–reperfusion injury and requires preservation techniques when subjected to extended storage times prior to transplantation. While static cold storage functions to reduce ischemic damage and is widely employed in clinical settings, there exists no consensus on the ideal preservation solution for vascularized composite allotransplantation. This review aims to highlight current clinical and experimental advances in preservation solution development and their critical role in attenuating ischemia–reperfusion injury in the context of vascularized composite allotransplantation.
The shortage of organ donors remains the major limiting factor in lung transplant, with the number of patients on the waiting list largely exceeding the number of available organ donors. Another issue is the low utilization rate seen in some types of donors. Therefore, novel strategies are continuously being explored to increase the donor pool. Advanced age, smoking history, positive serologies, and size mismatch are common criteria that decrease the rate of use when it comes to organ utilization. Questioning these limitations is one of the purposes of this review. Challenging these limitations by adapting novel donor management strategies could help to increase the rate of suitable lungs for transplantation while still maintaining good outcomes. A second goal is to present the latest advances in organ donation after controlled and uncontrolled cardiac death, and also on how to improve these lungs on ex vivo platforms for assessment and future specific therapies. Finally, pushing the limit of the donor envelope also means reviewing some of the recent improvements made in lung preservation itself, as well as upcoming experimental research fields. In summary, donor lung optimization refers to a global care strategy to increase the total numbers of available allografts, and preserve or improve organ quality without paying the price of early-, mid-, or long-term negative outcomes after transplantation.
Lung transplantation is the procedure of choice in many patients with end-stage lung disease and is being performed more frequently around the world. However, there continues to be shortage of donor organs with the ever-expanding number of recipients on the waiting list, leading to liberalization of the lung donor selection criteria with increasing acceptance of marginal donors while striving for excellent results. This has placed an increasing emphasis on the technique of donor lung procurement and preservation from marginal donors. Good judgment and procurement techniques are necessary to obtain high-quality donor lungs for transplantation and optimize long-term results. This is a review of our current technique used for the procurement of the lungs from brain-dead donors.
In recent years, medical advances make lung transplantation become a standard treatment for terminal lung diseases (such as emphysema, pulmonary fibrosis, pulmonary cystic fibrosis, and pulmonary arterial hypertension) that cannot be cured by drugs or surgery (Lund et al., J Heart Lung Transplant 34:1244, 2015). However, the current number of donor lungs that meet the transplant criteria is no longer sufficient for transplanting, causing some patients to die while waiting for a suitable lung. Current methods for improving the situation of shortage of lung transplant donors include the use of donation after cardiac death (DCD) donors, smoker donors, and Ex Vivo Lung Perfusion (EVLP). Among them, EVLP is a technique for extending lung preservation time and repairing lung injury in the field of lung transplantation. By continuously assessing and improving the function of marginal donor lungs, EVLP increases the number of lungs that meet the transplant criteria and, to some extent, alleviates the current situation of shortage of donor lungs. This chapter reviews the clinical application and research progress of EVLP in the field of lung transplantation.
The world’s first successful lung transplant was performed more than 30 years ago; since then there have been significant advancements not only in the donor management and the preservation technique but also related to the surgical procedure itself. The operative mortality and early and late outcomes continue to improve. The objective of this chapter is to describe the donor management, the surgical techniques of bilateral lung transplantation as performed in the Toronto Lung Transplant Program, as well as the most important complications during the donor surgery, recipient surgery, and after the transplant.
Introduction:
Lung transplantation remains the definite treatment for various end-stage lung diseases. Cold flush perfusion, the standard method for organ procurement has severe limitations. Organ Care System (OCS; TransMedics, Inc., Andover, USA) is an approved method to preserve hearts for transplantation that allows for greatly reduced cold ischemic time. Consequently, the use of an adapted OCS lung as a portable full ex-vivo lung perfusion system in lung transplantation is currently under close evaluation.
Areas covered: The aim of this article is to review the advantages and the role of the OCS in the field of lung transplantation by reviewing the latest literature and evaluating this novel procurement technique in the context of conventional methods like cold flush and regular ex-vivo lung perfusion.
Expert Commentary: The use of OCS in the field of lung transplantation has great potential for improved patients outcomes and is justified in cases with (i) marginal donor lungs, (ii) foreseeable long time of transportation (iii) high-risk recipient or donor /recipient profiles, particularly in the setting of an overall increasing need for suitable donor organs. Results from two major multi-centre prospective studies are pending to objectively assess the possible advantages of this portable ex-vivo lung perfusion system.
Purpose of review:
The number of patients listed for lung transplantation largely exceeds the number of available transplantable organs because of both a shortage of organ donors and a low utilization rate of lungs from those donors. A novel strategy of donor lung management, ex-vivo lung perfusion (EVLP), that keeps the organ at physiological protective conditions has shown great promise to increase lung utilization by re-evaluating, treating, and repairing donor lungs prior to transplantation.
Recent findings:
Clinical trials using EVLP have shown the method to be well tolerated and it allows for reassessment and improvement in function from high-risk donor lungs from both brain death and cardiac death donors prior to transplantation. When these lungs were transplanted, low rates of primary graft dysfunction were achieved, and the early outcomes were similar to those with conventionally selected and transplanted lungs. Preclinical studies have also shown a great potential of EVLP as a platform for the delivery of novel therapies to repair injured organs ex vivo and thus further increase the donor lung utilization rate.
Summary:
Development of an ex-vivo treatment arsenal ranging in complexity from pharmacologic to gene and cellular therapies will soon allow clinicians to utilize the full potential of the donor organ pool improving outcomes of lung transplantation.
Although numerous studies over the past 40 years have addressed this problem, initial graft failure is still a key question in clinical lung transplantation. As a possible tool to avoid and treat initial graft failure after lung transplantation, laboratory evidence and clinical reports currently emphasize the role of substitution therapy of surfactant combined with inhaled nitric oxide.
The blood–gas barrier (BGB) is subjected to a variety of stressors during all the phases of lung transplantation. These result in ischemia-reperfusion (IR) injury and can manifest clinically as primary graft dysfunction (PGD). IR injury affects the epithelium, interstitium, and endothelium of the alveolar septa as well as the pulmonary surfactant system. It leads to functional and morphological damage and death of pulmonary cells, largely due to an inflammatory response by activated resident cells as well as inflammatory cell infiltration, which is governed by a large number of mediators. Since PGD is the major cause of early morbidity and mortality after lung transplantation, much effort is undertaken from organ procurement to preservation and implantation to prevent or ameliorate IR injury, including surgical management procedures and pharmacological additives to perfusion solutions or ventilation gas. In particular, to increase the rate of transplantable donor organs, very promising results are achieved by the new technique of ex vivo lung perfusion (EVLP). Beyond the immediate transplantation period, the BGB is jeopardized in certain forms of acute rejection and chronic lung allograft dysfunction.
Lung transplantation is an established life-saving therapy for patients with end-stage lung disease. Unfortunately, greater success in lung transplantation is hindered by a shortage of lung donors and the relatively poor early-, mid- and long-term outcomes associated with severe primary graft dysfunction. Ex vivo lung perfusion has emerged as a modern preservation technique that allows for a more accurate lung assessment and improvement in lung quality. This review outlines the: (I) rationale behind the method; (II) techniques and protocols; (III) Toronto ex vivo lung perfusion method; (IV) devices available; and (V) clinical experience worldwide. We also highlight the potential of ex vivo lung perfusion in leading a new era of lung preservation. This article is protected by copyright. All rights reserved.
This chapter covers pediatric lung and heart-lung transplantation, with sections on the historical background, indications and contraindications, timing of referral, allocation of organs, donor selection, anesthetic and operative considerations, operative technique, postoperative management, and outcome.
The number of patients listed for lung transplantation largely exceeds the number of available transplantable organs because of a shortage of organ donors and a low utilization rate of lungs from those donors who are available. In recent years, novel strategies have been developed to increase the donor lung pool: improved donor management, the use of lungs from donations after cardiac death (DCD), the use of lobar lung living-donors (LLLD) and the use of ex-vivo lung perfusion (EVLP) to assess and repair injured donor lungs.
An adapted donor management strategy could expand the donor pool up to 20%. DCD lung transplant is an increasing part of the donor pool expansion. Outcomes after controlled DCD seem to be similar to donation after brain death. LLLD transplantation has excellent results for small and critically ill patients. EVLP treatment allows for a significant increase in the rate of suitable lungs and represents an optimal platform for lung reconditioning and specific lung therapies.
A significant increase in the number of available lungs for transplantation is expected in the future because of the wider use of lungs from controlled or uncontrolled DCD and LLLD lungs, and with organ-specific EVLP treatment strategies.
Despite improvement of lung preservation by the introduction of low-potassium dextran (LPD) solution, ischemia-reperfusion injury remains a major contributor to early post-lung transplant graft dysfunction and mortality. After favorable experimental data, Celsior solution was used in our clinical lung transplant program. Data were compared with our historic LPD cohort.
Between January 2002 and January 2005, 209 consecutive lung transplantations were performed with LPD. These were compared to 208 transplants between February 2005 and September 2007 with Celsior. Endpoints included posttransplant PaO2/FiO2 ratio at different timepoints after intensive care unit (ICU) admission, posttransplant ventilation time, ICU stay and 30-day mortality, follow-up survival, and bronchiolitis obliterans syndrome-free survival.
Ratios of sex, urgency status, type of procedure, length of posttransplant ICU stay, and age did not show significant differences between the 2 groups. Mean ischemia times were significantly longer in the Celsior group (LPD, 355 ± 105 minutes vs Celsior, 436 ± 139 minutes, P < 0.001). Overall 3-year-survival (LPD, 66.5% vs Celsior, 72.0%; P = 0.25) was nonsignificantly improved in the Celsior cohort.
A trend toward better survival (P = 0.09) and increased freedom from bronchiolitis obliterans syndrome (P = 0.03) was observed in the Celsior group despite prolonged ischemic times compared with LPD. Lung preservation with Celsior is safe and effective and may carry advantages.
The number of patients listed for lung transplantation exceeds the number of available transplantable organs because of a shortage of organ donors and a low utilization rate of donated lungs. A novel strategy of donor lung management, called ex vivo lung perfusion (EVLP) can keep the organ in a physiologic protective condition, and promises to increase lung utilization by reevaluating, treating, and repairing donor lungs before transplantation. Preclinical studies have shown great potential for EVLP as a platform for the delivery of novel therapies to repair injured organs ex vivo and improve the success of lung transplantation.
Lung transplantation (LTx) is the definitive treatment of patients with end-stage lung disease. Availability of donor lungs remains the primary limitation and leads to substantial wait-list mortality. Efforts to expand the donor pool have included a resurgence of interest in the use of donation after cardiac death (DCD) lungs. Unique in its physiology, lung viability seems more tolerant to the variable durations of ischemia that occur in DCD donors. Initial experience with DCD LTx is promising and, in combination with ex vivo lung perfusion systems, seems a valuable opportunity to expand the lung donor pool.
Thoracic organ transplantation is offered to patients with end stage cardio pulmonary disorders. Distant organ procurement is a reality with the evolution of techniques of preservation and transportation of thoracic organs and we report a case of successful Heart Lung Transplant with technique of preservation of donor lungs.
Hypothermic preservation of donor grafts is imperative to ameliorate ischemia related cellular damage prior to organ transplantation. Numerous solutions are in existence with widespread variability among transplant centers as to a consensus regarding the optimal preservation solution. Here, we present a concise review of pertinent preservation studies involving cardiac and pulmonary allografts in an attempt to minimize the variability among institutions and potentially improve graft and patient survival. A biochemical comparison of common preservation solutions was undertaken with an emphasis on Euro Collins (EC), University of Wisconsin (UW), histidine-tryptophan-ketoglutarate (HTK), Celsior (CEL), Perfadex (PER), Papworth, and Plegisol. An appraisal of the literature ensued containing the aforementioned preservation solutions in the setting of cardiac and pulmonary transplantation. Available evidence supports UW solution as the preservation solution of choice for cardiac transplants with encouraging outcomes relative to notable contenders such as CEL. Despite its success in the setting of cardiac transplantation, its use in pulmonary transplantation remains suboptimal and improved outcomes may be seen with PER. Together, we suggest, based on the literature that the use of UW solution and PER for cardiac and pulmonary transplants, respectively may improve transplant outcomes such as graft and patient survival.
Although lung transplantation has become a life-saving option for patients with end-stage lung disease, this intervention is hampered by a shortage of lungs in view of the growing number of people on the waiting list. Lungs are retrieved from only a small percentage of multiorgan donors, and the transplantation and intensive-care communities have recognised the need to develop innovative methods to expand the donor pool. Advancements in lung-preservation techniques in the preretrieval and postretrieval periods have increased the pool of available donors, and novel research and discoveries in this area have steadily improved post-transplantation adverse events. This Review summarises current best practice and the latest research on intensive-care management of a potential lung donor. We also discuss lung-preservation techniques, including advancements in normothermic ex-vivo lung perfusion, and the potential for a personalised medicine approach to the organ.
After a brief review of conventional lung preservation, this article discusses the rationale behind ex vivo lung perfusion and how it has shifted the paradigm of organ preservation from conventional static cold ischemia to the utilization of functional normothermia, restoring the lung's own metabolism and its reparative processes. Technical aspects and previous clinical experience as well as opportunities to address specific donor organ injuries in a personalized medicine approach are also reviewed.
El daño por isquemia-reperfusión es causa de morbimortalidad en pacientes con trasplante pulmonar. Se desconoce si la solución de preservación habitual del pulmón puede contribuir a la deficiencia de antioxidantes, favoreciendo el estrés oxidativo en el receptor. Objetivo: Evaluar si existe pérdida de glutatión desde pulmones de conejo a la solución de preservación para trasplante. Resultados: Encontramos una disminución en el contenido de glutatión total del pulmón, sin aumento en el contenido de glutatión oxidado. Esto se asoció a la aparición y aumento sostenido de glutatión en la solución de preservación desde los 30 min. Conclusiones: Existe salida de glutatión desde el pulmón no mediada por oxidación de éste y posiblemente favorecida por el gradiente de concentración de glutatión reducido. Esta pérdida deja al tejido vulnerable frente a las condiciones de estrés oxidativo en el receptor.
Lung transplantation has become an effective treatment for patients with end-stage pulmonary disease. Despite several decades of experience, however, lung transplantation continues to be associated with significant morbidity and mortality. Even with the implementation of improved surgical techniques, 5-year survival according to the International Society for Heart and Lung Transplantation remains a somewhat disappointing 45%. Non-cytomegalovirus-associated infections and primary graft failure account for the majority of short-term mortality, whereas bronchiolitis obliterans syndrome continues to be the leading cause of death over longer periods. Concurrently, the mortality rate of potential lung transplant recipients while on the waiting list consistently remains approximately 10% to 15% annually because of the severe shortage of suitable organs. Recent trends suggest that short-term survival rates are improving, perhaps in part because of several strategies that appear to decrease ischemia-reperfusion injury. Furthermore, several promising approaches have been developed or are currently under investigation, which may help to improve long-term survival rates of lung transplant recipients and expand the donor pool.
Objective
Compare the influence of two preservation liquids, Euro-Collins (EC) and Perfadex (P) in the pulmonary graft function in the initial phase of lung transplant in humans.
Design
Retrospective study.
Scope
Lung transplant unit of the ICU of a university hospital.
Patients
A total of 79 patients were subjected to a transplant of both lungs. The pulmonary grafts were preserved with EC in 23 cases and with P in 56 cases.
Variables of interest
Pulmonary function was assessed on admission in the intensive care unit (ICU) with the PaO2/FiO2 ratio. Mortality, graft dysfunction stay in ICU and time of mechanical ventilation were also assessed at 30 days.
Results
The PaO2/FiO2 ratio was significantly greater in the P group than in the EC both on admission (p < 0.006) and at 12 hours (p = 0.032) in the ICU. Graft dysfunction incidence was less in group P than in EC (p < 0.045). There were no differences in regards to mortality at 30 days, stay in ICU and time of mechanical ventilation between both groups.
Conclusion
Preservation of the pulmonary graft with P as preservation liquid compared with EC is associated with better graft function in the initial phases of transplant of both lungs and with a decrease in the incidence of graft dysfunction.
There is a critical mismatch between the number of donor lungs available and the demand for lungs for transplantation. This has created unacceptably high waiting-list mortality for lung transplant recipients. Currently (2012) in the United Kingdom, there are 216 patients on the lung transplant waiting list and 17 on heart and lung transplant list. The waiting times for suitable lungs average 412 days, with an increasing mortality and morbidity among the patients on the lung transplant list. Ex vivo lung perfusion (EVLP) has emerged as a technique for the assessment, resuscitation, and potential repair of suboptimal donor lungs. This is a rapidly developing field with significant clinical implications. In this review article, we critically appraise the background developments that have led to our current clinical practice. In particular, we focus on the human and animal experience, the different perfusion-ventilation strategies, and the impact of different perfusates and leukocyte filters. Finally, we examine EVLP as a potential research tool. This will provide insight into EVLP and its future development in the field of clinical lung transplantation.
The objective of preservation studies is to extend storage times and to minimize ischemic and reperfusion injury in the harvested organ. Clinical studies compare different perfusates and preservation techniques for liver, kidney, pancreas, small bowel, heart, and lung allografts. Although advances in preservation solutions and methods continue to result in outcome improvements for the recipient, the impact of prolonged cold ischemia times and the importance of minimizing its negative effects should not be overlooked.
Limited availability of donor organs is a major factor restricting the clinical application of lung transplantation. Improvements in preservation techniques are essential for prolonging storage time and improving lung function following transplantation. The present investigation used primary cultures of adult rat alveolar type II cells as a model for evaluating lung-preservation solutions. Type II cells were plated onto tissue-culture plastic at a density 5 x 10(5) cells/cm2 and maintained in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum (D10) for 40 hr. Cells were then exposed to Euro-Collins solution or a low-potassium-dextran solution (LPD). At designated time points, measurements of lactate-dehydrogenase (LDH) release, protein content, and incorporation of 3H-thymidine into cellular DNA were made. During 12 hr of "storage" at 37 degrees C, cells maintained in LPD released less LDH (14.3 +/- 1.2% of cellular total, mean +/- SEM, n = 5) than their counterparts stored in EC (20.6 +/- 1.6%, P less than 0.05). During the 36 hr following a 6-hr exposure to preservative solutions, LPD-treated cells incorporated more thymidine per mg of protein (2566 +/- 419.8 cpm/micrograms protein, mean +/- SEM, n = 6) compared with cells maintained continuously in D10 (1431 +/- 351, P less than 0.05). By contrast, cells exposed to EC incorporated less thymidine (82.2 +/- 62.8 cpm/micrograms protein) than either cells maintained in LPD or D10 (P less than 0.01 for each comparison). These results suggest that LPD solution is less cytotoxic than EC and that LPD enables higher levels of metabolic activity in recovering epithelial cells. In vitro cultures of type II epithelial cells are a useful model system for the study of lung preservation and posttransplantation lung injury.
The clinical application of lung transplantation is severely limited by the shortage of suitable donor organs. Current techniques of lung preservation allow a maximum of 4 to 6 hours of safe ischemic time. The function of canine left lung allografts stored for 12 hours after being cooled by pulmonary artery flush was studied. Two types of flush solution were used: group I; Euro-Collins solution; group II, low-potassium-dextran solution. Lung function was studied immediately and 3 days after transplantation. This protocol enables study of acute preservation-related lung injury and the delayed manifestations of ischemic and reperfusion injury after a 3-day period of recovery. Inflatable cuffs were placed around each pulmonary artery at operation and were attached to subcutaneous injection ports. Temporarily occluding either pulmonary artery allowed independent study of the native or transplanted lung. Using this model, we were able to demonstrate reliable and reproducible preservation of lungs for 12 hours. The low-potassium-dextran solution provided significantly better immediate function of the preserved lung than the Euro-Collins solution: arterial oxygen tension 509 +/- 15 mm Hg versus 111 +/- 16 mm Hg (p less than 0.0001). Function on the third day was excellent for both groups. Pulmonary artery pressure, pulmonary vascular resistance, and carbon dioxide tension were not significantly different between the groups immediately or on day 3.
The lung is the only organ to which oxygen may be supplied after its blood supply is stopped. Before this study, we were not certain whether lung cells were able to maintain aerobic metabolism with the oxygen in the alveoli during preservation. Excised rabbit lungs were used to measure changes in the concentration of oxygen and carbon dioxide in the airway and changes in glucose, glucose-6-phosphate, lactate, adenosine triphosphate, and phosphocreatine levels in the lung tissue during preservation under different conditions. Twenty-seven lungs were flushed with low-potassium dextran electrolyte solution, inflated with room air, and preserved at 1 degree C (n = 8), 10 degrees C (n = 8), or 22 degrees (n = 11) for 4, 12, or 24 hours. Eight additional lungs were inflated with 100% nitrogen and preserved at 10 degrees C for 4 (n = 4) or 24 (n = 4) hours. Oxygen levels decreased and carbon dioxide levels increased in the airway of the lungs that were inflated with room air at rates dependent on the preservation temperature. The increase of carbon dioxide in the lungs that were inflated with 100% nitrogen was very small. When the oxygen was not available in the alveoli, lactate accumulated, and adenosine triphosphate and phosphocreatine decreased in the lung tissue. We concluded that lung cells are able to maintain aerobic metabolism with the oxygen in the alveoli during preservation and that the maintenance of aerobic metabolism may be essential to maintain the optimum viability of preserved lung tissue.
Lung transplantation is limited by the effects of ischaemia. Previous clinical studies related graft ischaemia duration to post-operative pulmonary function in the ICU, morbidity, and overall survival. This report describes the intraoperative pulmonary allograft function immediately after reperfusion. 23 lung transplantations (15 bilateral, 8 single) were analysed. Donor selection and organ procurement were identical. After pulmonary vasodilation with prostacyclin, allografts were flush-perfused with cold modified Euro-Collins solution. Mean duration of lung ischaemia was 255.1 +/- 35.1 min (190-314 min). Ischaemia times did not differ with respect to the recipient's disease or the use of extracorporeal circulation. After reperfusion, oxygenation indices deteriorated in 73.9% of patients compared with the native lungs (313.4 +/- 163.5 vs 427.2 +/- 96.1, p = 0.006). Linear regression analysis and subgroup analysis both revealed a significant influence of the duration of allograft ischaemia on early transplant function. Ischaemia of more than 4 hours resulted in an acceptable but significantly lower PaO2 (254.9 +/- 143.3 mmHg vs 463.0 +/- 149.2 mmHg, p = 0.011). However, mean time until extubation and time spent in the ICU were not affected. It is concluded that flush-perfusion of the lung with modified Euro-Collins solution provides reliable preservation of lung function up to four hours. Longer ischaemia, up to six hours, is followed by an acceptable but progressively reduced early transplant function.
Flush perfusion of pulmonary grafts with cold modified EuroCollins solution supplemented by prostaglandin treatment was introduced clinically 10 years ago. Primary graft failure remains a major cause of morbidity and death after lung transplantation. During the last decade, much experimental work has led to reports of alternative storage solutions, differing storage conditions, and pharmacologic interventions that improve pulmonary graft performance. It is unclear how these findings have influenced current clinical practice.
A worldwide survey of the 125 centers performing lung transplantation was conducted by questionnaire.
One hundred twelve replies were received (90%). Most centers (n = 86) continue to use EuroCollins solution (77%), of whom 69% include prostaglandin therapy and 32% donor steroid treatment. University of Wisconsin solution (UW) is used by 15 centers (13.5%), of which 10 (67%) use prostaglandin and seven (47%) use donor steroids. Nine centers use Papworth solution and one uses donor core cooling. The volume of flush used varied widely, from 20 to 120 ml/kg, with median volumes of 60, 60, and 30 ml/kg in centers using EuroCollins, UW, and Papworth solutions, respectively. Two thirds of centers using EuroCollins solution store grafts at 0 degrees to 5 degrees C, and one third at 5 degrees to 10 degrees C. One center that uses EuroCollins solution stores grafts at 10 degrees to 15 degrees C. Centers using UW solution are evenly split at 0 degrees to 5 degrees C and 5 degrees to 10 degrees C. Most centers that use Papworth solution store grafts at 5 degrees to 10 degrees C. Only six centers use superoxide radical scavengers. The maximum ischemic period accepted by centers varies from 4 to 12 hours, with median periods of 8, 7, 6, and 6 hours for the UW, EuroCollins, Papworth, and donor core cooling centers, respectively. All but one of the UW centers (93%) expressed satisfaction with the quality of graft preservation achieved by UW solution. Only 58 of the 86 centers using EuroCollins solution (67%) were satisfied. Six of nine centers using Papworth solution were satisfied.
There has been a trend toward the use of UW solution and a slightly warmer storage temperature. However, for most centers, graft storage techniques have changed little over the last decade.
