Retrograde flush perfusion with low-potassium solutions for improvement of experimental pulmonary preservation

doi:10.1016/S1053-2498(00)00189-3

The Journal of Heart and Lung Transplantation

Volume 19, Issue 10, October 2000, Pages 976-983

This manuscript was accepted for presentation at the 20th Annual Meeting and Scientific Sessions of the International Society for Heart and Lung Transplantation, Osaka, Japan, April 5–8, 2000.

https://doi.org/10.1016/S1053-2498(00)00189-3 Get rights and content

Abstract

Background

Optimal preservation of post-ischemic organ function is a continuing challenge in clinical lung transplantation. Retrograde instillation of preservation solutions has the theoretic advantage of achieving homogeneous distribution in the lung because of perfusing both the pulmonary and the bronchial circulation. So far, we have seen no experimental studies that include stereologic analysis of intrapulmonary edema concerning the influence of retrograde preservation on post-ischemic lung function after preservation with Perfadex and Celsior.

Methods

In an extracorporeal rat model, we perfused 8 lungs, each, using either antegrade or retrograde perfusion technique with Celsior (CE_ant/CE_ret) and Perfadex (PER_ant/PER_ret). Results were compared with low-potassium Euro-Collins. Post-ischemic lungs were reventilated and reperfused mechanically. We continuously monitored relative oxygenation capacity (ROC), pulmonary artery pressure, flush time, and wet/dry ratio. Furthermore, we used stereologic means to evaluate edema formation. Statistics comprised different analysis of variance models.

Results

Relative oxygen capacity of CE_ant-protected lungs was superior to that of PER_ant preservation (p = 0.05). Use of PER_ret resulted in significantly higher ROC as compared with PER_ant (p < 0.001) and was comparable to results obtained with CE-preservation, which was not further improved with retrograde application.

Conclusion

Celsior provides better lung preservation than does Perfadex when administered antegradely. Retrograde application of Perfadex results in significant functional improvement as compared with antegrade perfusion, which reaches the standard of Celsior-protected organs. Additional in vivo experiments in combination with ultrastructural analysis are warranted to further evaluate retrograde delivery of preservation solutions, which could be used in clinical lung transplantation to further optimize current results.

Section snippets

Surgical methods and functional assessment

Lungs of 40 anesthetized and mechanically ventilated male inbred Sprague-Dawley rats (400 to 500 g) were used for the experiments. All animals received humane care in compliance with the Principles of Laboratory Animal Care, formulated by the National Society for Medical Research, and the Guide for the Care and Use of Laboratory Animals, prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Pub. No. 80–23, revised 1985). We performed

Flush perfusion time

The perfusion time was significantly lower in the Celsior groups compared with Perfadex, both with an antegrade (CE_ant, 66 ± 14sec; PER_ant, 102 ± 15sec; p = 0.005) and a retrograde technique (CE_ret, 64 ± 17sec; PER_ret, 115 ± 26sec; p < 0.001). Retrograde application of either solution generally did not have any significant effect on the flush time compared with the corresponding antegrade application (CE, p > 0.8; PER, p > 0.3). Preservation time was longest but extremely variable in the LPEC

Comment

Lung transplantation is an effective treatment for many types of end-stage pulmonary disease. Compared with initial results, improved outcome mainly relates to optimized immunosuppression regimens and modified protocols for pulmonary preservation. However, early graft dysfunction remains a continuing problem, resulting from multifactorial lung injury starting within the donor and continuing through harvesting, organ storage, implantation, and post-ischemic reperfusion. Currently modified EC

Conclusions

Celsior provides better lung preservation than does Perfadex when administered antegradely. Retrograde application results in significant functional improvement of Perfadex-preserved lungs as compared with antegrade perfusion and reaches the standard of Celsior-protected organs, but fails to further optimize the preservation quality of Celsior.

Additional experiments using an in vivo porcine model with extended ischemic and post-ischemic observation periods have been initiated to further clarify

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Cited by (23)

Brain Death and Its Influence on the Lungs of the Donor: How Is It Prevented?
2009, Transplantation Proceedings
Citation Excerpt :
Chest radiographs should also be performed every 3–4 hours, looking for possible mucus or inflammation cell collections.9 Finally, it has been proposed that retrograde flushing of the lung can remove various potential harmful molecules and improve the quality of the graft.37,39,40 The “autonomic storm” that follows BD is a well described induction factor for pulmonary edema due to increased pulmonary capillary pressure and increased capillary permeability.7,14
The need for lung grafts is currently greater than ever. Unfortunately, the availability of grafts is insufficient for this demand. So we are forced to request organs for transplantation in the “waste bin.” One possible solution to this problem may be the use of grafts from brain-dead patients. Sadly brain death is followed by devastating hemodynamic, inflammatory, and neurohumoral reactions in the potential donor which not only inflict direct damage, but also induce activation of the immune system which can cause rejection or even graft failure. Therefore, various groups have examined measures to prevent this outcome. In this review, we attempt to reconstruct the events that follow brain death, suggesting an algorithm to prevent a brain-dead patient's lungs from further damage. Finally, we are proposing potential measures of graft's protection of further investigation.
Pitfalls in donor lung procurements: How should the procedure be taught to transplant trainees?
2009, Journal of Thoracic and Cardiovascular Surgery
The current trend in lung transplantation has led to liberalized lung donor selection criteria and use of marginal donors, with a corresponding requirement for improved procurement techniques to obtain high-quality donor grafts. Few reports, however, have provided recommendations for successful lung procurement procedures.
We retrospectively studied 47 lung procurements performed by the University of Pittsburgh Medical Center team from January 2007 to December 2007. From those findings, we compared outcomes, as well as technical errors encountered, between procurements performed by trainees with limited transplant experience and by experienced transplant surgeons.
Twenty-two of the procurements (47%) were performed by experienced transplant surgeons and 25 (53%) by supervised trainees. Patient characteristics and technical difficulties were comparable between the two groups. The trainees took more time to complete the procedure than did the experienced surgeons, although the difference was not significant. Furthermore, 21 of the cases performed by trainees (84%) had one or more technical errors in the sequential steps of the procurement, including inadequate placement of the perfusion cannula in the main pulmonary artery (60%), insufficient topical cooling (56%), and inadequate timing of the start of pulmonary artery perfusion (44%).
Donor lung procurements performed by beginners with limited transplant experience included frequent technical errors with regard to adequate graft preservation, which may lead to serious complications after transplant. Sequential steps in lung procurement techniques and better understanding of organ preservation should be an integral part of a lung transplant training program.
Late Retrograde Perfusion of Donor Lungs Does Not Decrease the Severity of Primary Graft Dysfunction
2008, Annals of Thoracic Surgery
Citation Excerpt :
Retrograde perfusion of pulmonary grafts presents a number of theoretical advantages including a more homogenous distribution of the perfusate through a low resistance venous system, flushing the bronchial circulation through the bronchopulmonary anastomoses and evacuating blood clots, debris, and fat emboli from the pulmonary vascular bed [7, 15, 16]. Experimentally, retrograde flushing improves oxygenation, decreases airway resistance, and reduces edema formation [6, 8, 17]. Also, histologic and ultrastructural studies have shown better preservation of type I pneumocytes, capillary endothelial cells, bronchial epithelial cells, and surfactant function [18, 19].
The ideal preservation strategy has yet to be established in lung transplantation. This clinical study compares primary graft dysfunction using antegrade and retrograde perfusion of donor lungs.
Over a 6-year period, 153 consecutive patients underwent lung transplantation in our institution. Group I consists of 65 patients who received lungs preserved with an antegrade flush of modified Euro-Collins solution. Group II includes 65 patients who received lungs preserved with an antegrade flush of low-potassium dextran (LPD) solution. Group III consists of 23 patients who received lungs preserved with an antegrade and a preimplantation retrograde flush of LPD solution. Endpoints evaluated were the following: acute lung injury (ALI) score, time to achieve a fraction of inspired oxygen (Fio₂) of 40% and a positive end-expiratory pressure (PEEP) of 5, length of ventilation, length of intensive care unit (ICU) stay, 90-day operative mortality, and patient survival rates.
The patient demographic data, underlying diagnosis, number of single and double lung transplants, use of cardiopulmonary bypass, and mean ischemic times were similar in all 3 groups. The mean ALI score (6.2, 5.8, and 6.0) and the median length of ventilation (23.5, 24.0, and 27.0 hours) in groups I, II, and III, respectively, were not significantly different. The length of ICU stay, the 90-day operative mortality, and the survival rates were not significantly different in the 3 groups.
Our results suggest that late retrograde perfusion of donor lungs does not decrease the severity of primary graft dysfunction when compared with standard antegrade techniques.
Nebulized N-acetyl cysteine protects the pulmonary graft inside the non-heart-beating donor
2005, Journal of Heart and Lung Transplantation
The use of lungs from non–heart-beating donors (NHBD) might significantly alleviate the organ shortage. The tolerable warm ischemic period after cardiac arrest, however, is limited to approximately 1 hour. If the lung could be safely protected inside the cadaver, this time period may be prolonged. This would help to obtain family consent and to organize organ retrieval.
Pigs (30.8 ± 0.6 kg) were killed, left untouched for 3 hours, and divided into 3 groups. Nebulized N-acetyl cysteine (NAC) (300 mg), a precursor of the antioxidant agent glutathione, was administered during 10 minutes before death in Group I (NAC-NHBD, n = 6) and 15 minutes after death in Group II (NHBD-NAC, n = 6). In the control group, no aerosol was administered (NHBD, n = 6). After a warm ischemic interval of 3 hours, both lungs in all groups were topically cooled for 1 hour. Thereafter, the left lung was prepared for evaluation in an isolated reperfusion circuit. Hemodynamic, aerodynamic, and oxygenation parameters were measured. Wet-to-dry weight ratio (W/D) was calculated after reperfusion. The right lung was used to measure reduced glutathione (GSH) and oxidized glutathione (GSSG) levels (μmol/g) in lung homogenates and total protein levels in bronchial lavage fluid.
Pulmonary vascular resistance, mean airway pressure, and W/D were significantly decreased in NAC-NHBD (1930 ± 144 Dynes · sec · cm⁻⁵, 14.2 ± 0.5 cm H₂O, and 7.4 ± 0.4; p < 0.01, 0.01, and 0.05, respectively) and NHBD-NAC (1837 ± 180 Dynes · sec · cm⁻⁵, 13.3 ± 1.2 cm H₂O, and 7.3 ± 0.3; p < 0.01, 0.05, and 0.05, respectively) when compared with the control group (5051 ± 530 Dynes · sec · cm⁻⁵, 17 ± 0.4 cm H₂O, 8.5 ± 0.1, respectively). GSH/GSSG ratio was significantly higher and protein levels were significantly lower in NAC-NHBD (1.7 ± 0.1 and 1315 ± 60 μg/ml; p < 0.05 and 0.05, respectively) and NHBD-NAC (1.7 ± 0.2 and 1475 ± 159 μg/ml; p < 0.05 and 0.05, respectively) when compared with the control group (1.2 ± 0.1 and 2150 ± 200 μg/ml).
Nebulized NAC administered before or shortly after death attenuates early ischemia reperfusion injury via upregulation of glutathione. NAC might be a promising tool to protect the pulmonary graft from both controlled and uncontrolled NHBD.
Experimental lung transplantation: Impact of preservation solution and route of delivery
2005, Journal of Heart and Lung Transplantation
Optimal preservation of allograft integrity is essential to reduce post-ischemic organ dysfunction after lung transplantation. Retrograde organ preservation leads to homogeneous intrapulmonary distribution and eliminates intravascular thrombi. So far, no comparative studies exist with regard to preservation quality following retrograde preservation with Perfadex and Celsior after extended cold-ischemia intervals.
In an in vivo pig model, 5 lungs each were preserved for 27 hours using antegrade or retrograde perfusion techniques with Celsior (Ce_ant/CE_ret) and Perfadex (PER_ant/PER_ret). After left lung transplantation and contralateral lung exclusion, hemodynamics, oxygenation and dynamic compliance were monitored for 6 hours and compared with sham-operated controls. Pulmonary edema was determined stereologically. Statistics consisted of analysis of variance (ANOVA) with repeated measures.
Mortality of all Celsior-protected lungs was 100% due to severe reperfusion injury with profound lung edema. In contrast, organ preservation with PER_ant led to sufficient graft function without mortality. Preservation quality after retrograde administration of Perfadex resulted in optimized oxygenation capacity compared with PER_ant (p = 0.046). Furthermore, intra-alveolar edema was reduced and generally comparable with sham controls. In general, retrograde preservation led to continuous washout of small blood and fibrin clots from the pulmonary capillary system.
Perfadex solution provided sufficient lung preservation for 27 hours of cold ischemia, and its retrograde application led to significant functional and histologic improvement compared with antegrade perfusion. In contrast, preservation with Celsior solution resulted in lethal post-ischemic outcome, regardless of the route of administration, and therefore must be considered unsuitable for extended lung procurement.
Donor pretreatment using the aerosolized prostacyclin analogue iloprost optimizes post-ischemic function of non-heart beating donor lungs
2005, Journal of Heart and Lung Transplantation
Ischemia-reperfusion injury accounts for one-third of early deaths after lung transplantation. To expand the limited donor pool, lung retrieval from non-heart-beating donors (NHBD) has been introduced recently. However, because of potentially deleterious effects of warm ischemia on microvascular integrity, use of NHBD lungs is limited by short tolerable time periods before preservation. After intravenous prostanoids are routinely used to ameliorate reperfusion injury, the latest evidence suggests similar efficacy of inhaled prostacyclin. Therefore, the impact of donor pretreatment with the prostacyclin analogue iloprost on postischemic NHBD lung function and preservation quality was evaluated.
Asystolic pigs (5 per group) were ventilated for 180 minutes of warm ischemia (Group 2). In Group 3, 100 μg iloprost was aerosolized during the final 30 minutes of ventilation with a novel mobile ultrasonic nebulizer. Lungs were then retrogradely preserved with Perfadex and stored for 3 hours. After left lung transplantation and contralateral lung exclusion, hemodynamics, rO₂/F_iO₂, and dynamic compliance were monitored for 6 hours and compared with sham-operated controls (Group 1). Pulmonary edema was determined both stereologically and by wet-to-dry weight ratio (W/D). Statistics comprised analysis of variance with repeated measures and Mann-Whitney test.
Flush preservation pressures, dynamic compliance, inspiratory pressures, and W/D were significantly superior in iloprost-treated lungs, and oxygenation and pulmonary hemodynamics were comparable between groups. Stereology revealed a trend toward lower intraalveolar edema formation in iloprost-treated lungs compared with untreated grafts.
Alveolar deposition of Iloprost in NHBD lungs before preservation ameliorates postischemic edema and significantly improves lung compliance. This easily applicable innovative approach, which uses a mobile ultrasonic nebulizer, offers an important strategy for improvement of pulmonary preservation quality and might expand the pool of donor lungs.

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Organ preservationRetrograde flush perfusion with low-potassium solutions for improvement of experimental pulmonary preservation

Abstract

Background

Methods

Results

Conclusion

Section snippets

Surgical methods and functional assessment

Flush perfusion time

Comment

Conclusions

Ann Thorac Surg

J Heart Lung Transplant

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

Ann Thorac Surg

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

J Surg Res

J Surg Res

J Thorac Cardiovasc Surg

Pulmonary graft preservationa worldwide survey of current clinical practice

J Heart Lung Transplant

Reduced lipid peroxydation and ischemia-reperfusion injury after lung transplantation using low-potassium dextran solution for lung preservation

Am J Resp Crit Care Med

A comparison of the new preservation solution Celsior to Euro-Collins and University of Wisconsin solutions in lung reperfusion injury

Transplantation

The effect of prostacyclin as a constituent of a preservation solution in protecting lungs from ischemic injury because of its vasodilator properties

Transplantation

Organ preservation
Retrograde flush perfusion with low-potassium solutions for improvement of experimental pulmonary preservation