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Ann Thorac Surg 2002;73:226-232
© 2002 The Society of Thoracic Surgeons

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Original article: general thoracic

Pulmonary blood flow is inhomogeneously reduced after Euro Collins-preservation and lung transplantation

^a Anesthesiology and Intensive Care Medicine, Cardiothoracic Surgery, University of Essen, Essen, Germany
^b Cardiothoracic Surgery, Institute of Medical Epidemiology, Biostatistics and Informatics, Martin Luther University of Halle, Halle, Germany

Accepted for publication September 25, 2001.

* Address reprint requests to Dr Friedrich, Cardiothoracic Surgery, Martin-Luther-Universitat Halle, Ernst Grube Str 40, 06097 Halle, Germany
e-mail: ivar.friedrich{at}medizin.uni-halle.de

	Abstract

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Background. Vasoconstriction after lung transplantation is a well-known phenomenon, but only limited information is available on blood flow distribution after ischemia and reperfusion. The aim of our study was to determine the regional flow characteristics in transplanted and native dog lungs after 24 hours of cold storage and preservation with Euro Collins-solution.

Methods. Six pairs of weight-matched Foxhounds (25 to 30 kg) were used. In donors and recipients, aortic and pulmonary artery catheters were inserted percutaneously and a reference withdrawal catheter was placed into the main pulmonary artery. For preservation, the lungs were perfused with modified Euro Collins-solution and stored at 4°C. After 24 hours, the left lung was transplanted. Regional pulmonary blood flow was assessed by injection of colored microspheres into the right atrium using the reference withdrawal technique. Measurements of regional pulmonary blood flow were conducted twice in donors and recipients (baseline and 3 hours after reperfusion). Tissue samples from five distinct regions (apical, medial, dorsal, ventral, and lateral) were taken to assess regional pulmonary blood flow and wet–dry ratios.

Results. The relative ( Confidence Intervals/100 mg dry weight) regional pulmonary blood flow was significantly reduced in the transplanted lung but not in the native organ. This reduction was most pronounced in apical regions and smallest in regions close to the hilum. Edema formation occurred in both lungs, as judged from wet-to-dry ratios of lung tissue specimen.

Conclusions. Two separate processes can be observed after single lung transplantation: (1) reduced regional pulmonary blood flow, which is a regional phenomenon restricted to the transplanted organ, and (2) extensive edema affecting both the transplanted and the native lung.

	Introduction

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Severe deterioration of gas exchange and decreased compliance are frequently observed early after lung transplantation, and represent a major clinical management problem [1]. This dysfunction has been attributed to ischemia and subsequent reperfusion of the transplanted organ and is commonly referred to as "ischemia-reperfusion injury" (IR-injury). It is characterized by increased microvascular permeability and elevated pulmonary vascular resistance. A variety of factors and mechanisms have been identified to contribute to IR-injury including free radicals, the release of inflammatory mediators, endothelial adhesion, and influx of neutrophils [2]. Conflicting results, however, have been published with regard to pulmonary blood flow distribution: a significantly increased vascular resistance or reduced regional pulmonary blood flows (rPBF) were reported after ischemia and reperfusion in isolated lung preparations [3] and in intact animals [4], whereas other authors demonstrated no reduction of rPBF in an intact animal model [5] or increased rPBF in human patients [6].

The current study aimed to address several questions: (1) What is the difference in blood flow between the transplanted and the native organ? (2) Is the blood flow distribution different in different lung areas? (3) Does the increased pulmonary resistance after ischemia and reperfusion depend on edema formation?

	Material and methods

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Donor preparation
Six Foxhounds (25 to 30 kg) were anesthetized with Thiopentone (30 mg/kg), intubated and ventilated in a volume controlled manner (Evita II, Dräger, Lübeck, Germany) to maintain the blood pCO₂ between 30 and 40 mm Hg (tidal volume: 20 ml/kg body weight). Ventilation pressures were registered by the ventilator (EVITA IV, Drager, Germany) and recorded once preoperatively and hourly after reperfusion. Anesthesia was maintained with fentanyl (0.7 mg/h), midazolam (5 mg/h), and rocuronium (15 mg/h) via continuous infusion, and an additional 1.5 mg dose of Fentanyl was administered just prior to thoracotomy.

Aortic and pulmonary artery catheters were placed percutaneously for pressure and cardiac output measurements. A lateral thoracotomy was performed under sterile conditions. Pressure transducers were positioned at mid-heart level and referenced to the atmosphere; cardiac output was measured with the thermodilution method from the mean of three injections. Prior to lung dissection, a reference withdrawal catheter was inserted into the main pulmonary artery and the chest was closed. The animal was then brought into the prone position on a vacuum mattress and rPBF measurements were made. After returning the animals to the lateral position, the thorax was re-opened, the animals were heparinized, the lungs were perfused with modified Euro Collins-solution (EC) (60 ml/kg), inflated with oxygen at 30 cmH₂O, and heart and lungs were excised en bloc and stored at 4°C for 24 hours. Modified EC-solution (100 µg/l PGE₂ added) was infused into the pulmonary trunk from a height of 40 cm, resulting in a perfusion pressure of 30 mm Hg. The time needed to infuse 1,500 ml EC was about 4 minutes.

Recipient preparation
Anesthesia and instrumentation were as described above. Again, microsphere measurements of rPBF were obtained in the lateral and prone position prior to excising the recipient’s left lung. Two endotracheal tubes, one in the trachea and one in the left main bronchus, were inserted via tracheostomy, allowing separate but synchronized ventilation of each lung by two Evita II ventilators ("master and slave" mode). Ventilation was performed with constant volumes at a rate of 10 min^-1 with the right lung receiving 60% and the left lung 40% of the total tidal volume. Ventilation was adjusted to maintain normocapnia in lung veins of either side, and was then left unchanged for the remainder of the experiment. One hour after reperfusion, the chest was provisionally closed and microsphere flow measurements were performed. At the end of the surgical procedure, the animals were positioned prone and remained in that position until the end of the observation period. Three hours after reperfusion, a last measurement of rPBF was conducted. After the observation period, the animals were exsanguinated and the lungs excised.

Hemodynamic monitoring
A femoral-arterial and a pulmonary-arterial catheter (Swan-Ganz, Baxter Healthcare, Irvine, CA) were placed percutaneously to characterize pulmonary and systemic hemodynamics, and for blood sampling. Intravascular (Millar Micro Tip, Millar Instruments Inc, Houston, TX) pressure transducers were positioned at mid-heart level, referenced to the atmosphere, and were used to record mean arterial pressure (MAP), mean pulmonary arterial pressure (PAP) and left atrial pressure (LAP). Using a Sirecust 9000 Monitor (Siemens Medical Products, Erlangen, Germany), cardiac output (CO) was assessed by thermodilution and cardiac index (CI), systemic vascular resistance index (SVRI), and pulmonary vascular resistance index (PVRI) were calculated according to standard formulas. Body surface area (BSA) was calculated as follows: BSA[m²] = (0.1*[kg body weight]^2/3).

Lung function
Central venous, arterial, and left and right pulmonary venous blood samples were withdrawn hourly. Measurements included blood gas analysis, hemoglobin and potassium concentrations which were determined with a blood gas analyzer (ABL 4, Radiometer, Copenhagen, Denmark). Similarly, dynamic ("ventilator") compliance, mean and peak ventilation pressures, and minute volume were obtained from the ventilator on an hourly basis.

Flow measurements
Six million colored microspheres (15 µm, Triton, San Diego, CA) were carefully vortexed in 10 ml of saline and then injected into the right atrium of donors and recipients. Microspheres (red, blue, violet, and yellow, in random order) were injected over four respiratory cycles at two time intervals: (1) prior to transplantation (baseline); (2) 3 hours after onset of reperfusion. At the same time, cardiac index measurements were performed. At the end of the experiment, tissue samples (approximately 3 to 4 cm³) were obtained from five different regions of each lung: apical, lateral, medial, ventral, and dorsal. Details of this procedure have been described by Kowallik and associates [7]. The ratio of the number of microspheres in the reference sample (N_ref) and the (known) reference flow (F_ref) equals the quotient of the number of microspheres in the region of interest (N_ri) to the (unknown) flow to the region of interest (F_ri). Thus, rPBF (ml/min) is obtained by solving the equation F_ri = F_ref*N_ri/N_ref. Fractional pulmonary blood flow was calculated as follows: rPBF/cardiac index = of the CI at the timepoint when microspheres were injected.

Regional pulmonary vascular resistance
Regional vascular resistances (rPVR) are calculated from the quotient of the transpulmonary pressure gradient (mean PAP–PCWP) and the rPBF. In the transplanted and the native lung, these data were obtained from different regions (lateral, medial, apical, ventral, dorsal) at baseline (before clamping) and at 3 hours of reperfusion.

Wet-to-dry-ratio
Wet-to-dry ratios were separately calculated for both lungs of donor and recipient. The donor’s right lung served as control for the recipient’s right lung after transplantation and the recipient’s left lung served as control for the donor’s left (transplanted) lung, respectively. Thus, we could obtain normal values for right and left lungs before and after transplantation.

Statistical methods
Data are presented as mean ± standard error of the mean (SEM) unless otherwise stated. For statistical analysis, we selected nonparametric techniques (signed rank test, nonparametric analysis of variance [ANOVA]) whenever possible, to account for possible non-normality of data and small sample sizes. If required, analyses allowed for the fact that measurements were repeatedly (in time course and different regions) taken from the same dogs [8]. Pairwise comparisons were Bonferroni adjusted to avoid spurious significances. We set up nonparametric repeated measurement ANOVA models to assess differences in regions, time points, and lungs for fractional blood flow and resistance. Hemodynamic parameters (MAP, PAP, PCWP, PVRI, SVRI) were compared by means of the signed-rank test. Due to convergence problems, we had to specify a parametric (assuming normality of data) repeated measurement ANOVA model to estimate the effect of time and specific lung on ventilation pressures. According to our experience, this approach leads to more conservative results compared with nonparametric analysis. All calculations were performed by SAS Version 8e (SAS Institute, Inc, Cary, NC).

The study was approved by the local authorities and all animals received humane care in compliance with the "Principles of Laboratory Animal Care" published by the National Institutes of Health (NIH publication no. 85-23, revised 1985).

	Results

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Hemodynamic parameters
During the entire procedure of transplantation and reperfusion, all animals were hemodynamically stable and did not require any catecholamine therapy (Table 1). Cardiac index (2.21 ± 0.07 versus 2.96 ± 0.06 l/min*m²) increased significantly from baseline to 3 hours of reperfusion with a concomitant decrease in systemic vascular resistance index (SVRI baseline: 2,385 ± 145.42 dyne; 3 h rep: 1,699.7 ± 41.06 dyne; p < 0.05) and mean arterial pressure (MAP: 71.17 ± 3.0 versus 66.7 ± 0.95 mmHg, respectively).

View larger version (24K): [in this window] [in a new window]   Fig 1. Fractional pulmonary blood flows of the transplanted organ before (baseline) and after reperfusion (3 h) in different lung regions. Data were calculated as of the cardiac index/100 mg dry weight of the lung samples (mean ± SEM); statistical significance is indicated. (CI = cardiac index.)

View larger version (18K): [in this window] [in a new window]   Fig 2. Regional blood flow changes as calculated from the difference between pre-transplantation (baseline) and 3 hours of reperfusion. The bars represent the differences of each lung of an individual animal before and after reperfusion (n = 6). Data are presented as mean ± SEM. (CI = cardiac index; NAT = native lung; TX = transplanted lung.)

View larger version (31K): [in this window] [in a new window]   Fig 3. Regional pulmonary vascular resistance (rPVR). Left: rPVR for transplanted lungs; middle: rPVR for native lungs. These data were calculated as transpulmonary gradient/fractional blood flow. Right: Total pulmonary vascular resistance (tPVR) calculated with thermodilution method. Data are presented as mean ± SEM (n = 6); *p < 0.05 (comparison of baseline versus 3 hours reperfusion); ***p < 0.001.

View larger version (32K): [in this window] [in a new window]   Fig 4. Wet-to-dry ratios of baseline (removed recipient lung), preserved (preserved and stored but not transplanted right donor lung) native (right recipient lung), and transplanted (TX) lungs before and after reperfusion. Data are presented as mean ± SEM (n = 6); statistical significance is indicated. (n.s. = not significant.)

	Comment

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Taking into account these limitations, nevertheless, we observed severe alterations in regional blood flow of the transplanted organ that were also likely to occur in clinical conditions. Increase in pulmonary vascular resistance and decrease of pulmonary compliance with concomitant deterioration of gas exchange are the primary symptoms of the pathology of reperfusion injury. In order to see worse deterioration of organ function, our model was designed for an extended storage time of 24 hours. Several modifications to common transplantation models were necessary to separate pathophysiological changes caused by ischemia and reperfusion from model-related influences. If both lungs are ventilated through the same endotracheal tube in standard transplantation models, reperfusion-induced changes of the transplanted lung cannot be assessed well, as decreasing compliance in the transplanted lung will direct an increasing fraction of the applied tidal volume to the native lung, thereby subjecting the transplanted lung to hypoventilation. In the current model, the lungs were ventilated separately but in a synchronized manner, using a master–slave setting in order to prevent the tidal volume from shifting from the transplanted lung (poor compliance) to the native lung (good complicance). Separate ventilation in a pressure-limited and volume-controlled mode ensures a near-normal gas exchange in the transplanted organ, thus rendering an increase in pulmonary vascular resistance due to hypoxic vasoconstriction very unlikely. Furthermore, the animals were in the prone position after chest closure in order to avoid compression of the native lung or gravitational effects on blood distribution. The underlying mechanism of the increase in vascular resistance after IR-injury of the lung is not fully explained. Release of vasoconstrictive substances like endothelin, a lower secretion of vasodilating substances like nitric oxide (NO) [9], or altered angiotensin converting enzyme metabolism [3] are possible explanations. The current therapeutic approach is the inhalative administration of NO [10]. In experimental studies, endothelin inhibitors were proven to be effective [11]. Blood flows were expressed as fractional flow ( of cardiac index/100 mg lung dry weight) for reasons of comparability because of the wide range of the cardiac index during the reperfusion period. Under such conditions, a given region may receive increased flow (due to higher cardiac output) despite marked vasoconstriction (due to the IR-injury). Focusing on fractional flows provides for an unbiased analysis making vascular changes more apparent. Weight normalization was necessary to permit valid comparisons between the time points because, during the experiment, the weights of both lungs increased considerably as indicated by the wet–dry ratios. Samples for flow measurements were obtained from both lungs from five different regions. The different anatomy of the left (two lobes) versus the right (three lobes) lung makes the definition of "corresponding" regions somewhat difficult. On the other hand, the colored microsphere method allows sequential blood flow assessments in the same lung tissue specimen because each region is compared to itself. The comparison of regional blood flows before and after reperfusion is therefore the most important part of our study. Reduced blood flow to the transplanted organ was firstly described by Yanes and colleagues [12]. Malperfusion was apparent after transplantation but not after denervation. Transplanted organs did not regain their preoperative perfusion especially if vasculitis (rejection?) occurred [12]. Similarly, in the current study, blood flows to left lung regions were significantly reduced after reperfusion when compared to fractional pulmonary blood flows before transplantation. This reduction was most pronounced in the apical regions and smallest in the medial regions closest to the hilum. These regional differences correspond well to the findings of Hakim and associates [13] who found a central-to-peripheral gradient of PBF. It has been suggested that the spatial distribution of PBF is to a large extent determined by pulmonary vascular properties. A mathematical model that takes the vessel lengths and three-dimensional branching patterns into account, was shown to accurately predict regional differences in PBF [14]. Thus, the difference in decrease of rPBF between the apical and medial regions can be explained by each region’s different location along the vascular tree. Similar to the regional blood flows, rPVR were also different from one region to the next. Apical regions experienced a marked vasoconstriction resulting in severe hypoperfusion, dorsal regions still demonstrated a twofold increase in rPVR, whereas all regions of the right lung developed only insignificant changes. These findings demonstrate a clearly separate vascular response to the IR-injury in the left as opposed to the right lung. They also indicate that vasoconstriction is limited to the transplanted organ and is hence a regional phenomenon rather than mediated by systemically circulating mediators. Remarkably, the pronounced rise in rPVR was not detectable by PA-pressure measurements: PAP in the main or right pulmonary artery remained unchanged at these points in time. Additionally, the very low flow to the transplanted organ was not evident from pulmonary arterial pressure measurements and not even from calculated pulmonary vascular resistance indices. This result illustrates the sensitivity of our method in detecting microvascular changes, which are inaccessible to conventional measurements of pulmonary hemodynamics. Reduced blood flow after ischemia and reperfusion is a well-known phenomenon which occurs not only after crystalloid preservation with solutions such as EC or University of Wisconsin solution and cold storage [15] but also after warm ischemia [16, 17]. The duration of perfusion with EC adds to the effects on postoperative organ function. Haverich and coworkers demonstrated that a volume of 60 ml/kg EC given over a short time was superior to 20 ml/kg EC with respect to increasing pulmonary vascular resistance and edema formation after transplantation and reperfusion [18]. In our study, perfusion took 4 minutes and preservation was accomplished with 60 ml/kg EC. As pointed out above, significant capillary leakage due to the increased permeability for water and proteins with consecutive pulmonary edema, is a major aspect of pulmonary IR-injury [19]. The donor’s explanted right lung and the recipient’s explanted left lung served as controls (before transplantation) to be compared with the transplanted lung and the native right lung (after transplantation). After reperfusion, both native and transplanted lung developed severe pulmonary edema as expressed by increased wet-to-dry ratios. Similarly to our results, Palazzo and colleagues described a smaller extent of capillary leakage for the native right as compared to the transplanted lung; these authors used entirely different methods to assess leakage [5]. Capillary leakage and pulmonary edema after IR-injury have been interpreted as inflammation-mediated effects. The circulation and ubiquitous presence of inflammatory mediators and PMNs explain the formation of an IR-response not only in the transplanted lung but also in the native, previously nonischemic lung. Several studies address the pulmonary response as organ-specific not only after IR-injury of the contralateral lung but also after ischemia and reperfusion of other organs such as gut or liver. This phenomenon is known as remote injury and may be due to the sensitivity of the lung to inflammatory mediators which are released into the systemic circulation after reperfusion [20]. The permeability increase leads to a large accumulation of proteins in the intraalveolar compartment with subsequent deterioration of surfactant function. This results in decreased pulmonary compliance and increased ventilation pressures [21].

Thus, our results demonstrate that the IR-response after single lung transplantation produces two clearly distinguishable reactions: a pronounced vasoconstriction in the transplanted lung that is locally variable and more pronounced in the peripheral regions, and a mediator-induced deterioration of the endothelial barrier which is apparent in both the native and the transplanted organ. Pulmonary edema is not associated with decreased pulmonary blood flow or increased pulmonary vascular resistance per se. These findings were in line with observations of Boujoukos and associates who pointed out, that the severity of edema formation seen in chest roentgenograms is independent from the blood supply to the transplanted organ in patients with emphysema or pulmonary hypertension [22]. The grade of malperfusion of the transplanted organ cannot be assessed by clinical monitoring with a Swan-Ganz catheter. The prophylactic use of NO in lung transplantation may be of value but must be validated in further studies. Further studies may show beneficial effects of new preservation strategies on pulmonary vascular resistance.

	Acknowledgments

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The study was supported by generous grants from the Hans und Gerti-Fischer Stiftung für Herz- und Kreislaufforschung, Mühlheim, Germany.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Fred H. Splittgerber Ivar Friedrich Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brinkmann, M. Articles by Friedrich, I. Search for Related Content PubMed PubMed Citation Articles by Brinkmann, M. Articles by Friedrich, I. Related Collections Lung - transplantation