Eur J Cardiothorac Surg 2002;21:1073-1079
© 2002 Elsevier Science NL
Pulmonary preservation with Bretscheider's HTK and Celsior solution in minipigs
Gregor Warneckea,
Martin Strübera*,
Jens M. Hohlfeldb,
Jost Niedermeyerb,
Sebastian P. Sommera,
Axel Havericha
a Department of Thoracic and Cardiovascular Surgery, Hannover Medical School, 30623 Hannover, Germany
b Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
Received 18 April 2001;
received in revised form 15 February 2002;
accepted 15 February 2002.
* Corresponding author. Tel.: +49-511-532-6588; fax: +49-511-532-8446
e-mail: strueber{at}thg.mh-hannover.de
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Abstract
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Background: Pulmonary preservation with high potassium/low oncotic pressure Euro-Collins (EC) solution is associated with endothelial dysfunction and reduced surfactant function. We compared two low potassium solutions, histidine-tryptophane-ketoglutarate (HTK) and Celsior, to EC in lung ischemia-reperfusion injury. Methods: In 19 minipigs, the left lung was perfused in situ with cold preservation solution (EC, n=6; HTK, n=6; Celsior, n=7). Reperfusion was started after 90 min of warm ischemia. The right pulmonary artery and main bronchus were clamped. Bronchoalveolar lavage (BAL) was obtained before ischemia and after 2 h of reperfusion. Surfactant activity was determined from the BAL in a pulsating bubble surfactometer. Results: Animals in the EC group survived 3.7±1.4 h. Six Celsior and five HTK treated animals survived the observation period of 7 h (P<0.001). Compliance of the reperfused lung deteriorated less in both Celsior and HTK groups (P<0.001). In EC and HTK animals, the pO2/FiO2 ratio was lower (P=0.002), and pulmonary vascular resistance was higher (P=0.02) than in Celsior animals. Surfactant function was impaired after reperfusion in all groups. Conclusions: Compared to EC, HTK solution showed moderate and Celsior distinct improvement of post-ischemic pulmonary function. However, surfactant function was not well preserved in any group.
Key Words: Ischemia-reperfusion injury • Lung transplantation • Celsior solution • Surfactant function
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1. Introduction
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Ischemia-reperfusion injury remains a common cause for early morbidity after pulmonary transplantation [1]. Euro-Collins solution (EC) has been extensively used in clinical pulmonary preservation until recently [2]. It provides an intracellular electrolyte composition and its high potassium concentration has been associated with endothelial cell injury, causing pulmonary vasoconstriction and edema formation [3,4]. Above that, high potassium solutions have been found to impair the preservation of isolated type II pneumocytes [5]. We previously reported on markedly improved pulmonary preservation comprising well maintained surfactant function in our established minipig model of lung ischemia-reperfusion injury after perfusion with low potassium dextran (LPD) solution [6] and on superior clinical results after application of LPD [7].
If the potassium concentration would determine preservation properties of a perfusion solution for lung preservation, then a well defined solution of extracellular composition, such as Bretschneider's histidine-tryptophane-ketoglutarate (HTK), which is used for cardioplegia and for solid organ preservation prior to transplantation, should provide improved pulmonary preservation comparable to the above mentioned intervention. Another more recently developed solution of extracellular electrolyte composition is Celsior. Primarily developed for heart transplantation, Celsior showed improved pulmonary graft preservation in several experimental models in rats [8–10].
Bretschneider's HTK solution has occasionally been used by some transplant programs for clinical lung preservation, however it has not been evaluated precisely in experimental pulmonary preservation yet. To our knowledge no large animal model for application of Bretschneider's HTK or Celsior solutions in lung preservation has been published. The purpose of our study was to evaluate initial graft function after preservation with Celsior or Bretschneider's HTK solutions in comparison to EC as the clinical standard of many years. In addition, surfactant function analysis was carried out as a sensitive parameter for the quality of lung preservation.
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2. Material and Methods
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2.1. Experimental design
Left lungs of 19 minipigs were preserved by flush perfusion with cold (4 °C, 40 ml/kg) Celsior solution (n=7), HTK solution (n=6) or EC solution (n=6) in situ. The left lungs remained ischemic for 90 min without additional cooling and under continued ventilation thereafter. Upon 10 min of left lung reperfusion the right main bronchus, right main pulmonary artery and right upper lobe artery were clamped. During the observation period of 7 h the animals were kept fully dependent on left lung function. The quality of lung preservation was compared among groups by means of analyses of sequential measurements of arterial oxygenation index, dynamic lung compliance, pulmonary vascular resistance (PVR) and surfactant function.
2.2. Animal preparation
In 19 minipigs (Ellegaard, Denmark, weight range 25–35 kg), anesthesia was induced with azaperon (5 mg/kg, i.m.), atropine (0.5 mg total dose, i.m.) and 15 mg/kg thiopental sodium intravenously. Animals were intubated and underwent pressure controlled mechanical ventilation with pmax=30 cm H2O, positive end-expiratory pressure=5 cm H2O, FiO2=0.5 and I:E=1:1. The mechanical ventilation settings were not changed during the experiment. Maintenance anesthesia was administered intravenously as a continuos thiopental sodium (5 mg/kg per h) and fentanyl (1 µg/kg per h) infusion. A Swan–Ganz catheter was inserted into the right internal jugular vein and a carotid artery catheter was used for monitoring systemic arterial pressure. All animals received humane care in compliance with the ‘Principles of Laboratory Animal Care’ 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 publication No. 85-23, revised 1985).
2.3. Bronchoalveolar lavage
A fiberoptic bronchoscope (Olympus P10, Tokyo, Japan), wedged into a segmental bronchus of the right middle lobe (before surgery), or into the lingula of the left lung (after 2 h of reperfusion) was used for bronchoalveolar lavage. Five aliquots of 20 ml saline were instilled. Following instillation, each aliquot was aspirated with gentle suction, the bronchoalveolar lavage fluid (BALF) was pooled and the recovered volume recorded. After filtration through sterile gauze and centrifugation at 150xg for 10 min, the cell-free supernatant was frozen at -80 °C until further analysis. From the cell pellet the total number of cells in the BALF was counted and a manual differential cell count was performed using standard techniques.
2.4. Operation
The pericardium was opened via a left thoracotomy in the fourth intercostal space. A catheter was inserted into the left atrium for blood sampling and pressure measurement. The left and right pulmonary arteries and the right main bronchus were encircled with umbilical tapes for subsequent snaring. Heparin sodium (200 units/kg) was administered intravenously. A cannula to infuse preservation solution was inserted into the left pulmonary artery and secured by tightening the umbilical tape. The left pulmonary veins were clamped and incised. Under continued ventilation, the left lung was flushed for 5 min with cold (4 °C, 40 ml/kg) preservation solution. Animals were alternately assigned to one of the following groups: modified EC (n=6, EC kidney perfusion solution, Fresenius AG, Bad Homburg, Germany), Bretschneider's HTK (HTK, n=6, Custodiol®, Dr F. Köhler Chemie, Alsbach-Hähnlein, Germany) or Celsior (n=7, Pasteur Mérieux Sérums et Vaccins, Lyon, France) solution (Table 1). Thereafter, the incisions in the pulmonary veins were suture-closed. After 90 min of warm ischemia and 10 min of reperfusion of the left lung, epinephrine infusion was started at a rate of 0.5 µg/kg per min and the right pulmonary artery and main bronchus were clamped. A part of the right lower lobe was excised for determination of lung water content. Additional right lung tissue samples were harvested and immediately snap frozen for histology. The chest was temporarily closed and a body temperature of 36.0 °C was maintained. Arterial and venous blood gas analyses, dynamic lung compliance and hemodynamic parameters were recorded at 30 min intervals during 7 h of reperfusion. Blood gases were measured on a blood gas analyzer (Ciba Corning, USA) and dynamic lung compliance was monitored continuously using a modified Evita II ventilator (Dräger, Lübeck, Germany). After 7 h, experiments were terminated with an overdose of sodium pentobarbital. Criteria for early termination of the experiment were low systemic arterial blood pressure (pmean<40 mmHg) or an arterial oxygenation index of <100 mmHg. Lung tissue samples from the left lower lobe were obtained for measurement of lung water content or snap frozen for histology.
2.5. Phospholipid analysis
BALF specimens from the right lungs before and from left lungs after the ischemia/reperfusion cycle were analyzed. Aliquots of the cell-free supernatant were used for determination of phospholipid concentrations according to the method of Bartlett [11]. This assay is based on a phosphorus determination carried out on the lipids extracted with chloroform/methanol [12]. All assays were performed in two separate samples and the mean value was reported.
2.6. Surfactant aggregate isolation
For surfactant isolation, the cell-free supernatant was centrifuged at 48,000xg for 60 min at 4 °C to pellet large surfactant aggregates (LA). The supernatant, containing small surfactant aggregates (SA), was removed and the LA pellet was resuspended in Ringer's solution. The phospholipid contents of the LA pellets and the SA supernatants were determined as described above. By adding Ringer's solution, the phospholipid concentration of the LA suspension was adjusted to 1 mg/ml for studying surface properties with the pulsating bubble surfactometer.
2.7. Surface activity evaluation with the pulsating bubble surfactometer
The surface activity of BALF was measured with a pulsating bubble surfactometer (Electronetics, Buffalo, NY) [13]. Briefly, 40 µl of the LA suspension was used for filling the sample chamber. Before starting bubble pulsation, the initial surface tension after bubble formation (
o) was measured. The adsorption rate was evaluated by determining the surface tension 10 s after formation of a bubble (ads). Minimal surface tension (min) was determined as the value at minimal bubble size after 5 min of bubble pulsation at a rate of 20 cycles/min at 37 °C.
2.8. Histology
Sections of 5 µm thickness were cut from several levels of frozen right and left lung tissue samples with a cryotome (Leica, Germany) and stained with hematoxylin and eosin using standard techniques. Histological evaluation on each section was performed using a score of 0–3 for neutrophil counts, interstitial thickening and for alveolar edema.
2.9. Statistical analysis
Data were expressed as means±standard deviation (SD). Analysis of continuous data was performed by repeated-measures analysis of variance (ANOVA) [14]. If data were compared to the control (EC-) group, repeated-measures ANOVA was restricted to 3 h of follow-up, due to that group's short survival. Data without repeated measurements were analyzed by one-way ANOVA. If differences were found, the Bonferroni post-hoc test was used for significance testing: P values less than 0.05 were considered significant.
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3. Results
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3.1. Animal survival
Left lungs preserved for 90 min of warm ischemia with EC solution rapidly failed after reperfusion and animals developed severe right heart failure (mean survival of control animals 3.7±1.4 h, n=6). In the HTK (n=6) and Celsior (n=7) groups all but one animal from each group survived the observation period of 7 h. Survival was significantly prolonged in both HTK- and Celsior-flushed groups (P<0.001).
3.2. Hemodynamic and respiratory parameters
The arterial pO2/FiO2 ratio was not improved in lungs preserved with HTK as compared to lungs preserved with EC. Animals with Celsior-flushed lungs showed significantly improved arterial oxygenation throughout the experiment compared to both other groups (P=0.002, Fig. 1)
. Dynamic compliance of the lung was significantly better preserved in both HTK and Celsior preserved lungs than in the EC group (P<0.001, Fig. 2)
. A trend towards higher values in Celsior animals compared to HTK animals after reperfusion was statistically not significant (P=0.3). An early rise in PVR resulted in right heart failure in EC animals (Fig. 3) . Both HTK and Celsior treated animals also showed a substantial rise in PVR, which did not differ significantly from the EC group (P=0.6), and continued to increase during the observation period. PVR was significantly lower in the Celsior group, as compared to HTK animals (P=0.02).
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Fig. 1. PO2/FiO2 ratio in arterial blood samples drawn from the left atrium over 7 h of reperfusion. Data are shown as the mean±SD. Ratios before surgery (0) did not differ significantly among groups. *Significant difference in PO2/FiO2 ratio in the Celsior group when compared to the HTK and EC groups (P=0.002, repeated-measures ANOVA).
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Fig. 2. Dynamic compliance of the lung over 7 h of reperfusion. Data are shown as the mean±SD. Before surgery (0), values did not differ significantly among groups. Clamping the right main bronchus after 15 min of reperfusion caused a significant decrease of dynamic compliance in all groups (P<0.05, paired Student's t-test). *Significant elevation in dynamic compliance in both Celsior and HTK groups when compared to the EC group (P<0.001, repeated-measures ANOVA).
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Fig. 3. PVR over 7 h of reperfusion. Data are shown as the mean±SD. PVR did not differ significantly among groups before surgery (0). Clamping the right main pulmonary artery caused a significant increase in PVR in all groups (P<0.05, paired Student's t-test). PVR was not significantly different among groups during the first 3 h of reperfusion. *After more than 3 h of reperfusion, PVR was significantly lower in the Celsior group when compared to the HTK group (P=0.02, repeated-measures ANOVA).
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3.3. Lung water content
Lung water content was significantly increased in left lungs after 7 h of reperfusion in all groups when compared to native right lungs (wet/dry ratio: 8.36±1.73 vs. 9.17±2.28 vs. 7.98±2.14 vs. 5.41±0.66 for EC, HTK, Celsior and native right lungs, respectively, P=0.0004). After reperfusion, the wet/dry ratio of left lungs was lowest in Celsior animals, however, differences were not statistically significant among groups.
3.4. Bronchoscopic lavage fluid analysis
All animals showed normal cell counts without significant differences among groups in BALF from right lungs with a predominance of macrophages (around 90%) before surgery. After reperfusion, the overall cell count was slightly increased in all groups in BALF from left lungs. This increase was due to a rise in neutrophil counts. The increase in the percentage of neutrophils was most pronounced in control animals, less evident in the Celsior group and least pronounced in HTK treated animals (Table 2). The phospholipid content in BALF was not different among groups at baseline. After 2 h of reperfusion the phospholipid content was increased in all groups (Table 2). The ratio of SA to LA was determined as an indicator for metabolic conversion of the surfactant material. The SA/LA ratio was low under baseline conditions in all groups and increased substantially after 2 h of reperfusion in the control group (P=0.02, Table 2). The SA/LA ratio was also increased in HTK and Celsior animals, although not significantly.
3.5. Surface activity evaluated with the pulsating bubble surfactometer
The adsorption rate ads, defined as the surface tension of the uncycled bubble 10 s after bubble formation, was approximately 28 mN/m in all groups at baseline (right lungs, Table 2). After 2 h of reperfusion, ads was increased in all groups. In the EC group, ads was more increased than in HTK or Celsior animals (Table 2). The mean surface tension at minimal bubble size after 5 min of pulsation (min) was 2 mN/m in all groups at baseline (Fig. 4)
. After reperfusion, min increased in all groups. Differences among groups were not significant.
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Fig. 4. Surface tension at minimal bubble size after 5 min of bubble pulsation (min) in BALF before surgery (BAL I) and 2 h after reperfusion (BAL II). Each column represents the mean±SEM of n=6 animals.
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3.6. Histology
Severe histologic lung injury was evident in left lungs in the EC group with alveolar edema, neutrophil infiltration and interstitial thickening. While these changes were present in all groups, they were less prominent in HTK and Celsior treated animals. Histology from native right lungs showed normal tissue in all groups.
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4. Comment
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Ischemia-reperfusion injury has an important impact on clinical results after lung transplantation [15]. In a recent retrospective study, King et al. found an incidence of severe ischemia-reperfusion damage in 22% of lung recipients, contributing to an ultimately fatal outcome in 9%, when EC was used for graft preservation [1]. Flush perfusion with EC has been the standard technique for 15 years [16]. The quest for optimized lung protection has led to experimental evaluation of several new preservation techniques [17,18].
In recent years, increasing evidence on the advantage of low potassium ‘extracellular’ solutions has emerged [19]. The ‘intracellular’ ion composition – and thus the high potassium concentration – of the original EC solution had aimed at reducing transmembrane gradients, thereby reducing energy expenditure. This potassium concentration, however, has been associated with vascular spasm, endothelial dysfunction and type II pneumocyte dysfunction in preserved lungs [3–5].
LPD solution has been shown to improve pulmonary preservation in a variety of experimental setups [5,6,20,21]. In an ex situ rat lung model Celsior solution showed superior lung function upon reperfusion when compared to EC and LPD [22]. No experimental evidence exists for the use of Bretschneider's HTK solution in pulmonary transplantation. Bretschneider's solution was developed two decades ago and is widely used for cardioplegic arrest in open heart surgery as well as for liver and kidney transplantation [23–25]. We have previously reported on the beneficial effect of LPD in our minipig model of lung ischemia and reperfusion [6]. In this model we have now investigated the effect of Celsior and Bretschneider's HTK solutions as compared to EC. The experimental ischemic load of 90 min of warm ischemia of the left lung in minipigs with subsequent ligation of the right pulmonary artery and main bronchus leads to a reliable and reproducible severe reperfusion injury, invariably causing death from right heart failure in the EC group within 2–5 h of reperfusion. All injuries seen in left lungs are due to ischemia and reperfusion, since confounding variables such as rejection or anastomotic stenoses are excluded. An important potential restriction of this model could be considered to be the difference between the experimental extended warm ischemia after an initial flush with 4 °C solution and the clinical setting of extended cold ischemia before reperfusion. However, as we discussed previously [6,26], all important changes related to severe ischemia-reperfusion injury in the clinical setting – i.e. low arterial oxygenation index, increased PVR, decreased compliance and high permeability edema – are evident in our model. Therefore, 90 min of warm ischemia appear to provide a model of accelerated reperfusion injury equivalent to a considerably longer cold ischemic period.
Our results support previous findings in that EC solution may not be optimal for clinical lung preservation. Both extracellular solutions tested in this study compare favorably, giving improved survival and better lung function after 1.5 h of warm ischemia. Pulmonary edema was least pronounced with Celsior solution, resulting in a significant advantage in arterial oxygenation in comparison to Bretschneider's HTK solution. Severe hypoxemia developed in all animals of the EC group during reperfusion. Among the solutions tested, Celsior preservation resulted in the best post-ischemic pulmonary function. This could be due to the fact that only Celsior solution contains antioxidant compounds (Table 1). PVR increased markedly in EC but also in HTK animals. Thus, the right ventricle in these animals eventually had to handle an elevated afterload similar to EC animals, presumably leading to similar, but only delayed, right heart failure. Although PVR was lower in the Celsior group, there was still a steady rise. The dynamic compliance of the lung was initially better preserved in Celsior and HTK treated lungs, but showed a tendency to decrease in all groups during the observation period. This differs from results obtained from previously published studies in the same model after lung preservation using LPD solution [6] or using combined NO ventilation and exogenous surfactant substitution [26]. LPD and surfactant/NO animals revealed stable PVR and stable dynamic compliance during the observation period.
While survival was prolonged in Celsior and also HTK animals (during the limited course of observation applied in this study), none of the preservation solutions could maintain surfactant function. This is shown by an increased SA/LA ratio and increased minimal surface tension as determined in the bubble surfactometer in all groups after reperfusion. Thus, surfactant activity was severely depressed to a degree which would translate into clinical problems for at least a transitional period in the clinical situation. In an earlier study using the same minipig model to assess LPD solution, no such reduction of surfactant function was found. Therefore, HTK and Celsior solutions provide inferior preservation of surfactant function, although all three solutions (LPD, Celsior and HTK) are of extracellular electrolyte composition. However, since our model represents a worst case scenario, HTK and Celsior might still be considered as suitable preservation solutions, which are clearly superior to EC. The potassium concentration of a preservation solution for pulmonary transplantation is an important variable and explains the superiority of all three extracellular solutions compared to EC. However, differences with respect to surfactant preservation rely on additional factors which are not yet completely understood. Plasma protein inhibition probably is the single most important cause of early surfactant dysfunction after lung injury [27,28]. Plasma protein exudation into the alveolar space is a consequence of reperfusion edema formation due to pulmonary endothelial dysfunction [17]. Therefore, it could be speculated that this is counteracted more effectively by the high molecular dextrane content of LPD solution than by the relatively low molecular mass components of Celsior or HTK solutions (Table 1).
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Acknowledgments
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The authors thank Claudia Kelle, Adine Timke and Jost Dörr for their invaluable assistance. This work has been supported in part by Dr F. Köhler Chemie, Alsbach-Hähnlein, Germany.
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Abstract
1. Introduction
