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Eur J Cardiothorac Surg 1998;14:508-515
© 1998 Elsevier Science NL

Hypothermic preservation of isolated rat lungs in modified bicarbonate buffer, EuroCollins solution or St Thomas' Hospital cardioplegic solution

Roland L. Featherstonea, Frank J. Kellya, Michael J. Shattocka, David J. Hearsea, David J. Chambersb

a Cardiovascular Research, The Rayne Institute, St Thomas' Hospital, London, SE1 7EH, UK
b Cardiac Surgical Research, The Rayne Institute, St Thomas' Hospital, London, SE1 7EH, UK

Received 9 February 1998; received in revised form 26 May 1998; accepted 22 June 1998.

Corresponding author. Tel.: +44 171 9289292, ext. 3371; fax: +44 171 9280658; e-mail rfeather@rayne.umds.ac.uk


   Abstract
Top
 Abstract
Introduction
Methods
 Results
 Discussion
References
 
Objectives: Inadequate preservation solutions limit lung storage times and, consequently, transplant programs. To address this problem we established an isolated, ventilated and perfused rat lung preparation. Here we report the effects of hypothermic storage in EuroCollins solution, St Thomas' Hospital cardioplegic solution and a modified bicarbonate buffer solution. Methods: Lungs from male Wistar rats (230–330 g) were perfused via the pulmonary artery with modified bicarbonate buffer (37°C, 15 ml/min, constant flow) and ventilated by positive pressure (tidal volume:1.6–1.8 ml, 80 breaths/min). Vascular resistance (pulmonary artery pressure:perfusate flow ratio) and airways compliance (tidal volume:tracheal pressure ratio) were measured. After a control perfusion period (20 min), lungs were flushed with, then immersed in, bicarbonate buffer (4°C) for varying periods (0–24 h). After storage, lung function was assessed during 20 min reperfusion. Having established a suitable period for study, storage in EuroCollins, St Thomas' Hospital cardioplegic solution or bicarbonate buffer were compared. Results: Pulmonary compliance (ml/cmH2O) was significantly (P<0.05) reduced in lungs stored for 6 h in modified bicarbonate buffer (0.026±0.008), EuroCollins solution (0.013±0.002) or St Thomas' Hospital solution (0.025±0.005) compared to unstored lungs (0.068±0.007). Vascular resistance, (1.32±0.13 cmH2O/ml per min) in unstored lungs, was similar in lungs stored in St Thomas' Hospital solution but increased significantly in lungs stored in modified bicarbonate buffer (3.22±0.78 cmH2O/ml per min) or EuroCollins solution (4.66±0.57 cmH2O/ml per min). Conclusions: Hypothermic storage of rat lungs for 6 h in modified bicarbonate buffer or St Thomas' Hospital solution causes less increase in vascular resistance on reperfusion than EuroCollins solution.

Key Words: Lung • Transplantation • EuroCollins • St Thomas' Hospital solutions


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
References
 
Lung transplantation is an accepted therapy for end-stage pulmonary disease but limited safe periods of tissue storage currently restrict transplant programs [1]. Primary graft failure, an extreme form of the reimplantation response, still occurs in a number of cases; subsequent development of bronchiolitis obliterans is a common problem affecting as many as 50% of patients within 5 years of transplantation [2].

A single flush with a cold preservation solution is widely used in the harvesting of a range of organs for transplant, including the heart and lungs [3]. A modified EuroCollins (EC) solution is the most frequently used medium for lung flushing and preservation [4], although University of Wisconsin (UW) solution has also been advocated and clinically assessed [5] [6]. Both these solutions were originally developed for the preservation of abdominal organs, primarily the kidneys [3].

Key issues relating to the basic composition of lung preservation solutions are the questions of intra-cellular versus extra-cellular types of solution and the use of oncotic agents in the solution [1] [7] [8]. The central issue regarding intra-cellular versus extra-cellular type solutions relates to the use of high potassium solutions which result in vasoconstriction [9] [10] and the loss of endothelial relaxant functions [11]. Evidence that low potassium solutions may be superior in terms of preservation of lung function assessed immediately post-preservation has recently been reported [12] [13].

In order to study the effects of using different preservation solutions on lung function after hypothermic storage we established an isolated, ventilated and perfused rat lung in which we compared three solutions for lung flushing and storage; EC solution, which is often used in lung preservation, is representative of the intracellular type of preservation solutions with a high potassium concentration (115 mM). St Thomas' Hospital (STH) solution which was originally developed as a cardioplegic solution for cardiac surgery [14] and has been successfully employed in this respect [15], was examined as an example of an extracellular composition type solution with a moderately high potassium concentration (16 mM). Thirdly, a modified bicarbonate buffer (BB) solution was included as a control for hypothermic preservation; it is extracellular in terms of its ionic composition, with a physiological potassium ion concentration (5 mM) and has been modified to contain 2% bovine serum albumin. The oncotic pressure exerted by the presence of macromolecules has been suggested to be important in protection of the lung during storage [16] [17].


   Methods
Top
 Abstract
 Introduction
Methods
Results
 Discussion
References
 
Materials
All chemicals used in perfusate and storage solutions were supplied by BDH, Leicestershire, UK. Pentabarbitone was purchased from Rhone Merieux, Harlow, UK.

Lung preparation
Lungs were obtained from male Wistar rats weighing 230–330 g. All animals received humane care in compliance with the `Principles of Laboratory Animal Care' formulated by the National Society for Medical Research (USA), the `Guide for the Care and Use of Laboratory Animals' prepared by the Institute of Laboratory Animal Resources, published by the National Institutes of Health (USA) and with the `Guidance on the Operation of the Animals (Scientific Procedures) Act 1986' published by Her Majesty's Stationary Office, London, England.

Rats were anaesthetized by intraperitoneal injection of pentabarbitone (2 ml/kg of a 60 mg/ml solution). After tracheal intubation the animals were ventilated at 80 breaths/min by positive pressure applied by a Harvard Small Animal Ventilator. Following laparotomy, the diaphragm was removed and heparin (500 IU) injected into the right ventricle. The animals were then exsanguinated by transection of the inferior vena cava and the thorax opened. A cannula was inserted into the pulmonary artery and held in place by tightening a ligature previously placed around the pulmonary artery and aorta. Perfusion with modified bicarbonate buffer (BB, composition mmol/l: NaCl 118.5, KCl 3.8, KH2PO4 1.2, NaHCO3 25.0, CaCl2 2.0, MgSO4 1.2, Glucose 10.0 plus 2% bovine serum albumin) at a flow rate of 5 ml/min was immediately started at this stage. Between 1.5 and 2 min elapsed between transection of the inferior vena cava and lung perfusion. Next, a cannula was secured in the left atrium to receive the perfusate leaving the lungs. The lungs were then removed and suspended in a sealed, water jacketed chamber maintained at 37°C. The tubing connecting the pulmonary artery cannula to the perfusion pump, the tracheal cannula to the ventilation pump and the left atrium cannula to the buffer reservoir all passed through airtight outlets in the chamber lid.

Once the lung was in the chamber the perfusate flow rate was adjusted to 15 ml/min and maintained at this value by a peristaltic pump (Watson Marlow 501). The BB was held in a heated reservoir and gassed with 100% CO2. In control lungs this produced a pH of 7.2–7.3 entering the lungs and 7.4–7.5 leaving the lungs. Buffer leaving the lungs via the left atrial cannula was returned to the reservoir and recycled. Oxygenation of the perfusate was by the isolated lungs which were ventilated with room air.

The initial tidal volume of the lung was adjusted by altering a tap on a side-arm of the tubing entering the tracheal cannula from the ventilator; progressive closing or opening of the tap allowed more, or less, air to be pumped into the lung thereby increasing or reducing the tidal volume. As this was set at the beginning of perfusion, any subsequent fall in lung compliance resulted in less air entering the lung and more venting via the side arm. This system, where changes in lung compliance are reflected by a fall in tidal volume at constant tracheal pressure, rather than ventilating the lung at constant volume and measuring changes in tracheal pressure, avoids the possibility of additional damage to the lung caused by application of high pressures to maintain tidal volume as compliance falls.

An additional tap on the out-flow (exhalation) side of the ventilator head connected to the tracheal cannula could be adjusted to give a positive end-expiratory pressure (PEEP) of 1–2 cmH20, which prevented total collapse of the lung at end-exhalation and also helps delay the onset of oedema formation [18] [19]. At the end of each respiratory cycle the perfusion chamber was briefly opened to the atmosphere by a valve controlled by the ventilator. This ensured a constant baseline pressure within the chamber and avoided artefacts due to, for example, leakage of perfusate into the chamber reducing its volume and artificially raising pressure.

Measurement
A differential pressure transducer (Sensystem) attached to a side arm of the tracheal cannula measured tracheal pressure (TP). Another pressure transducer connected to the inside of the sealed perfusion chamber measured changes in chamber pressure due to filling and emptying of the lung during ventilation. Injection of a known volume of air into the lung by syringe prior to commencement of each experiment allowed this transducer to be calibrated in terms of tidal volume (TV). The ratio of TV to TP was taken as a measure of lung compliance. A third pressure transducer (Bell and Howell, Pasadena, CA) was connected via a side-arm to the tube flowing into the pulmonary artery cannula; this pressure, divided by the perfusate flow rate, measured the vascular resistance. The output of each of the three pressure transducers was recorded using a Gould 4-channel chart recorder.

Ports on the perfusate inflow and outflow tubing allowed collection of samples of perfusate entering and leaving the lung for pH and blood gas analysis. Since the lung exhales CO2 the perfusate becomes more alkaline as it passes through the lung and this increase in pH can be taken as an indicator of the gas exchanging ability of the lung [20].

Experimental protocol
Lungs were perfused for an initial 20 min (control) period, during which time control lung function parameters were measured (as above). By switching a three-way tap to open a reservoir, the lungs were then flushed with the storage solution, which was infused at a pressure of 30 cmH20. Lungs were initially flushed with 10 ml of this solution at room temperature (20–25°C): this has been shown to reduce cold induced vasoconstriction caused by sudden infusion of storage solution at 4°C in the heart [21]. After this initial 10 ml perfusion, flushing was continued with a further 20 ml of the same storage solution at 4°C.

The flushed lungs were stored inflated and immersed in the storage solution, with the vasculature open to the storage solution; they were maintained at 4–6°C throughout the storage period. Lung inflation was achieved by attaching a syringe to the tracheal cannula after removal of the lungs from the perfusion chamber and injecting 2 ml of air, the trachea was tied off to keep the lungs inflated. Previous studies have demonstrated the benefit of maintaining lungs inflated during storage [1] [22].

After the storage period, lungs were removed from the storage solution, reattached to the perfusion circuit and reperfusion (at 37°C) was instituted for a 20 min period. During reperfusion, lung function parameters were measured.

Protocol 1: Determination of the optimal storage duration
In an initial study, lungs were perfused with modified bicarbonate buffer solution at 37°C and subsequently flushed with, and stored in, this solution at 4°C for periods of 0, 0.5, 2, 4,6 and 24 h. Lungs were then reperfused with modified bicarbonate buffer at 37°C.

Protocol 2: Comparison of storage solutions on lung recovery
Having established that 6 h was a suitable storage duration with modified bicarbonate buffer, a comparison was made between EuroCollins solution (composition mmol/l: KCl 15.0, KH2PO4 15.0, K2HPO4 42.5, NaHCO3 10.0, Glucose 139.0) and St Thomas' Hospital cardioplegic solution (composition mmol/l: NaCl 110.0, KCl 16.0, NaHCO3 10.0, CaCl2 1.2, MgSO4 16.0) and the standard modified bicarbonate buffer solution. Lungs were perfused with modified bicarbonate buffer solution at 37°C and subsequently flushed with and stored at 4 oC for 6 h in either modified bicarbonate buffer or EuroCollins or St Thomas' Hospital solution before being reperfused for 20 min with modified bicarbonate buffer solution at 37°C. An additional group of unstored lungs perfused for a total of 40 min was studied as a control.

Determination of wet:dry weight ratios
At the end of the 20 min reperfusion period the lungs were removed from the perfusion chamber, the surface fluid was blotted off and then they were weighed. The lungs were then stored in an oven for 24 h at 80°C and reweighed, no further decrease in weight occurred after this period. In one further group (n=5), lungs were removed directly from the animal for a baseline wet:dry weight ratio.

Statistics
The data are displayed as mean±SEM, the normality of distribution was tested for using the Kolmogorov–Smirnov test. Each group is comprised of studies on lungs from six to eight animals. In order to compare the effects of the various treatments on lung function over the time course of reperfusion, trapezoid integration was used to calculate the area under the time-response curve for each parameter for each animal and these individual values were then employed for statistical comparisons of the various groups. Comparisons between groups were carried out by one-way analysis of variance and, if this revealed significant differences, Dunnett's test was used to compare multiple values to control. Where multiple values were to be compared to each other Student–Newman–Keul's test was employed. In the case of wet:dry weight ratios in control perfusion lungs (no storage) compared to unperfused lungs an unpaired, two-tailed Student's t-test was employed. In all tests a P value of less than 0.05 was taken as indicating significance.


   Results
Top
 Abstract
 Introduction
Methods
 Results
Discussion
References
 
Protocol 1: Optimal storage duration
After 20 min perfusion control (0 h storage) lungs had a tidal volume of 1.57±0.06 ml, and a tracheal pressure of 37.0±2.5 cmH2O, which gave a compliance (tidal volume:tracheal pressure ratio) of 0.043±0.002 ml/cmH2O. Vascular resistance was 1.92±0.33 ml/min per cmH20, a constant flow rate of 15 ml/min producing a pulmonary artery pressure of 28.8 cmH2O. With a buffer pH entering the lung of 7.23±0.05 the pH difference across the lung was 0.17±0.02 (Table 1). Similar pre-storage values were obtained for all the storage groups.


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  		Table 1. Values of physiological parameters in perfused lungs at the end of control perfusion and post storage reperfusion periods for lungs stored in modified bicarbonate buffer

 
Flushing and storage of lungs with BB caused a time-dependent fall in lung compliance (TV:TP ratio, Fig. 1 and Table 1) which became significant after 6 h storage. A similar effect on vascular resistance was seen except a significant increase was only apparent after 24 h storage ( Fig. 2 , Table 1). In these particular lungs, fluid was visible in the trachea shortly after commencement of reperfusion, as was fluid dripping from the pleural surfaces of the lung, indicating extensive damage to the vascular system and consequent oedema formation.



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  		Fig. 1. Change in compliance (the ratio of tidal volume:tracheal pressure, ml/cmH2O) in isolated rat lungs before and after storage in modified bicarbonate buffer (0.5–24 h). Data are expressed as mean±SEM with between six and eight lungs studied in each group. *Significantly different from unstored tissues after 20 min reperfusion (Dunnett's test, P<0.05).

 


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  		Fig. 2. Change in vascular resistance with perfusion time before and after storage in modified bicarbonate buffer. Data are expressed as mean±SEM with between six and eight lungs studied in each group. *Significantly different from unstored tissues after 20 min reperfusion (Dunnett's test, P<0.05).

 
The perfusate pH difference tended to decrease with increasing storage time although this did not reach significance until 24 h (Table 1). Storage for 6 h in BB caused a significant increase in the wet:dry weight ratio compared to control lungs although the significance of this difference was lost in lungs stored for 24 h due to increased variability in this parameter (Table 2).


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  		Table 2. Wet:dry weight ratios in rat lungs subjected to different storage protocols

 
Protocol 2: Comparison of storage solutions on lung recovery
Fig. 3 A compares the values of compliance (TV:TP) in control (0 h storage) lungs with those seen after reperfusion in lungs stored for 6 h in BB, EC, or STH. In each of the three groups, at the end of 20 min reperfusion, compliance (TV:TP) was significantly lower than in controls but no significant difference between the three solutions was apparent. On the other hand, vascular resistance increased significantly in lungs stored for 6 h in BB solution when compared to control lungs and those lungs stored in EC solution showed a further, significant, increase whilst storage in STH solution caused no increase in vascular resistance compared to controls ( Fig. 3B). The pH change in perfusate on passage through the lung was significantly reduced in each of the three groups of stored lungs compared to controls (Table 3) but the storage groups did not differ from each other. Wet:dry weight ratios increased significantly in lungs stored for 6 h in any of the three solutions studied (Table 2).



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  		Fig. 3. The effects of 6 h storage in modified bicarbonate buffer (BB), EuroCollins solution (EC) or St Thomas' Hospital solution (STH) on: (A) Compliance (the tidal volume:tracheal pressure ratio) in the isolated rat lung, compared to controls (0 h storage). Data show the 20 min reperfusion values after storage, mean±SEM of between six and eight determinations. *Significantly different from control (Dunnett's test, P<0.05). The three 6 h storage groups did not differ from each other (Student–Newman–Keul's test). (B) Vascular resistance in the isolated rat lung, compared to controls (0 h storage). Data show the 20 min reperfusion values after storage, mean±SEM of between six and eight determinations. *Significantly different from control (Dunnett's test, P<0.05). {dagger}Significantly different from storage in St Thomas' hospital solution or modified bicarbonate buffer (Student–Newman–Keul's test, P<0.05).

 

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  		Table 3. The effect of 6 h storage in various solutions on the physiology of the isolated, perfused rat lung

 

   Discussion
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
References
 
Our initial aim in this study was to establish an appropriate isolated lung preparation to examine the effects of various lung storage solutions. The physiological parameters measured in the isolated, perfused and ventilated lung preparation we established compare well with those reported for other perfused rat lung models. For example, Bhabra et al., using constant pressure perfusion at 25–27 cmH2O, reported perfusate flow rates of 12 ml/min [23] and Uhlig and Wollin found a pH increase across the lung of 0.17 after 60 min control perfusion [20]. Peak tracheal pressures are less easily compared since they are influenced by such factors as the respiratory rate and tidal volumes chosen. Values have been reported in the range of 20–37 cmH2O [12] [23] and the tracheal pressures we employed are comparable to these. Therefore the preparation does constitute an appropriate model for the study of the effects of storage on lung function. However, it should be borne in mind that the effects seen will refer primarily to very acute changes occurring immediately upon reperfusion in the airways' smooth muscle and the vascular smooth muscle and endothelium. Other factors that depend on blood elements or require longer to develop, such as neutrophil infiltration and activation, which may also contribute to acute graft failure in clinical lung transplant, will not be assessed by this model.

In our initial study, when lungs were stored in BB, significant changes, in the compliance after 6 h storage and in vascular resistance after 24 h, were seen. At the latter time, the lungs were extensively damaged as evidenced by the appearance of oedema fluid in the trachea on commencement of reperfusion and fluid dripping from the pleural surfaces of the lung. The change in pH across the lung tended to decrease after 6 and 24 h storage in BB. However, analysis of variance did not indicate any significant differences between these and control values in terms of the absolute value of this parameter after 20 min reperfusion. When affects were assessed as AUC values, a significant decline was seen but only in lungs stored for 24 h. This finding should be interpreted cautiously as the high variability of this parameter, particularly at intermediate storage times (0.5 and 4h) means that the test applied has a lower power (<0.80) than desired to be confident of detecting a true difference between the groups.

When lungs stored for 6 h in BB, STH or EC were compared (protocol 2), measurable declines in lung compliance were also seen, TV:TP being reduced in all cases. Lungs stored in BB or EC also showed an increased vascular resistance at this time point whilst lungs stored in STH had vascular resistances comparable to control values. The pH change across the lungs was also significantly reduced after 6 h storage in all three of the solutions studied when these values were compared to controls.

The finding of impaired lung function following 6 h hypothermic storage is in line with other reports in the literature which have shown significantly increased vascular resistance and decreased lung compliance when lungs are reperfused after 6 h storage in EC solution [23] [24] [25] or phosphate buffered sucrose [23]. Indeed, significant differences in the function of isolated lungs (increased vascular resistance and reduced oxygenation of perfusate) have been seen after only 2 h storage in normal, compared to low, potassium EuroCollins solution [12].

EuroCollins solution is extensively used as a flushing and storage solution for human lungs for transplantation despite reports of its potentially damaging effects on lung physiology. In particular, these worries centre around the loss of vascular endothelial function and stimulation of vasoconstriction which are thought to arise due to the high potassium content of this solution [12] [24] [26]. The data presented here confirm its potent vasoconstrictory effect. However, it is not clear from these which region of the vasculature is most affected by preservation in high potassium solutions. Future studies employing the arterial and venous double occlusion technique described by Hakim et al. to determine segmental vascular resistances [27] [28] should provide a more detailed insight into the effects of preservation on the pulmonary vascular bed. Clinically, prostacyclin or prostaglandin E1 is often added to EuroCollins solution to attenuate this effect [29] but this practice is now questioned following reports that prostaglandins may have a detrimental effect on lung preservation [30] [31]. The EC solution used in this study also differs from that used clinically in some centres in not being further modified by the addition of magnesium [32]. A number of low potassium solutions have been tested in experimental models of lung preservation [8] [9] [10] [12] [13] and found to allow longer preservation periods than high potassium solutions such as EuroCollins, suggesting that this may be a more effective approach to this problem. The data presented here are consistent with the hypothesis that very high potassium solutions are less effective in lung preservation although it must be borne in mind that the BB and STH solutions employed here differ from EC solution in other aspects of their ionic composition in addition to potassium ion concentration. Indeed, STH solution was less damaging to lungs than BB despite having a moderately higher potassium concentration. This is in line with studies by other authors which suggest that there may not be a straightforward linear relationship between the potassium concentration of the storage medium and the degree of damage occurring on reperfusion [33].

The modified bicarbonate buffer used in this study contained 2% bovine serum albumin as an additive to increase the osmotic pressure of the buffer and counteract oedema formation [34]. We therefore hypothesized that this should also improve its properties as a storage solution. However, the deterioration seen in compliance in lungs stored for 6 h in BB was comparable to that seen after 6 h in STH which contained no macromolecular component. Control perfusion with BB, without storage, also caused a significant increase in wet:dry weight ratio. This finding is in line with other reports on isolated rat lungs perfused with buffer and ventilated at positive pressure [20] [34] [35] and may contribute to the lack of a clear cut effect.

To conclude, this relatively simple, buffer-perfused, isolated and ventilated rat lung preparation shows a time-dependent decline in function following hypothermic storage and displays differing responses to storage in different solutions. As such, it offers a useful model system for exploring the effects of long term preservation in the lung without the relative expense, or complexity, of some previously described models such as the use of perfused rat lungs with a support animal [36] or canine lung transplantation [37].


   Acknowledgments
 
This work was supported by grants from STRUTH and the British Heart Foundation


   References
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
References
 

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