Low-potassium Dextran Group Research Articles

A new preservation solution for lung transplantation: Evaluation in a porcine transplantation model

Lung preservation injury is still a major problem in lung transplantation. The aim of the current study was to evaluate the effects of a new preservation solution (Custodiol-N) for lung preservation. Using an in vivo pig model, 7 lungs each were preserved for 24 hours after perfusion with: low-potassium dextran (LPD) solution as control (Group I); base solution of Custodiol-N without iron chelators (Group II); Custodiol-N (Group III); or Custodiol-N supplemented with dextran 40 (Group IV). Four animals received a sham operation. After left lung transplantation and contralateral lung exclusion, hemodynamics and blood gases were monitored for 6 hours; tissue samples were taken at the end of the experiments. All animals survived the transplantation procedure. Base solution- and Custodiol-N-preserved lungs (Groups II and III) showed graft function similar to that of LPD-preserved lungs (Group I), showing a trend toward improved values. Custodiol-N with dextran (Group IV) led to a significant reduction of mean pulmonary arterial pressure (20 ± 2 vs 28 ± 3 mm Hg, p < 0.01) and pulmonary vascular resistance (410 ± 51 vs 588 ± 83 dyne/s/cm(5), p < 0.01), and oxygenation ratio was significantly higher (536 ± 52 vs 313 ± 107 mm Hg at 6 hours, p < 0.01) and PCO(2) values were significantly lower (51 ± 9 vs 77 ± 5 mm Hg at 6 hours, p < 0.01) at 6 hours compared with LPD (Group I). Custodiol-N (Groups II to IV) showed a trend toward a lower wet/dry ratio and reduced oxidative stress; in the presence of dextran (Group IV), the difference was again statistically significant, when compared with LPD (Group I). Custodiol-N solution is a new alternative preservation solution for lung transplantation that offers significantly superior protection compared with LPD when dextran 40 is added.

Comparing the Performance of Rat Lungs Preserved for 6 or 12 Hours After Perfusion With Low-Potassium Dextran or Histidine–Tryptophan–Ketoglutarate

Introduction In lung transplantation, graft dysfunction is a frequent cause of mortality; the etiopathogenesis is related to ischemia–reperfusion injury. We sought to compare the lung performance of rats after reperfusion after presentation with 3 solutions at 2 ischemia times. Methods We randomized 60 male Wistar rats to undergo anterograde perfusion via the pulmonary artery with low-potassium dextran (LPD), histidine–tryptophan ketoglutarate (HTK), or saline. After extraction, the heart–lung blocks were preserved in a solution at hypothermia for 6 or 12 hours before perfusion with homologous blood for 60 minutes using ex vivo system Isolated Perfused Rat or Guinea Pig Lung System (Harvard Apparatus). Respiratory mechanics, pulmonary weight, pulmonary artery pressure (PAP), and relative lung oxygenation capacity (ROC) measurements were obtained every 10 minutes. Results Comparing tidal volume (TV), compliance, resistance, ROC, PAP, and pulmonary weight the LPD, HTK, and saline group did not differ at 6 and 12 hours. The TV was higher in the lungs with 6-hour ischemia in the LPD, HTK, and saline groups. Compliance was higher in the lungs with 6-hour ischemia in the LPD and saline groups. There were no differences in ROC values comparing lungs with 6- versus 12-hour ischemia in the LPD group. A significant difference was observed between lungs in the HTK and saline groups. Resistance was higher in the lungs with 12-hour ischemia among the LPD, HTK, and saline groups. There was a gradual weight increase in the lungs, particularly those undergoing 12-hour ischemia, despite the absence of a significant difference between groups. Conclusion Rat lungs perfused with LPD and HTK preservation solutions showed similar reperfusion performances in this ex-vivo perfusion model.

Effect of systemically administered low potassium dextran solution on oxidative stress in a rat model of lung ischemia

Systemic administration of the low-potassium dextran solution on the peripheral oxidative stress was evaluated in an animal model of lung ischemia-reperfusion in rats. In one experiment, male Wistar rats were divided into two groups (n=5): one received intravenous saline, whereas in the other the animals were given intravenous low potassium dextran solution. In another experiment, male Wistar rats were divided into four groups (n=5): control, ischemia, saline and low potassium dextran. Except for the control animals, all groups were submitted to left hilar clamping for 30 min, followed by reperfusion for 30 min. Saline or low potassium dextran was administered intravenously immediately before clamp removal. In the first experiment there were no significant differences in lipid peroxidation. Total radical trapping potential measurements showed a significant increase in animals receiving low potassium dextran; in the second experiment, there was an increase in lipid peroxidation in both saline and ischemia groups compared to controls, and low potassium dextran. Low potassium dextran group showed an increase in total radical trapping potential measurements compared to all other groups. Ischemia-reperfusion injury mediated by reactive oxygen species was attenuated by the systemic use of low potassium dextran in this animal model of ischemia-reperfusion of the lung.

Does the method of lung preservation influence outcome after transplantation? An analysis of 681 consecutive procedures

Despite 50 years of lung preservation research, the optimal preservation technique is undefined. Using data from a national cohort, we investigated outcomes with different preservation methods after adult lung transplantation. Early (30-day), late (30-day to 3-year), and overall (3-year) mortalities, adjusted for differences in donor and recipient characteristics, were compared by using Cox regression. Intensive care unit length of stay and the number of rejection episodes were secondary outcomes. Six hundred eighty-one eligible lung transplantations between July 1995 and June 2003 were preserved with Euro-Collins solution (n = 284), blood albumin (n = 139), core cooling (n = 107), or low potassium dextran solution (n = 151). There was significantly increased use of low potassium dextran solution over time (P < .001). Unadjusted 3-year survival was similar across the groups (P = .72), with the highest 3-year survival in the low potassium dextran group (62%; 95% confidence interval, 51%-72%) and the lowest in the blood albumin group (49%; 95% confidence interval, 39%-58%). Risk-adjusted early (P = .70), late (P = .27), and overall (P = .72) survival was similar across the groups and was not affected by ischemic time. Freedom from death caused by primary graft dysfunction was again highest in the low potassium dextran group (95%; 95% confidence interval, 90%-98%) and lowest in the blood albumin group (91%; 95% confidence interval, 85%-95%). There was no difference in intensive care unit length of stay. An increased incidence of rejection was apparent with increasing ischemic time (P = .067). The methods of lung preservation in current use do not seem to affect early or midterm survival after transplantation, but increasing ischemic time might predispose to increased rejection.

Does Perfadex Affect Outcomes In Clinical Lung Transplantation?

The use of a low-potassium-based preservation solution improves gas exchange in experimental models of lung transplantation. However, its efficacy in reducing the incidence of primary graft dysfunction (PGD) and improving patient outcomes in the clinical setting is controversial. In this study we measured: oxygenation index (OI); International Society of Heart and Lung Transplantation (ISHLT) PGD grades; extubation times; intensive care unit (ICU) and hospital length of stay; 30-day, 90-day and 1-year survival rates; and bronchiolitis obliterans syndrome (BOS)-free survival. We compared 115 consecutive (2001 to 2004) lung recipients who received allografts preserved with Perfadex, a low-potassium dextran (LPD) solution, and compared the results with the previous 116 consecutive (1999 to 2001) lung recipients who received allografts preserved with modified Euro-Collins (MEC) solution. Recipients were classified as having severe PGD (ISHLT Grade III) if the lowest arterial oxygenation (P) to fraction of inspired oxygen (F) (P/F ratio) within 48 hours post-transplantation was <200. Baseline characteristics of the 2 cohorts were similar except for recipient age (LPD 53.5 vs MEC 49.9 years; p = 0.03). There were no differences in donor age, gender, category of transplant, indication for transplant, use of cardiopulmonary bypass or pre-operative pulmonary artery pressures. When gas-exchange parameters were measured upon arrival to the ICU (T0), at 24 hours post-transplant (T24) and at 48 hours post-transplant (T48), the only significant finding was that the incidence of ISHLT Grade III PGD at T24 was lower in the LPD group compared with the MEC group (8% vs 20%, p = 0.03). The incidence of severe PGD at other timepoints was not statistically different (LPD vs MEC: T0, 17% vs 26%; T0 to T48, 25% vs 31%). Both groups had similar extubation rates at 48 hours post-transplant (LPD 64% vs MEC 67%). The 30-day survival (LPD 93% vs MEC 95%), 90-day survival (LPD 89% vs MEC 89%), 1-year patient survival (LPD 80% vs MEC 77%) and 1-year BOS-free survival (LPD 70% vs MEC 74%) were not statistically different. Lung preservation with LPD as compared with MEC does not improve early gas exchange or impact 90-day and 1-year mortality. Continued investigation into lung preservation solution composition is necessary to reduce the incidence of PGD.

Aprotinin attenuated ischemia–reperfusion injury in an isolated rat lung model after 18-hours preservation

Ischemia-reperfusion injury is a major factor in the early phase of lung transplantation. We hypothesized that aprotinin, a nonspecific serine protease inhibitor, attenuates ischemia-reperfusion lung injury by inhibiting the inflammatory response and suppressing NADPH oxidase. We used an isolated rat lung model to test the above. A Control group was immediately perfused with fresh heparinized allogeneic blood after lung harvest without an ischemic period. Study lungs were flushed with low-potassium dextran (LPD) solution and stored for 18h at 4 degrees C then divided into two groups: the LPD group was flushed with LPD solution only, and the LPD+A group was flushed with LPD solution +200KIU/ml aprotinin. Lungs in all three groups were then reperfused with fresh heparinized allogeneic blood for 120min at 37 degrees C. Throughout reperfusion, PO(2) levels in the LPD+A group were similar to those in the Control group; although in the LPD group, PO(2) levels were significantly lower (P<0.05). Tissue MDA levels were significantly higher in the LPD group than the Control and LPD+A groups (P<0.05). IL-8 levels were significantly higher in the LPD group than the Control group (P<0.05), while in the LPD+A group they were similar to those in the Control group. Histological evaluation showed interstitial edema accompanied by neutrophil extravasation in the LPD group, whereas this effect was modest in the LPD+A group. An additional study of ischemia-reperfusion in an alveolar macrophage culture showed that the activitvation of NADPH oxidase, and translocation of p47(phox) from the cytosol to the membrane were suppressed in aprotinin group. Aprotinin attenuates ischemia-reperfusion lung injury by inhibiting the early inflammatory response, neutrophil extravasation and the production of oxygen free radicals through inhibition of the activation of the NADPH oxidase. The inhibition of p47(phox) translocation in alveolar macrophage seemed involved in this mechanism of aprotinin.

Glutathione improves the function of porcine pulmonary grafts stored for twenty-four hours in low-potassium dextran solution

Flush perfusion with low-potassium dextran is the standard strategy in clinical lung preservation. Despite improved outcome, endothelial cell injury and surfactant dysfunction remain a significant problem after lung transplantation. The radical scavenger glutathione has been shown to be responsible for the efficacy of Celsior solution in lung preservation. We tested the hypothesis that the addition of glutathione to low-potassium dextran might further improve graft function by ameliorating ischemia-reperfusion injury. In 12 domestic pigs, lungs were flush preserved with either low-potassium dextran (n = 6) or low-potassium dextran supplemented by 5 mmol glutathione (n = 6). Left single lung transplantation was performed after 24-hour storage in low-potassium dextran at 8 degrees C. After 15 minutes of reperfusion the right main bronchus and pulmonary artery were crossclamped. Hemodynamic and respiratory measures were recorded in 30-minute intervals for a total observation period of 7 hours. Bronchoalveolar lavage fluid was obtained from the native lung and 2 hours after reperfusion from the graft. Bronchoalveolar lavage fluid and surfactant composition, and surfactant function analyses were performed. Neutrophil sequestration was assessed by myeloperoxidase activity assay. Tissue water content was calculated from wet/dry weight ratios at the end of the experiment. In the low-potassium dextran group, 2 animals died during reperfusion. After reperfusion, pulmonary vascular resistance (P = .01) and pulmonary artery pressure remained lower in the glutathione/low-potassium dextran group, which was associated with a higher cardiac output (P = .05) in this group. Also, the oxygenation index at the end of the observation period was higher in the glutathione/low-potassium dextran group compared with the low-potassium dextran group (430 +/- 130 vs 338 +/- 184, respectively; P < .05). The graft water content representing postreperfusion lung edema was not different between the 2 study groups. Alteration of surfactant was less in the glutathione/low-potassium dextran group with a significantly decreased small to large aggregate ratio (P = .03) versus low-potassium dextran group. Myeloperoxidase activity was twice as high in the low-potassium dextran group when compared with the glutathione/low-potassium dextran group (glutathione/low-potassium dextran: 134 +/- 110 mU/g vs low-potassium dextran: 274 +/- 168 mU/g, P = .07). The addition of glutathione to low-potassium dextran preservation solution reveals beneficial effects on vascular function and surfactant composition in transplanted lungs. Therefore, glutathione ameliorates ischemia-reperfusion injury in a preclinical model of lung transplantation. Future studies are needed to evaluate this promising modification in clinical lung transplantation.

Comparison of University of Wisconsin, Euro-Collins, low-potassium dextran, And Krebs-Henseleit solutions for hypothermic lung preservation

Objective: We sought to test the effectiveness of 4 different solutions for hypothermic rat lung preservation. Methods: One hundred ninety-two rats were used. The rats were divided into 4 groups, and University of Wisconsin, Euro-Collins, low-potassium dextran, or Krebs-Henseleit solution was used in each group. They were further divided into 6 subgroups of 8 rats each. The lungs were preserved at 4°C for 0, 4, 6, 8, 12, or 24 hours, respectively, and lung function was studied by using a living rat perfusion model. Results: Pulmonary arterial flow decreased in each group after 4 to 6 hours of preservation; the low-potassium dextran group decreased the least and the Krebs-Henseleit group decreased the most. Pulmonary vascular resistance increased in each group after 6 hours of preservation; the Krebs-Henseleit group increased the most. Although airway pressure increased, static lung compliance and gas exchange capacity decreased after 8 hours of preservation; the Krebs-Henseleit group exhibited the worst values. Lung tissue wet/dry weight ratio increased gradually during preservation; the University of Wisconsin group exhibited the least increase. An ultrastructural study indicated the least morphologic changes in the low-potassium dextran group at 24 hours. Conclusions: At 4°C, all solutions preserved rat lungs for 4 hours with acceptable function. However, 6 hours of preservation resulted in damaged pulmonary function in some lungs, and this damage increased when preservation time was extended. The lungs preserved in low-potassium dextran solution had the best overall function, but the lungs preserved in University of Wisconsin solution had less edema. (J Thorac Cardiovasc Surg 2000;119:921-30)

Lung procurement by low-potassium dextran and the effect on preservation injury. Munich Lung Transplant Group.

This clinical study was performed to evaluate the effect of low-potassium dextran (LPD) solution on organ function in human lung transplantation. A total of 80 patients were included in this study. Donor lungs were flushed with Euro-Collins (EC) solution in 48 cases or LPD (Perfadex) in 32 cases. Subsequently, single- (EC: n = 31; LPD: n = 15) or double-lung transplantations (EC: n = 17; LPD: n = 17) were performed. The evaluation parameters of transplant function were the reperfusion injury score (grade I to V); the alveolar/arterial oxygen ratio; the duration of respirator therapy; and the length of intensive care treatment and survival. Incidence and severity of reperfusion injury score were more severe in the EC group (31 of 48: grade I: n = 13; II: n = 8; III: n = 5; IV: n = 2; V: n = 3; LPD group: 17 of 32 patients; grade I: n = 12; II: n = 1; III: n = 3; IV: n = 0 grade V: n = 0), leading to death in three patients. In the LPD group, despite of the use of cardiopulmonary bypass, alveolar/arterial oxygen ratio values were significantly (P = 0.009) better during the early postoperative phase. Thirty-day mortality was 12% in the EC group and 6% in the LPD group. The one-year survival rate was 79% after the use of LPD (vs. EC: 62%). Graft preservation using LPD leads to better immediate and intermediate graft function after pulmonary transplantation and also results in better long-term survival.

Acellular Low-Potassium Dextran Preserves Pulmonary Function After 48 Hours of Ischemia

Background. We previously have shown that extracellular preservation solutions provide superior pulmonary protection after 18 hours of cold ischemia at 4°C in an isolated, whole-blood–perfused, rabbit lung model. We also reported that the addition of 20% whole blood to a low-potassium dextran solution (BLPD) conferred no discernible advantage over low-potassium dextran (LPD) alone in this same model. Our current study was aimed at documenting the importance of blood in buffering extracellular preservation solutions during 24 to 48 hours of hypothermic ischemia. Methods. We studied three groups of lungs using an isolated, whole-blood–perfused, ventilated, rabbit lung model. Lungs were flushed with Euro-Collins, LPD, or BLPD solution, and then were reperfused after 24, 36, or 48 hours of hypothermic storage at 4°C. Continuous measurements of pulmonary artery pressure, pulmonary vascular resistance, left atrial pressure, tidal volume, and dynamic airway compliance were obtained. Fresh, non-recirculated venous blood was used to determine single-pass pulmonary venous-to-arterial O 2 gradients. Results. The 24-hour Euro-Collins group could not be completed because of immediate reperfusion failure. The 36-hour LPD group oxygenated significantly better than the 36-hour BLPD group (363.3 ± 65.1 versus 145.3 ± 40.3 mm Hg, respectively; p = 0.015). The 48-hour LPD group also experienced significant improvements in oxygenation when compared with the 48-hour BLPD group (pulmonary venous-arterial O 2 difference of 239.4 ± 48.4 versus 70.7 ± 19.5 mm Hg, respectively; p = 0.012). The 48-hour LPD group also displayed significant improvements in pulmonary artery pressure (34.72 ± 0.96 versus 55.52 ± 7.37 mm Hg, respectively; p = 0.031) and pulmonary vascular resistance (39,737 ± 1,291 versus 67,594 ± 9,467 dynes · s · cm −5, respectively; p = 0.027) when compared with the 48-hour BLPD group. There were no significant differences between the three LPD groups. Conclusions. Extracellular solutions provide improved pulmonary preservation in an isolated rabbit lung model after 48 hours of cold ischemia. The addition of blood to extracellular preservation solutions diminishes pulmonary function when combined with ischemic periods of 36 to 48 hours.

Equivalent eighteen-hour lung preservation with low-potassium dextran or Euro-Collins solution after prostaglandin E1 infusion

Improved techniques of pulmonary preservation would help alleviate the critical shortage of donor organs in lung transplantation and would improve early graft function. A previous study demonstrated that cold pulmonary artery flush with low-potassium dextran solution was superior to Euro-Collins solution in preservation of canine lung allografts stored for 12 hours when no pulmonary vasodilator was used before donor lung flush. The present study was designed to determine whether donor pretreatment with prostaglandin E1 would affect the superiority of low-potassium dextran as a preservation solution. Prostaglandin E1 was infused (50 micrograms/min) in 12 donor dogs until potent vasodilation was demonstrated. Low-pressure pulmonary artery flush (50 ml/kg) with either Euro-Collins or low-potassium dextran solution (n = 6 for each group) was performed at 4 degrees C in a randomized, blinded fashion. Heart-lung blocks were extracted and stored at 4 degrees C for 18 hours before left lung allografting. Inflatable cuffs were placed around each pulmonary artery, allowing independent study of the native and transplanted lungs. All 12 recipient dogs survived the 3-day assessment period. Lungs flushed and stored in Euro-Collins or low-potassium dextran solution provided equivalent gas exchange function on day 0 (arterial oxygen tension: Euro-Collins 289 +/- 105 mm Hg versus low-potassium dextran 265 +/- 111 mm Hg; mean +/- standard error of the mean) and on day 3 (Euro-Collins 516 +/- 45 mm Hg versus low-potassium dextran 354 +/- 77 mm Hg; p = 0.10). Mean pulmonary artery pressures in the transplanted lung were not significantly different in the Euro-Collins and low-potassium dextran groups on day 0 (21.4 +/- 2 mm Hg versus 33.7 +/- 5 mm Hg, respectively; p = 0.09) or on day 3 (20.2 +/- 2.7 mm Hg versus 24.2 +/- 5.1 mm Hg, respectively; p = 0.50). We conclude that there was no advantage of low-potassium dextran over Euro-Collins as a flush solution in this 18-hour canine single lung allograft model in which prostaglandin E1 was administered before pulmonary artery flush.

Comparison of the University of Wisconsin preservation solution and other crystalloid perfusates in a 30-hour rabbit lung preservation model

The University of Wisconsin solution, which contains a high potassium concentration (120 mmol/L), was evaluated for rabbit lung preservation by comparing it with a modified University of Wisconsin solution with low potassium (4 mmol/L), a low-potassium dextran solution (4 mmol/L), and simple surface cooling. In the first three groups rabbit lungs were flushed in situ with the solution (n = 5 in each group); then the lung-heart block was harvested and stored at 10 degrees C for 30 hours. In the surface cooling group the lungs were harvested without flushing and then simply immersed in saline and stored. For assessment, the stored lung was ventilated with room air and perfused with fresh venous blood at a rate of 40 ml/min for 10 minutes. Assessment of lung function included gas analysis of effluent blood, mean pulmonary artery perfusion pressure, and peak airway pressure. Among these parameters, oxygen tension was most sensitive. Oxygen tension at 10 minutes' perfusion in the modified University of Wisconsin (95 +/- 6 mm Hg) and low-potassium dextran (99 +/- 4 mm Hg) groups was significantly higher than that in the surface cooling (61 +/- 7 mm Hg) and University of Wisconsin (51 +/- 7 mm Hg) groups. There was no difference between the modified University of Wisconsin and low-potassium dextran groups or between the surface cooling and University of Wisconsin groups. We conclude that the low-potassium University of Wisconsin solution is superior to the high-potassium University of Wisconsin solution and that the lactobionate and raffinose included in the University of Wisconsin solution as impermeants do not improve lung preservation in this model.

THE EFFECT OF PGE1 AND TEMPERATURE ON LUNG FUNCTION FOLLOWING PRESERVATION

We studied the effect of a vasodilator (prostaglandin E1) as well as flush (F) and storage (S) temperatures (4 degrees C or 10 degrees C) on lung preservation in an isolated rabbit lung perfusion model. Low-potassium dextran (LPD) or Euro-Collins (E-C) solution was used as flush solution. Six groups of six animals were studied: group 1 (LPD, 4 degrees C F-S), group 2 (LPD with PGE1, 4 degrees C F-S), group 3 (E-C with PGE1, 4 degrees C F-S), group 4 (LPD, 10 degrees C F-S), group 5 (LPD with PGE1, 10 degrees C F-S), group 6 (E-C with PGE1, 10 degrees C F-S). After 18-hr preservation, left lungs alone were ventilated, and reperfused with fresh venous blood. PaO2, PaCO2, pulmonary artery pressure (PAP), tracheal pressure (Pt) during reperfusion, and wet/dry weight (W/D) ratios were measured. PaO2 after LPD with or without PGE1 was significantly higher than after E-C with PGE1 at 4 degrees C (95.8 +/- 11.5 mmHg in group 1 or 102.7 +/- 8.6 in group 2 vs. 41.8 +/- 10.5 in group 3, P less than 0.01) and at 10 degrees C (119.3 +/- 2.3 in group 4 or 131.1 +/- 6.2 in group 5 vs. 54.6 +/- 5.2 in group 6, P less than 0.01). PaCO2, PAP, Pt, and W/D ratios in the LPD groups were lower than in the E-C groups. LPD/PGE1 and LPD alone produced similar pulmonary preservation. PaO2 of lungs flushed with LPD and preserved at 10 degrees C was higher than that of lungs stored at 4 degrees C. We conclude that LPD solution is superior to E-C solution in this ex vivo rabbit lung preservation model, even when PGE1 is used. A moderate dose of PGE1 did not improve the performance of LPD as a flush solution. Pulmonary preservation with LPD at 10 degrees C is superior to preservation at 4 degrees C.