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J Thorac Cardiovasc Surg 1999;117:787-793
© 1999 Mosby, Inc.

SURGERY FOR ADULT CARDIOVASCULAR DISEASE

PULMONARY THROMBOENDARTERECTOMY FOR CHRONIC THROMBOEMBOLIC OBSTRUCTION OF THE PULMONARY ARTERY IN PIGLETS

From the Laboratoire de Chirurgie Expérimentale et Département de Radiologie, Centre Chirurgical Marie-Lannelongue, Université Paris Sud, Le Plessis Robinson, France^a; and Department of Surgery, Massachusetts General Hospital, Boston, Mass.^b

Supported by Cook-France Inc, Charenton, France.

Received for publication Aug 11, 1998. revisions requested Oct 30, 1998. revisions received Nov 25, 1998. Accepted for publication Dec 2, 1998. Address for reprints: Elie Fadel, MD, Centre Chirugical Marie- Lannelongue, 133 Avenue de la Résistance, 92250, Le Plessis Robinson, France.

	Abstract

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Objective: The 2 main causes of death after thromboendarterectomy for chronic pulmonary thromboembolism are incomplete repermeabilization responsible for persistent pulmonary hypertension and acute high-permeability pulmonary edema. We wish to establish an experimental model of chronic pulmonary thromboembolism to replicate the conditions encountered during and after pulmonary thromboendarterectomy.
Methods: Multiple-curled coils and tissue adhesive were embolized in 6 piglets to induce complete obstruction of the left pulmonary artery, documented by angiography. After 5 weeks, the main pulmonary artery was repermeabilized by thromboendarterectomy during circulatory arrest. The left lung was reperfused ex vivo with autologous blood at constant flow, and patency of the pulmonary artery was evaluated on a barium angiogram. The endarterectomy-reperfusion procedure was also done in 6 nonembolized piglets that served as the controls. The severity of lung injury induced by 60 minutes of reperfusion was assessed on the basis of measurements of the lung filtration coefficient and of lung myeloperoxidase activity.
Results: Marked hypertrophy of the bronchial circulation was seen in the chronic pulmonary thromboembolism group. Thromboendarterectomy removed the organized obstructing thrombus that was incorporated into the arterial wall and restored patency of the pulmonary artery. Acute lung inflammation and high-permeability edema occurred after reperfusion, as indicated by a 1.5-fold increases in both lung filtration coefficient and lung myeloperoxidase values in the chronic pulmonary thromboembolism group; these 2 variables being correlated.
Conclusions: Our model replicated the perioperative conditions of pulmonary thromboendarterectomy, suggesting that it may prove useful for improving the repermeabilization technique and for investigating the mechanisms and prevention of reperfusion injury.

	Introduction

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Pulmonary thromboendarterectomy is becoming an alternative to lung or heart-lung transplantation in patients with severe chronic pulmonary thromboembolic hypertension (CPTE). As compared with transplantation, thromboendarterectomy has important advantages that include lower acute and long-term mortality rates, better functional results, and no requirement for long-term immunosuppressive therapy. ¹ However, in our experience ² and in that of Jamieson and colleagues, ³ there are 2 significant causes of postoperative death after pulmonary thromboendarterectomy, namely persistent pulmonary hypertension as the result of incomplete desobstruction of the pulmonary arteries, and acute high-permeability pulmonary edema.

No animal model of CPTE is available as yet for improving the thromboendarterectomy technique and for investigating the mechanisms and prevention of acute lung injury after repermeabilization.

We designed a piglet model of chronic thromboembolic obstruction of the left pulmonary artery treated by thromboendarterectomy followed by lung reperfusion, with the goal of replicating the perioperative conditions of thromboendarterectomy in patients with CPTE.

	Methods

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Twelve piglets (large White; mean weight ± SE, 24.7 ± 6.2 kg) were used. The study complied with the "Principles of Laboratory Animal Care" developed by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" written by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH publication No.86-23, revised in 1985).

Study groups
The piglets were randomly allocated to 2 groups, the CPTE group (n = 6) and the control group (n = 6).

Thromboembolic obstruction of the left pulmonary artery
Anesthesia was induced with intramuscular ketamine (100 mg/kg) and maintained with intravenous pentobarbital (10 mg/kg bolus followed by a continuous infusion of 0.1 mg/kg/min). After paralysis with pancuronium (0.3 mg/kg) and endotracheal intubation, intermittent positive-pressure ventilation was provided (MMS 107 ventilator; MMS, Pau, France) at a tidal volume of 15 mL/kg, with a respiratory rate of 18 cycles/min and a fraction of inspired oxygen of 0.5. Body temperature was maintained at 37°C. With the animal placed in the supine position, a right jugular vein cutdown was performed under sterile conditions through a short cervical incision. An introducer sheath was placed into the right jugular vein, and a 5F pigtail angiographic catheter was passed over a guide wire, through the introducer sheath, and placed in the left pulmonary artery under fluoroscopic guidance. The tip of the pigtail catheter was positioned close to the left pulmonary artery bifurcation, and contrast agent was injected under fluoroscopy to document the position of the lobar arteries (Fig. 1, A). Four to 8 embolization multiple-curled coils (Cook Inc, Bloomington, Ind), ranging from 12 to 15 mm in diameter and 5 to 15 cm in length, were placed in the main left pulmonary artery and the first 3 cm of the left lower lobar artery during a single session under angiographic control. Because a preliminary study indicated that coil embolization alone failed to produce complete pulmonary artery obstruction, 0.1 mL of the tissue adhesive enbucrilate (Histoacryl; B. Braun, Melsungen, Germany) was injected through the catheter and propelled to the embolization site with 5% dextrose solution to secure the coils firmly to the pulmonary vessel walls and, thereby, to induce thrombosis. At the end of the procedure, complete occlusion of the left pulmonary artery was documented angiographically (Fig. 1, B). The catheters and the introducer sheath were removed; the jugular vein was ligated; the skin was sutured, and the animals were allowed to recover.

View larger version (115K): [in this window] [in a new window]   Fig 1. A typical example of selective left pulmonary angiogram. A, Before embolization. B, After embolization of multiple-curled coils and tissue adhesive in the main left pulmonary artery and the first 3 cm of the left lower lobar artery. The angiogram shows a complete obstruction of left pulmonary artery.

Lung reperfusion
The lungs were reperfused as described previously. ⁴ Briefly, the left lung was harvested and suspended by the left main bronchus to a force-displacement transducer placed in a humidified chamber to allow monitoring of weight changes. An MMS 107 respirator set at 20 breaths/ min with a tidal volume of 200 mL and a positive end-expiratory pressure of 2 cm H₂O was used to ventilate the left lung with a humidified warm gas mixture (20% oxygen, 75% molecular nitrogen, and 5% carbon dioxide). The lung was perfused with 300 mL of heparinized autologous blood through a cannula placed in the left pulmonary artery. A constant flow of 0.03 mL/g body weight was maintained with a peristaltic pump (Ismatec; Bioblock, Strasbourg, France) placed in series with the arterial line. Venous blood was collected by gravity into a reservoir through a cannula in the left atrium and was recirculated for 60 minutes. Hematocrit and perfusate cell concentration were similar in the 2 groups. To prevent loss of reservoir volume via retrograde perfusion of the bronchial circulation, the bronchial arteries were ligated. Pulmonary arterial pressures (Ppa) and pulmonary venous pressures (Ppv) were continuously monitored with pressure transducers (model P23 ID; Statham, Paris, France) placed proximal to the lung, on the arterial line, and on the venous line, respectively. Pressure signals were amplified (model M52; Telco Systems, Norwood, Mass) and recorded on a polygraph recorder (ED 69; Alco, Paris, France). Zone 3 conditions (arterial > venous > alveolar pressures) were maintained throughout all experiments.

Assessment of lung injury after reperfusion
Measurements of pulmonary hemodynamics and microvascular lung permeability
Pulmonary capillary pressure (Ppc) was estimated by the double-occlusion method. ⁵ With this method, after simultaneous occlusion of the arterial and venous line Ppa and Ppv equilibrate to the same pressure, which is well correlated with Ppc. ⁵ Pulmonary arterial (Rpa) and venous resistances (Rpv) were calculated as follows: Rpa = (Ppa – Ppc)/Q, Rpv = (Ppc – Ppv)/Q, where Q is the flow. The filtration coefficient (K_fc) was used as an index of endothelial permeability to fluid and was measured by the isogravimetric method described by Drake and colleagues. ⁶ In brief, after an isogravimetric period of 30 minutes, Ppv was rapidly increased by 20 cm H₂O for 20 minutes by raising the outflow end of the venous reservoir connected to the left atrium cannula. The resultant increase in lung weight was recorded. The characteristic rapid weight gain as the result of vascular bed filling was followed by a phase of slower weight gain, reflecting filtration of fluid into the pulmonary interstitium. The rate of slow weight change (W/t) was analyzed by linear regression of the log₁₀-transformed weight changes per minute. The initial rate of weight gain was calculated by extrapolating W/t to time 0. K_fc was obtained by dividing W/t at time 0 by the change in Ppc that occurred after the venous outflow pressure increase, normalizing the result for the baseline wet lung weight and expressing it in milliliters per minute per centimeters of water/100 g lung tissue. Baseline wet lung weight was estimated by measuring the weight of the left lung at the beginning of the experiment and subtracting the weight of the extrapulmonary tissue measured after reperfusion.

Determination of lung myeloperoxidase activity
Myeloperoxidase lung activity was used as an indirect measure of tissue neutrophil infiltration. ⁷ Tissue biopsy samples were taken after the operation from the lower lobe of the right lung (n = 6, in the control group, and n = 6, in the CPTE group). At the end of the reperfusion, a large lung tissue biopsy sample was taken from the lower lobe of the left lung (n = 6, in the control group, and n = 6, in the CPTE group). These tissue biopsy samples were snap frozen in liquid nitrogen. The method described by Mullane and colleagues ⁷ was used. Frozen lung tissue was pulverized and homogenized in 10% wt/vol of hexadecyltrimethyl ammonium bromide buffer (0.5% hexadecyltrimethyl ammonium bromide in 50 mmol/L phosphate buffer at pH 6.0), with a Polytron homogenizer (Brinkman Instruments, Inc, Westbury, NY). The homogenate was sonicated on ice for 15 seconds, frozen at –70°C, and thawed 3 times, then centrifuged at 40,000g for 15 minutes. Spectrophotometry was used to assay myeloperoxidase in the supernatant. Twenty microliters of supernatant was combined with 12 µL of 25 mmol/L H₂O₂, 30 µL of 40 mmol/L O-dianisidine hydrochloride, and 1.938 mL of mmol/L phosphate buffer (pH 6.0). The change in absorbance was measured at 460 nm on a spectrometer (model 25 Spectrometer; Beckman, Paris, France). One unit of myeloperoxidase activity was defined as the activity degrading 1 µmol of peroxide in 1 minute at 25°C.

Morphologic findings
The gross appearance of the left lung was examined with special attention to the bronchial and systemic circulation supplying the left lung.

In 3 CPTE animals, cross sections of the obstructed left pulmonary artery were examined under the microscope after staining with hematoxylin and eosin. To check that the pulmonary artery was patent after thromboendarterectomy, left lung angiography was performed by injecting barium-gelatin through the left pulmonary artery after reperfusion.

Protocol
Five weeks after the left pulmonary artery embolization, left pulmonary thromboendarterectomy was performed, and the left lungs were reperfused with autologous blood for 1 hour. The same procedure was performed in the control animals. After reperfusion for 1 hour in both groups, pulmonary hemodynamics and lung permeability were measured. Lung tissue specimens were then obtained for myeloperoxidase lung determination, and barium-gelatin was injected through the left pulmonary artery to assess pulmonary artery patency.

Statistical analysis
All results are expressed as means ± SEM. Unpaired t test was used to compare control and CTPE groups.

	Results

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Hemodynamic measurements are shown in Table I. K_fc, Ppa, Ppc, and Rpa values were higher in the CPTE group than in the control group. Rpv and Ppv were not significantly different between the 2 groups.

The gross appearance of the lung parenchyma was unremarkable in the control and CPTE groups. In the CPTE group, there was ample macroscopic evidence of expansion of the systemic supply to the left lung. The bronchial circulatory system was hypertrophied, and in all 6 piglets the visceral pleura was supplied by vessels that either continued bronchial arteries or stemmed from mediastinal arteries (Fig. 2). Some of these pleural vessels traveled through the pulmonary ligament and coursed on the surface of the lower lobe of the lung (Fig. 2).

View larger version (144K): [in this window] [in a new window]   Fig 2. Surfaces of the left lungs of 2 representative piglets. One of the control group (A) and the other 5 weeks after left pulmonary artery obstruction with chronic thrombus (B). Large systemic arteries are visible on the lung surface under the visceral pleura on (B).

View larger version (100K): [in this window] [in a new window]   Fig 3. A typical example of pulmonary thromboendarterectomy in a piglet. The whitish chronic thrombus is adherent to the intima, and the thromboendarterectomy has to be performed through the media. Note extensions of the thrombus into the upper and the lower arteries.

View larger version (71K): [in this window] [in a new window]   Fig 4. Typical example of a pulmonary barium-gelatin angiogram after thromboendarterectomy shows normal patency of the left pulmonary arteries.

View larger version (146K): [in this window] [in a new window]   Fig 5. Cross sections of obstructed pulmonary in a piglet. Note the disruption of the intima by the thrombus, the recanalization of the thrombus by mutiluminal channels, the infiltrate of the thrombus by fibroblasts and inflammatory cells, and the hypertrophy of the vasa vasorum within the arterial wall. (Hematoxylin and eosin stain; original magnification, x12.5.)

	Discussion

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Large vessel CPTE is a disorder characterized by obstruction of central pulmonary arteries by long-standing, organized, thrombotic material. ^8,9 The thrombus resists fibrinolysis and undergoes organization, incomplete recanalization, and endothelialization. Because a preliminary study indicated that coil embolization alone failed to produce complete pulmonary artery obstruction, tissue adhesive was injected through the catheter and propelled to the embolization site to secure the coils firmly to the pulmonary vessel walls and, thereby, to induce thrombosis. In our study, pulmonary angiography after embolization of multiple-curled coils and tissue adhesive showed complete obstruction of the left pulmonary artery. This obstruction was still present in all the animals at the time of thromboendarterectomy 5 weeks after the embolization procedure, indicating the absence of effective fibrinolysis. White thrombotic material that was incorporated into the vascular wall was seen at the embolization site when the pulmonary artery was opened. Microscopic examination of the pulmonary artery cross section showed marked fibrosis with recanalization and disruption of the arterial intima similar to the findings in patients with CPTE ⁸ (Fig. 5).

As in our previous study after left pulmonary artery ligation ⁴ and in the study by Remy and colleagues ¹⁰ involving embolization of coils in the left pulmonary artery, expansion of the bronchial circulation was visible on gross examination, 5 weeks after embolization. We also noted neovascularization within the adventitia of the large left pulmonary arteries, which reflected development of systemic supply to the left lung. Increased bronchial circulation is the rule in patients with CPTE. ¹¹ Moreover, vigorous bronchial back-bleeding occurred during thromboendarterectomy in our animals; this phenomenon, which we also observe in our patients with CPTE, indicates significant bronchial-to-pulmonary anastomotic blood flow. ³

Pulmonary thrombectomy alone, without removal of the organized thrombotic material, has failed to provide adequate relief of obstruction ³ in patients with CPTE. We found that, similar to our patients with CPTE, our animals required removal not only of the intima but also of a variable amount of media. The procedure consistently restored pulmonary artery patency. It was performed during circulatory arrest to limit bronchial artery back-bleeding, which impairs vision of the operating site. 3,9

Pulmonary thromboendarterectomy for patients with CPTE has been followed by acute high-permeability edema in up to 60% of cases. ¹² Whether this complication was caused by the thromboendarterectomy procedure itself, as suggested by Levinson and colleagues, ¹³ or by reperfusion injury to the ischemic pulmonary endothelium remains unclear. ¹² In previous studies ^14-17 of intact animals or isolated lungs, reperfusion after a period of ischemia was associated with an increase in microvascular lung permeability and with pulmonary sequestration of activated polymorphonuclear neutrophils. Interaction between activated polymorphonuclear neutrophils and pulmonary endothelium was suggested as a central mechanism of lung injury in these studies. ^14-17 In our study, the lungs were reperfused ex vivo to normalize pulmonary blood flow and to ensure recruitment of the entire pulmonary vascular surface area. Moreover, the lungs were reperfused with autologous blood rather than buffer because polymorphonuclear neutrophils are key mediators and because autologous blood is used for lung reperfusion after thromboendarterectomy in patients with CPTE. K_fc was used to evaluate changes in lung microvascular permeability with the isogravimetric method, ^6,18,19 and lung neutrophil sequestration ^7,20 was assessed based on lung myeloperoxidase activity. ^7,20 In the control group, K_fc values after thromboendarterectomy were similar to those previously reported in normal piglet lungs. ⁴ As expected, K_fc, Rpa, and myeloperoxidase increased after thromboendarterectomy in the CPTE group. These changes were similar to those that we observed in lungs reperfused 5 weeks after left pulmonary artery ligation. ⁴ The changes in K_fc values were correlated with myeloperoxidase activity, indicating that pulmonary polymorphonuclear neutrophil activation and sequestration were also central mechanisms in our model. Taken in concert, these findings indicate that the acute high-permeability pulmonary edema seen after thromboendarterectomy for CPTE is due to an acute inflammatory response to ischemia-reperfusion and, contrary to the hypothesis of Levinson and colleagues, ¹³ is neither induced nor aggravated by the thromboendarterectomy procedure itself.

Our experimental model of CPTE with obstruction of the left pulmonary artery replicates the conditions encountered during and after pulmonary thromboendarterectomy in patients with CPTE and offers several advantages over other models of chronic pulmonary artery obstruction: (1) obstruction of the left pulmonary arteries is achieved without an operation, contrary to the left pulmonary artery ligation model ⁴; (2) obstruction of the left pulmonary artery is complete and reproducible, whereas variations in the sites and degrees of obstruction occur in the dog CPTE model developed by Moser and colleagues ²¹; (3) the macroscopic and microscopic aspects of the chronic thrombus are closely similar to those in patients with CPTE; (4) pulmonary thromboendarterectomy is performed under conditions similar to those in patients with CPTE, offering an opportunity for perfecting the repermeabilization technique; and (5) the lung is reperfused under standardized conditions, allowing for the investigation of the mechanisms underlying postthromboendarterectomy pulmonary edema.

Further studies with this model are ongoing with special attention to induction of pulmonary hypertension by serial obstruction of the left pulmonary artery and right lobar pulmonary arteries to replicate pulmonary hypertension as the result of CPTE in human beings.

	Acknowledgments

 
We thank Denis Petraz, Bruno Baudet, Frédéric Seccatore, Rémi Burel, Annick Dernoncourt, Chantal Verriest, Hégésippe Langouste, and Pascal Gusmini for their technical assistance.

	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): Alain Serraf Emile A. Bacha Philippe Dartevelle Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fadel, E. Articles by Dartevelle, P. Search for Related Content PubMed PubMed Citation Articles by Fadel, E. Articles by Dartevelle, P.