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Ann Thorac Surg 1996;61:973-976
© 1996 The Society of Thoracic Surgeons

Original Articles: General Thoracic

Low-Potassium Solution for Lung Preservation in the Setting of High-Flow Reperfusion

Nuno F. DeLima, MD, Oliver A. R. Binns, MD, Scott A. Buchanan, MD, Jeffrey T. Cope, MD, Michael C. Mauney, MD, Kimberly S. Shockey, MS, Curtis G. Tribble, MD, Irving L. Kron, MD

Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia Health Sciences Center, Charlottesville, Virginia

Accepted for publication November 13, 1995.


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background. We previously demonstrated that standard preservation using Euro-Collins solution impairs lung function in the setting of high-flow reperfusion because of potassium-induced vasoconstriction. Preservation strategies for single-lung transplantation are an important factor in patients with pulmonary hypertension. This study investigates the hypothesis that low-potassium preservation solution will improve function of lungs subjected to high-flow reperfusion.

Methods. Twenty-one New Zealand white rabbit lungs were harvested and studied on an isolated, blood-perfused model of lung function after 4 hours of cold ischemia at 4°C. Control lungs were preserved with 50 mL/kg of cold saline solution flush (group I). Experimental lungs were preserved with low-potassium solution (group II) or Euro-Collins solution (group III) at similar temperatures and volumes.

Results. The pulmonary arteriovenous oxygen gradient at the end of the 30-minute high-flow reperfusion period was significantly higher in group II compared with group III (121.3 ± 19.2 mm Hg versus 31.1 ± 4.2 mm Hg; p < 0.001). The pulmonary vascular resistance was significantly lower in group II than in group III (46.3 ± 1.8 x 103 dynes•s•cm-5 versus 79.8 ± 8.4 x 103 dynes•s•cm-5; p < 0.01). The percent decrease in dynamic airway compliance in group III was significantly greater than in groups I and II (-51.0% ± 13.3% versus -10.2% ± 3.4% and -11.2% ± 2.8%, respectively; p < 0.001). Similarly, the wet to dry ratio of the lungs in group III was significantly greater than in groups I and II (13.9 ± 2.3 versus 5.9 ± 0.2 and 6.0 ± 0.4, respectively; p < 0.001).

Conclusions. These data demonstrate that a low-potassium preservation solution yields improved lung function after high-flow reperfusion in an ex vivo rabbit lung model. Lung preservation should be aimed at the clinical setting.


   Introduction
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 Footnotes
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Despite a strong body of research demonstrating the superiority of and potential for prolonged clinical lung preservation with low-potassium solutions [1–6], the intracellular-type Euro-Collins solution remains the current clinical standard for lung graft preservation. Although Euro-Collins solution has been successful in most instances clinically, it has not been satisfactory for longer ischemic storage and single-lung transplantation for pulmonary hypertension [7, 8]. Therefore, alternative preservation solutions and methods tailored for specific clinical scenarios may be necessary to achieve optimal lung function after transplantation.

We [9] have previously demonstrated that high-flow reperfusion results in substantial impairment of lung function and that the high potassium concentration of Euro-Collins solution further potentiates the lung injury. The potent pulmonary vasoconstriction induced by the high potassium content of this intracellular solution severely increases the pulmonary vascular resistance (PVR) at high-flow reperfusion, thus leading to edema formation and lung dysfunction. We now hypothesize that pulmonary function after high-flow reperfusion would be better preserved with a low-potassium solution, thereby supporting the use of extracellular-type solutions as the preservation method of choice for single-lung transplantation in the setting of pulmonary hypertension. This hypothesis was investigated in isolated, blood-perfused rabbit lungs after 4 hours of cold ischemia.


   Material and Methods
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 Footnotes
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Lung-Heart Block Harvesting
Twenty-one New Zealand white rabbits weighing 3.0 to 3.5 kg were randomized to three groups of 7 animals each. All experimental protocols were reviewed and approved by an institutional animal use committee. All animals received humane care in compliance with the ``Guide for the Care and Use of Laboratory Animals'' published by the National Institutes of Health (NIH publication 85-23, revised 1985).

Each rabbit was anesthetized with intramuscular administration of ketamine hydrochloride (50 mg/kg) and xylazine (5 mg/kg). A tracheostomy was performed followed by induction of paralysis with metocurine iodide (0.2 mg/kg). Mechanical ventilation was instituted (ventilator model RSP1002; Kent Scientific Corporation, Litchfield, CT) using room air with a tidal volume of 12 mL/kg and a rate of 20 breaths/min. Median sternotomy and thymectomy were then performed. The superior and inferior venae cavae were loosely encircled with ligatures, and the pericardium was opened. Both the pulmonary artery (PA) and aorta were dissected free and similarly encircled. A pursestring suture was placed in the free wall of the right ventricle, and the rabbit was heparinized (500 U/kg). After injection of 30 µg of prostaglandin E1 (Alprostadil; The Upjohn Company, Kalamazoo, MI) into the PA, the venae cavae were ligated, and the time of onset of ischemia was charted. The PA was then cannulated through the right ventricular pursestring. The cannula was secured by tying both the right ventricular and PA ligatures.

After the left ventricle was vented and the aorta was ligated, 50 mL/kg of preservation solution at 4°C was infused into the PA from a height of 30 cm. Topical cooling was achieved with cold saline slush. During PA flush, the left atrium was cannulated through the left ventricle and a second pursestring tied around the cannula. After the PA flush, the inflow and outflow cannulas were clamped. Care was taken to leave the pleurae intact until completion of the flush to avoid parenchymal injury. The tracheostomy tube was clamped at end-inspiration, and the lung-heart block was excised, immersed in cold normal saline solution, and stored at 4°C.

Assessment of Lung Function
After 4 hours of storage, the lung-heart blocks were suspended from a force transducer in a warmed, humidified tissue chamber. Ventilation was reestablished with 95% oxygen and 5% carbon dioxide at a tidal volume of 12 mL/kg and a rate of 20 breaths/min. The lungs were reperfused with homologous, fresh whole venous blood from a main reservoir. A second venous blood reservoir was used to determine single-pass oxygenation. With care taken to avoid the introduction of air bubbles, the inflow and outflow cannulas were connected to the blood-filled perfusion circuit. The circuit (Kent Scientific Corporation) was designed to recirculate 200 mL of warmed blood through a 270-µm blood filter (model 2C7600; Baxter, Deerfield, IL) using a roller pump (model 7521-40; Cole Palmer Instrument Company, Chicago, IL) at a rate of 120 mL/min in accordance with the high-flow experimental protocol.

Continuous recording of PA pressure, pulmonary venous pressure, lung weight, airway flow, and airway pressure was carried out using a dynamic data-acquisition program (Workbench PC; Strawberry Tree, Inc, Sunnydale, CA) run on a desktop computer (model 470A; Compaq Prolinea, Houston, TX). This program allowed immediate calculation of PVR, tidal volume, and dynamic airway compliance. The pulmonary venous pressure was maintained within the physiologic range (4 to 8 mm Hg) by setting the appropriate height of a small outflow reservoir in the circuit. Pulmonary venous blood samples were collected for blood gas analysis (Corning 178 pH/blood gas analyzer, Medfield, MA) at 10, 20, and 30 minutes after the start of reperfusion; at each sampling time, inflow from the main reservoir was interrupted and the circuit filled with venous blood from the second inflow reservoir. Oxygen contact with exposed blood surfaces inside the reservoir containers was minimized by continuous passive infusion of 100% nitrogen. After 30 minutes of reperfusion, lung samples were taken for histologic analysis and wet to dry weight ratio calculation after passive desiccation (Fig 1Go).



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  		Fig 1. . Isolated, ventilated, blood-perfused rabbit lung model. (P = pressure transducer.)

 
Experimental Protocol
Lungs were flushed with normal saline solution (group I), low-potassium solution (group II), or Euro-Collins solution (group III) and reperfused at a high flow rate of 120 mL/min. The experimental protocol and the composition of flush solutions are shown in Table 1Go. An additional control group was designed to demonstrate baseline lung function. These lungs were flushed with saline solution and studied immediately after harvesting, thus not being subjected to 4 hours of cold ischemia. Saline solution was chosen to flush the lungs of the control groups because of its inert endothelial effects and lack of preservation properties. Data were obtained every 15 seconds and analyzed at the end of the 30-minute reperfusion period.


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  		Table 1. . Experimental Protocol and Composition of Flush Solutions
 
Statistical Analysis
Statistical analysis was performed by analysis of variance and Kruskal-Wallis nonparametric analysis of variance to compare the groups of stored lungs. Differences were considered significant if the p value was less than 0.05. All values are expressed as the mean ± the standard error of the mean.


   Results
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
There were no significant differences in donor weight, total ischemic time, or perfusate hematocrit between the groups. Mean hematocrit for all groups combined was 30.5% ± 0.4%. The arteriovenous oxygen gradient at the end of the 30-minute reperfusion period was significantly higher in the lungs preserved with low-potassium solution (group II) compared with lungs preserved with Euro-Collins solution (group III) (group II, 121.3 ± 19.2 mm Hg, versus group III, 31.1 ± 4.2 mm Hg; p < 0.001). In group I (saline solution), the oxygen gradient was 75.8 ± 13 mm Hg, an intermediate value compared with the other groups and not reaching significance. During reperfusion, lungs in group I showed a progressive and steeper decrease in oxygenation compared with group II, a finding probably related to poor lung preservation by saline solution. However, in group III, the arteriovenous oxygen gradient was already extremely low at 10 minutes of reperfusion, and this represented early lung damage (Fig 2Go).



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  		Fig 2. . Pulmonary arteriovenous (P A-V) oxygen gradient at 10, 20, and 30 minutes of reperfusion. Oxygenation declined significantly in group I lungs over the 30 minutes but was already low at 10 minutes of reperfusion in group III lungs. At 30 minutes, the oxygenation of group II lungs was significantly higher than that of group III lungs (p < 0.001). Data are shown as the mean ± the standard error of the mean. (EC = Euro-Collins solution; LP = low-potassium solution; S = saline solution.)

 
In this model of high-flow reperfusion, all three groups displayed pulmonary hypertension. However, the PA pressure and PVR at the end of the 30-minute reperfusion period were significantly lower in group II than in group III (p < 0.01). The percent decrease in dynamic airway compliance was significant in group III (p < 0.001). Similarly, the lung water content at 30 minutes of reperfusion, expressed as the wet to dry ratio, was significantly greater in group III (p < 0.001). These data and the immediate control group results are shown in Table 2Go.


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  		Table 2. . Results After 30 Minutes of Reperfusiona
 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Graft dysfunction after single-lung transplantation is more common in patients with pulmonary hypertension [8, 10]. In these patients, perfusion lung scans performed within 48 hours after transplantation demonstrated that 95% ± 7% of blood flows through the transplanted lung compared with only 60% ± 20% in patients with obstructive lung disease and 69% ± 17% in patients with idiopathic pulmonary fibrosis [10]. Results of experimental single-lung transplantation have also been shown to be dependent on the severity of pulmonary hypertension. Graft pulmonary edema resulted as a consequence of severe shunting of blood through the transplanted lung in the setting of pulmonary hypertension [11]. We [9] have shown that high-flow reperfusion results in substantial impairment of lung function and that Euro-Collins preservation further potentiates this lung dysfunction. Previous experimental evidence suggests that the intracellular-type Euro-Collins solution causes damage during the flush and storage phase of lung preservation and during reperfusion [2, 9]. The high potassium concentration causes vasoconstriction, thereby causing nonhomogeneous flushing of the graft and leaving areas of parenchyma poorly preserved. In addition, this potassium-induced vasoconstriction results in elevated PVR during early reperfusion. We [9] demonstrated that despite the use of prostaglandin E1 at the time of preservation, increased PVR was seen at normal and high-flow reperfusion. This increase in PVR was responsible for impairment of lung function in lungs preserved with Euro-Collins solution compared with those flushed with saline solution. In the present study, we tested a low-potassium solution, an extracellular-type solution differing from Euro-Collins solution only in sodium and potassium concentrations (see Table 1Go).

After a relatively short storage time of 4 hours, the lungs preserved with low-potassium solution demonstrated better lung function compared with Euro-Collins–preserved and saline solution–preserved lungs. The increased oxygenation capacity, lower PA pressure and PVR, lower percent decrease in dynamic airway compliance, and lower wet to dry ratio seen with low-potassium solution preservation were significant compared with Euro-Collins solution preservation. These results confirm the importance of low potassium concentrations in lung preservation solutions as previously suggested [12–14]; however, they also suggest that the detrimental effects of a high potassium concentration are due to direct effects on the pulmonary vasculature. A potential limitation of this model may be the inherent sensitivity of the rabbit vasculature to high concentrations of potassium. As always, results of these animal studies must be applied cautiously to the human situation.

The lungs preserved in low-potassium solution demonstrated an improved arteriovenous oxygen gradient along with lower PA pressure and PVR compared with saline solution–preserved lungs, but without reaching significance. The improved lung function seen late in the reperfusion period with low-potassium solution over saline solution may be due to advantageous glucose metabolism, osmotic effects, and the optimal pH of the phosphate-buffered low-potassium solution [6, 15–17]. The addition of dextran in low-potassium preservation solutions has also been shown to be advantageous because of its actions as an oncotic agent, oxygen-derived free radical scavenger, and enhancer of microvascular flow [13]. The beneficial effects of dextran were not tested in this model of high-flow reperfusion to emphasize the role of potassium in preservation solutions.

In conclusion, the low-potassium preservation solution provided superior protection of lungs subjected to high-flow reperfusion compared with those preserved with Euro-Collins solution. In an effort to adapt preservation methods to the clinical situation, the results of single-lung transplantation for pulmonary hypertension may be improved with the use of such an extracellular-type preservation solution.


   Acknowledgments
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This work was supported by the National Institutes of Health under grant HL 48242 and National Research Service Award fellowship F32HL09115-01A1. Additional support came from CNPq–Conselho Nacional de Desenvolimento Cientifico Tecnologico, Brazil.

The technical advice of Anthony J. Herring is acknowledged.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Address reprint requests to Dr Kron, Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia Health Sciences Center, Box 310, Charlottesville, VA 22908.


   References
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Keshavjee SH, Yamazaki F, Cardoso PF, et al. A method for safe twelve-hour pulmonary preservation. J Thorac Cardiovasc Surg 1989;98:529–34.[Abstract]
  2. Yamazaki F, Yokomise H, Keshavjee SH, et al. The superiority of an extracellular fluid solution over Euro-Collins' solution for pulmonary preservation. Transplantation 1990;49:690–4.[Medline]
  3. Sundaresan S, Lima O, Date H, et al. Lung preservation with low-potassium dextran flush in a primate bilateral transplant model. Ann Thorac Surg 1993;56:1129–35.[Abstract]
  4. Steen S, Kimblad PO, Sjöberg T, Lindberg L, Ingemansson R, Massa G. Safe lung preservation for twenty-four hours with Perfadex. Ann Thorac Surg 1994;57:450–7.[Abstract]
  5. Date H, Izumi S, Miyade Y, Andou A, Shimizu N, Teramoto S. Successful canine bilateral single-lung transplantation after 21-hour lung preservation. Ann Thorac Surg 1995;59:336–41.[Abstract/Free Full Text]
  6. Wisser W, Ringl H, Wekerle T, Wolner E, Klepetko W. A new flush solution for extended lung preservation. J Heart Lung Transplant 1995;14:289–95.[Medline]
  7. Keenan RJ, Griffith BP, Kormos RL, Armitage JM, Hardesty RL. Increased perioperative lung preservation injury with lung procurement by Euro-Collins solution flush. J Heart Lung Transplant 1991;10:650–5.[Medline]
  8. Bando K, Keenan RJ, Paradis IL, et al. Impact of pulmonary hypertension on outcome after single-lung transplantation. Ann Thorac Surg 1994;58:1336–42.[Abstract]
  9. DeLima NF, Binns OAR, Buchanan SA, et al. Euro-Collins solution exacerbates lung injury in the setting of high-flow reperfusion. J Thorac Cardiovasc Surg (in press).
  10. Davis RD Jr, Trulock EP, Manley J, et al. Differences in early results after single-lung transplantation. Ann Thorac Surg 1994;58:1327–35.[Abstract]
  11. Kawaguchi AT, Kawashima Y, Mizuta T, et al. Single lung transplantation in rats with fatal pulmonary hypertension. J Thorac Cardiovasc Surg 1992;104:825–9.[Abstract]
  12. Oka T, Puskas JD, Mayer E, et al. Low-potassium UW solution for lung preservation. Transplantation 1991;52:984–8.[Medline]
  13. Keshavjee SH, Yamazaki F, Yokomise H, et al. The role of dextran 40 and potassium in extended hypothermic lung preservation for transplantation. J Thorac Cardiovasc Surg 1992;103:314–25.[Abstract]
  14. Xiong L, Mazmanian M, Chapelier AR, et al. Lung preservation with Euro-Collins, University of Wisconsin, Wallwork, and low-potassium–dextran solutions. Ann Thorac Surg 1994;58:845–50.[Abstract]
  15. Date H, Matsumura A, Manchester JK, et al. Evaluation of lung metabolism during successful twenty-four hour canine lung preservation. J Thorac Cardiovasc Surg 1993;105:480–91.[Abstract]
  16. Shiraishi T, Igisu H, Shirakusa T. Effects of pH and temperature on lung preservation: a study with an isolated rat lung reperfusion model. Ann Thorac Surg 1994;57:639–43.[Abstract]
  17. Hiramatsu Y, Muraoka R, Chiba Y, Sasaki M. Influence of pH of preservation solution on lung viability. Ann Thorac Surg 1994;58:1083–6.[Abstract]



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