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Eur J Cardiothorac Surg 1999;15:481-489
© 1999 Elsevier Science NL
a Department of Cardiovascular Surgery, Albert-Ludwigs-University Freiburg, Freiburg, Germany
b Department of Thoracic and Cardiovascular Surgery, Johann Wolfgang Goethe-University Frankfurt/M., Frankfurt, Germany
c Faculdade de Medicina de Marilia e Faculdade de Medicina de Botucatu, State University of Sao Paulo, Sao Paulo, Brazil
Received 7 September 1998; received in revised form 6 January 1999; accepted 27 January 1999.
Corresponding author. Tel.: +49-761-270-2818; fax: +49-761-270-2550.
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Abstract |
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 Top Abstract Introduction
Material and methods
ResultsDiscussion
References |
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Key Words: Lung transplantation • Lung preservation • Pulmonary+bronchial perfusion
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Introduction |
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TopAbstractIntroduction
Material and methods
ResultsDiscussion
References |
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It has been suggested that the inadequate perfusion of the bronchial vascular bed during PA flush might be a possible mechanism of inadequate pulmonary preservation [4]. The high potassium concentration of certain preservation solutions (e.g. Euro–Collins solution, ECS) producing significant vasospasm of the perfused vascular bed may play a role in this process [5].
The retrograde flush could be an alternative way avoiding vasoconstriction induced by hyperkalemic preservation solution [2] [3]. Retrograde perfusion of isolated lungs has been used extensively for studying the mechanics of the pulmonary circulation [5] [6]. Alternatively, the simultaneous PA and BA flush through an isolated segment of aorta, seems to be a reasonable alternative, since it could reach directly the upper airways contributing for an adequate preservation of these structures [4]. Some physiological studies have used intact and isolated lung preparation for the determination from the different contribution of the bronchial and pulmonary circulation to the upper airways and to the lung parenchyma [7] [8] [9]. However, few studies have been carried out to investigate the distribution of preservation solutions both to lung parenchyma and airways [3] [4].
The present study was performed to investigate the influence of different routes of perfusion on the distribution of the preservation solutions in the lung parenchyma and upper airways in pigs, using systemic pretreatment of the donor with prostacyclin as used in clinical studies.
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Material and methods |
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TopAbstractIntroduction
Material and methods
ResultsDiscussion
References |
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Experimental preparation
The chest was opened by median sternotomy, the pericardium incised and cradled and heparin was administered (600 units/kg i.v.). A high-fidelity micromanometer-catheter (Millar Micro-Tip Catheter Pressure Transducer, Millar Instrument, Houston, TX) was inserted into the left ventricle for measurement of left ventricular pressure. In addition, the left atrium was cannulated to measure left atrial pressure (Isotec Receiver, Hugo Sachs-Electronics March, Freiburg/Br., Germany and Hellige Pressure Transducer, Hellige, Freiburg/Br., Germany). Cardiac output was measured with an electromagnetic flow probe (20 mm flow probe, Gould Flow-meter, Gould Medical Products, Oxnard, CA) positioned around the ascending aorta. All hemodynamic data were recorded on a 8-channel Video-Printer (Hellige, Freiburg/Br., Germany). In control animals, the appendage of the right and left atrium, pulmonary artery and aorta were cannulated with a 7 F catheter for injection of dye-labeled microspheres (DLM) (right and left atrium) and blood sample withdrawal (pulmonary artery and aorta) for dye-reference in blood. The ascending aorta was cannulated with a large bore needle to deliver cardioplegia. The distal thoracic aorta was also isolated.
The pulmonary artery was cannulated with a high-fidelity micromanometer-catheters (Millar Micro-Tip Catheter Pressure Transducer, Millar Instrument, Houston, TX) for measurement of pressure during the ECS-flush, and in the group with simultaneous delivery of ECS, the aortic root was also cannulated (Millar Micro-Tip Catheter Pressure Transducer, Millar Instrument, Houston, TX) through the right common carotid artery for measurement of aortic pressure.
After preparation was completed, the inferior and superior vena cava were occluded and incised, the aorta clamped and cardioplegia was administered. In the PA+BA group, the ascending aorta and distal thoracic aorta were clamped to isolate a 15 cm aortic segment. Immediately the subclavian arteries were clamped along with the left carotid artery. Thereafter, depending upon the route of flush perfusion, the PA, both aorta and PA, or the left atrium were cannulated on the placed purse-string sutures with a 30F-catheter (HKV47P, Jostra, Hirrlingen, Germany) and ECS was delivered. In the two groups with antegrade delivery of ECS the left atrial appendage was amputated to provide additional topical cooling. In the group with retrograde delivery cannulation of the left atrium with a 30 F catheter (HKV47P, Jostra, Hirrlingen, Germany) was done after aortic cross-clamping. Unmodified 4°C cold ECS (Euro–Collins Lösung, Fresenius, Bad Homburg, Germany) was used for lung preservation and storage. A storage period was used because the lungs had to be transported from the experimental or to the laboratory for investigating the colored microspheres. In all ECS perfusion groups, 20 ng/kg (every 10 min) of prostacyclin (Flolan, Wellcome, London, Great Britain) was administered just at the begin of the perfusion. In all experiments, the total volume of ECS administered was 60 ml/kg body weight given by gravity drainage from a height of 60 cm above the lung hilum [18]. This height is equivalent to approximately 80 mmHg which resulted in a pulmonary artery pressure of 10–20 mmHg (Table 1). The differences in these pressures are due to the resistance in the cannula and the tubing which was used for delivering the ECS. During the period of perfusion, the lungs were mechanically ventilated. After cardioplegia and ECS infusion the cannulas were removed, the heart excised, the trachea dissected and divided as far above the carina as possible and both the lung, the left atrial cuff, the pulmonary artery and the segment of aorta were removed as a bloc by blunt dissection. After 2 h of cold storage, biopsy samples were taken from 23 different sampling sites from the anterior and posterior part and assessed for total and regional perfusion (DLM technique) and water content.
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Antegrade delivery of ECS via the PA (n=6)
This group was designed to simulate the commonly used PA flush with 60 ml/kg body weight ECS at 4°C and the cold left atrium effluent was allowed to pool in the chest. In this group prostacyclin (20 ng/kg body weight every 10 min) was administered just before the flush perfusion. The double-lung bloc was stored for 2 h in cold ECS before final measurements were taken.
Simultaneous delivery of ECS via the PA and BA through a segment of aorta (n=8)
ECS was administered simultaneously via the PA and segment of aorta and the cold flush effluent was allowed to pool in the chest. Prostacyclin was administered just before the flush perfusion (20 ng/kg body weight every 10 min). The double-lung bloc was stored for 2 h in cold ECS before final measurements were taken.
Retrograde delivery of ECS via the left atrium and the pulmonary veins (PV) (n=6)
ECS was administered via the left atrium and the cold PA effluent was allowed to pool in the chest. Prostacyclin was administered just before the flush perfusion (20 ng/kg body weight every 10 min). After removal of the heart and storage of the double-lung bloc for 2 h in cold ECS, all variables were determined.
Measurements
Left atrial, left ventricular, pulmonary and aorta pressures
Left atrial, left ventricular, and (according with the perfusion group) pulmonary and aorta pressures were recorded continuously before and during delivery of ECS. PA pressure was not recorded in controls because there was already a cannula in place in this group for collecting the reference sample of the colored microspheres. Including another cannula for pressure measurement would have given unreliable data for technical reasons and therefore, this measurement was not performed.
Cardiac output
Cardiac output was continuously monitored with a flow probe around the aorta and expressed as ml/min. Cardiac index in ml/min per kg body weight was calculated by dividing the cardiac output (ml/min) by body weight (kg).
Total lung flow
Hemodynamic technique
In control experiments total lung flow (ml/min per g lung wet weight) was calculated by dividing cardiac output (ml/min) and lung weight (g). In the preservation studies total lung flow was calculated by dividing the perfusion rate (ml/min) and lung weight (g).
Dye labeled microspheres technique
For calculation of total lung flow, all 20 biopsy samples of both lungs were used and the average of these values represents total lung flow (ml/min per g lung wet weight).
Regional flow in lung parenchyma and airways
Details of the assessment of regional flow in lung parenchyma and airways using the dye-labeled microspheres technique is given in one of our previous publications
[3].
In the simultaneous PA+BA group a suspension of 3.0x106 white-DLM solution diluted in 5 ml saline was injected into the bag containing 2/3 of the ECS calculated (60 ml/kg body weight) and a suspension of 1.5x106 yellow-DLM solution diluted in 5 ml saline was injected into the bag containing 1/3 of the ECS calculated (60 ml/kg body weight) for the same animal. During delivery of ECS, a reference solution sample of 20 ml was withdrawn from the bag. A total of 26 tissue sample weighing 0.5–0.8 g were dissected from the lung bloc and airways. For investigating the flow in the main bronchi, the most distal 2 cm were used (distance between carina and intrapulmonary airways approximately 3 cm).
Intraparenchymal airways were not assessed.
Tissue water content
Biopsy specimens from lung parenchyma, trachea, and bronchi of approximately 0.5–1.0 g were taken and transferred on wax paper to a vial and dried for 24 h at a constant temperature of 80°C in a drying oven (Heraeus, Hanau, Germany). Weighing was done on a precision balance (Mettler, Zürich, Switzerland). Tissue water content is expressed in percent and calculated according to the following equation:
 | (1) |
Lung temperature
Lung temperature was continuously monitored with a temperature probe (Temperatur Sonde, Hellige, Freiburg/Br., Germany) which was inserted into the parenchyma of the left upper lobe to calculate an average start- and end-flush temperature in °C recognizing that there are regional differences in temperature in lung tissue that cannot be determined by single probe application.
Statistics
Statistical analyses were made with the use of the Statview II software package (Abacus Concepts, Berkeley, USA). Multiple groups comparisons were made with the use of analysis of variance (ANOVA). Differences were considered significant at the P<0.05 level. Data are expressed as mean±standard error of the mean (SEM).
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Results |
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TopAbstractIntroduction
Material and methods
ResultsDiscussion
References |
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Lung temperature
Temperature in the lung parenchyma fell from 36.5±0.6 to 17.9±1.8°C in the group with PA flush, from 34.7±0.5 to 20.4±0.7°C in the group with PA+BA flush, and from 35.1±0.7 to 15.6±1.1°C in the group with retrograde delivery of storage solution.
Water content of lung parenchyma and airways (Table 2)
Antegrade (PA, PA+BA) or retrograde flush (PV) did not change the water content of lung parenchyma and airways in comparison with controls.
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In the antegrade PA group, total lung flow (assessed by the DLM technique) was 6.311±1.500, significantly reduced in comparison with control experiments (9.429±1.000 ml/min per g lung wet weight, P=0.0034). In the PV group, the total lung flow was 2.693±0.900 ml/min per g, and significantly reduced in comparison with the PA and control groups (9.429±1.000 ml/min per g, P=0.0034). In the PA+BA group, the lung flow as assessed by the DLM technique was increased to 4.780±0.900 ml/min per g lung wet weight but without statistical difference to the PV group (2.693±0.900 ml/min per g), not significantly reduced to the PA group (6.311±1.500 ml/min per g), and significantly reduced in comparison with controls (9.429±1.000 ml/min per g lung wet weight, P=0.0034).
Regional blood flow in trachea (
Fig. 2
) and bronchi (
Fig. 3
)
Flows in the proximal (5–6 cm above carina) and distal trachea were 0.125±0.018 ml/g per min, respectively, 0.105±0.012 ml/g per min in control experiments and were reduced significantly in PA (0.023±0.007 ml/min per g, respectively, 0.024±0.07) and PV experiments (0.009±0.003 ml/min per g, respectively, 0.021±0.006). In contrast, flow rates were significantly (P=0.0119) increased by PA+BA delivery of the storage solution (0.970±0.400, respectively, 0.380±0.200 ml/min per g).
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Relative flows in the PA+BA group (Table 3)
The major portion of the flows to the airways in this group is provided by the bronchial arteries, and only a minor portion is delivered via the PA.
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Discussion |
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TopAbstractIntroduction
Material and methods
ResultsDiscussion
References |
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Background
In the 20 years after the first human lung transplantation in 1963 by Hardy et al.
[10], airway complications still occur in up to 20% of patients
[11]
[12]. In recent years a reduced incidence of airway complications was achieved by improved operative techniques, e.g. telescoping anastomotic technique of the bronchus, short length of donor bronchus, minimal bronchus dissection during implantation, bronchial artery revascularization
[13]
[14]
[15]. Increasing pulmonary to bronchial artery collateral flow by reducing the incidence of rejection and infection, and improvements in the composition of the preservation solutions also have improved the results
[16]
[17]
[18]
[19]. The rationale for resecting the trachea and carina and shorten the length of the donor bronchus are underlined by our data (
Fig. 2 and
Fig. 3) showing significantly reduced flows in these parts of the airway during antegrade perfusion.
The bronchial circulation supplies systemic arterial blood to the airways, pleura, lymph nodes, nerves and pulmonary blood vessels [20] [21]. Some studies have shown that the contribution from the systemic circulation to the trachea was markedly higher than that from the pulmonary circulation and that the contributions of pulmonary and systemic circulations to blood flow to the distal main bronchi appear to be approximately equal [7] [22]. These studies have also shown that the bronchial circulation has a dual venous drainage, a portion draining into the azygous vein and the remainder entering the pulmonary circulation [22] [23].
During the first few days after transplantation, viability of the donor bronchus must rely on collateral flow from the pulmonary artery, if no attempts are made to revascularize the bronchial artery. It is possible that a variety of parenchymal pulmonary processes such as rejection, infection or edema may reduce this flow during this early critical period. Furthermore, this collateral circulation may be inhibited by inotropic agents used during the immediate postoperative period. It is also reasonable to assume that poor graft preservation may inhibit pulmonary artery to bronchial artery collateral flow because of lung injury or interruption of microvascular circulation [24].
Influence of systemic prostacyclin pretreatment to the donor at the time of organ procurement
In comparison with our previous studies
[3] where either no prostacyclin or prostacyclin added to the preservation solution was used, the present data show no advantage of the retrograde route of lung preservation solution delivery. This confirms our previous hypothesis
[3] that the distribution of preservation solutions in lung parenchyma and airways is greatly dependent on other factors, including the type of prostacyclin pretreatment. In this study, we are able to show that systemic application of prostacyclin results in reduced flow to the airways if the retrograde delivery technique is used
[3]. However, flow to the lung parenchyma was increased during PA flush if systemic prostacyclin pretreatment was used
[3].
Simultaneous PA and BA delivery results in improved airway flow
Lung preservation is performed in most centers using PA flush technique in which the preservation solution may reach the upper airways only through the bronchial-pulmonary anastomoses. Problems with anastomotic ischemic sites in upper airways after PA flush are reduced, but still occur, and it is reasonable to assume that the PA flush technique may be insufficient to reach adequately the airways
[4]. Flow to the airways might even be further reduced if preservation solutions are used that produce significant vasoconstriction, e.g. ECS
[5].
Alternative ways of delivering of lung preservations are represented by the retrograde flush via the left atrium and PV [2] [3] or by the simultaneous PA+BA flush through an isolated segment of aorta [4].
In previous investigations on lung preservation, no attempts have been made to study uniformity of perfusion to lung parenchyma and the airways including all modes of delivery. The present study was therefore designed to investigate the distribution of ECS within the lung and the airways following simple flush perfusion.
We demonstrate a similar pattern of distribution of ECS in lung parenchyma in PA and PA+BA groups, both superior than in the PV group. LoCicero et al. [4] have demonstrated that lungs flushed through both routes had a lower intrapulmonary shunt fraction, were more compliant, and required less work to expand, even though there was only a minor difference in oxygenation. These improvements were mainly related to an apparent improvement in preservation of the airways.
Concerning the flow to the airways in our experiments, there was a significant improvement by simultaneous PA+BA ECS delivery in comparison with the other groups. This increase in flow was due to the delivery of preservation solution via the BA, only minor portions were delivered via the PA (Table 3). In contrast, the PA delivers the major portion of flow to the lung parenchyma.
LoCicero et al. [4] demonstrated better airway preservation with PA+BA flush, but did not quantify the magnitude of the flow improvement nor elucidate the reasons for the improvement in airway preservation. They hypothesized that the reasons could be: more efficient temperature decrease, lavage of plaques, leukocytes and other toxic substances [4].
Whether a better distribution of flow to the lungs and airways would lead to an improved survival of the transplanted lung cannot be answered by our data. However, Haverich et al. [16] have demonstrated a good correlation between quality of distribution of ECS and superior lung oxygenation, less increase in lung water and improved survival. Our experiments have stressed the importance of the bronchial circulation for the airways, and it may speculated that reimplantation of a bronchial artery will reduce airway complications in transplant recipients [15] [26].
Our observation that high flows to the trachea and main stem bronchi only occur if combined PA and BA flush is used, might explain the high failing rate of tracheal and proximal bronchi anastomoses in the past, when only PA flush was used. Furthermore, it underscores the importance of resection of as much bronchi as possible during transplantation, as it is done in most lung transplant programs.
In conclusion, it was demonstrated that the distribution of preservation solution in airways of pigs is significantly improved by simultaneous PA+BA delivery of ECS, is technically easy to perform and may be advantageous in the protection of the airways in lung transplantation.
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References |
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TopAbstractIntroduction
Material and methods
ResultsDiscussion
References |
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This article has been cited by other articles:
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  R. J. Novick Innovative techniques to enhance lung preservation J. Thorac. Cardiovasc. Surg., January 1, 2002; 123(1): 3 - 5. [Full Text] [PDF]
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M. Struber, J. M. Hohlfeld, T. Kofidis, G. Warnecke, J. Niedermeyer, S. P. Sommer, and A. Haverich Surfactant function in lung transplantation after 24 hours of ischemia: Advantage of retrograde flush perfusion for preservation J. Thorac. Cardiovasc. Surg., January 1, 2002; 123(1): 98 - 103. [Abstract] [Full Text] [PDF]
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