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Experimental Studies |
1 From the Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115 (N.K.); Department of Cardiology, Swiss Cardiovascular Center Bern, Switzerland (S.W., Y.B., B.M., O.M.H.); Department of Radiology, University Hospital Aachen, Germany (T.S.); Department of Clinical Investigation, University Hospital Bern, Switzerland (D.M.). Supported by Straub Medical, Wangs, Switzerland. Received July 23, 2004; revision requested September 23; revision received November 1; accepted December 14. Address correspondence to N.K. (e-mail: nkucher{at}partners.org).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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MATERIALS AND METHODS: Nine in vitro tests were performed by using porcine thrombi at a PE test station that provides continuous fluid output of 2 L/min at a pressure of 50 mm Hg. Macroembolization was defined as embolized particles larger than 1.5 mm in dimension; microembolization was defined as particles that range in size from 0.1 to 1.5 mm. In static in vitro tests, researchers measured plasma-free hemoglobin levels in a 36-year-old man to assess mechanical hemolysis. Investigational review board approval and informed consent were obtained. The Department of Agriculture, Veterinary Bureau, Bern, Switzerland approved in vivo tests. Researchers investigated device effectiveness in 10 pigs that developed cardiogenic shock but survived massive PE after injection of two or three porcine thrombi into the external jugular vein via a surgically implanted 24-F sheath. Pulmonary angiography and hemodynamic measurements, including mean aortic and mean pulmonary artery pressure, heart rate, and mixed venous oxygen saturation, were obtained at baseline, after embolization, and after thrombectomy. Repeated-measures analysis of variance was performed to compare hemodynamic measurements at baseline, after embolization, and after thrombectomy. Cardiovascular structures were examined at necropsy for rupture, perforation, dissection, or hemorrhage.
RESULTS: During a mean aspiration time of 69 seconds ± 19, thrombi were completely extracted from 14-mm test tubes, with an aspirated fluid volume of 201 mL ± 64. Although no macroembolization was observed, microembolization was quantified at 1.9 g ± 1.3. Catheter aspiration was not associated with an increase in plasma-free hemoglobin. In 10 animals, aortic pressure increased from 52 mm Hg ± 24 before thrombectomy to 90 mm Hg ± 32 after thrombectomy, mixed venous oxygen saturation increased from 48% ± 19% to 61% ± 12%, pulmonary artery pressure decreased from 33 mm Hg ± 9 to 22 mm Hg ± 4, and heart rate decreased from 162 beats per minute ± 24 to 114 beats per minute ± 14. We did not observe macro- or microscopic damage to treated or untreated cardiovascular structures.
CONCLUSION: The PE thrombectomy device was highly effective, facilitating rapid reversal of cardiogenic shock without device-related complications.
© RSNA, 2005
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Catheter intervention with or without embolectomy is a promising alternative to systemic thrombolysis or surgical embolectomy (10,11). The Greenfield suction embolectomy catheter (Medi-Tech/Boston Scientific, Watertown, Mass) has been available the longest time, and it is the only PE catheter approved by the U.S. Food and Drug Administration (12,13). Thrombus fragmentation without embolectomy by using balloon angioplasty (14) or a pigtail rotational catheter (15–17) was also reported. Several mechanical or rheolytic embolectomy devices were developed for use in blood vessels smaller than pulmonary arteries but were investigated in PE cohort studies (18–23). Currently available catheter thrombectomy devices used to treat PE are limited by effectiveness, steerability, mechanical hemolysis, and macro- or microembolization (11,23). The purpose of our study was to evaluate a percutaneous PE thrombectomy catheter that aspirates, macerates, and removes thrombus.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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In Vitro Tests
We designed and developed a PE test station (Fig 2) to investigate in vitro device effectiveness and macro- or microembolization of the catheter thrombectomy device (N.K.). We performed nine tests by using 4-day-old thrombi that were generated in vitro from fresh porcine blood obtained during slaughter at a slaughterhouse, according to a technique described previously (24). In addition, four tests were performed by using a mixture of precipitated porcine blood and fat tissue (ie, "blood sausage") to reproduce the consistency of older organized thrombi.
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For assessment of in vitro mechanical hemolysis, three blood samples were obtained without a tourniquet from an antecubital vein of a healthy 36-year-old man by using a 14-gauge needle. The investigational review board at the University Hospital of Bern approved this part of the study, and informed consent was obtained. Then, 300 mL of blood was drawn from this individual directly into three containers that contained heparin; there was 100 mL of blood in each container. Blood was aspirated with the thrombectomy catheter until approximately 80 mL of blood was removed from each of the containers. The 5-mL syringes were filled with the remaining blood from each of the containers. The blood samples containing heparin were centrifuged immediately for measurement of the plasma-free hemoglobin level by using a spectrophotometric assay (normal range, 0–50 mg/L).
In Vivo Tests
Pulmonary embolization.—In vivo tests were approved by the Department of Agriculture, Veterinary Bureau, Bern, Switzerland. Three investigators (N.K., S.W., O.M.H.) performed the in vivo experiments. After general anesthesia was achieved in 13 pigs (mean weight, 44 kg ± 5), a median cervicotomy was performed to obtain access to jugular vessels. A 24-F sheath was surgically inserted into the right external jugular vein (24). Then, 6-F sheaths were placed into the left external jugular vein, left internal jugular vein, and right common carotid artery, respectively. After the intravenous administration of 5000 U of unfractionated heparin, 5-F pigtail catheters were advanced over a J-tipped 0.035-inch guidewire (Emerald; Cordis, Miami, Fla) into the ascending aorta and superior vena cava. Two 4-day-old porcine thrombi, 5–6 cm in length and 1–2 cm in diameter, were injected with 20 mL of a saline solution through the 24-F sheath by using a tapered adapter (24). The tapered adapter enabled the injection of intact thrombi through the sheath. A third thrombus was injected in four animals because the mean aortic pressure remained higher than 70 mm Hg or the mean pulmonary artery pressure remained lower than 25 mm Hg after injection of two thrombi. The mean weight of the injected thrombi was 17 g ± 4. Of the 13 pigs, three died immediately after thrombus injection because of cardiogenic shock. Ten pigs developed cardiogenic shock but survived; two required an intravenous injection of a 1-mg bolus of epinephrine for profound systemic arterial hypotension after thrombus injection. Overall, a mean of 575 mL ± 120 intravenous saline was infused during in vivo tests.
Catheter thrombectomy.—The mean time between pulmonary embolization and thrombectomy in the 10 surviving animals was 10 minutes ± 4. Thrombectomy was initiated immediately after a decrease in mean aortic pressure to less than 70 mm Hg or an increase in mean pulmonary artery pressure to more than 25 mm Hg. After embolization, a 260-cm J-tipped exchange wire (Terumo, Leuven, Belgium) was advanced via the 24-F sheath into the distal right or left pulmonary artery, passing the proximal occlusion site. The thrombectomy catheter was introduced over the exchange guidewire and then advanced into a proximal occlusion site. The catheter device was gently withdrawn during aspiration. Catheter embolectomy was performed in the main pulmonary artery, the right and left main pulmonary arteries, and the right and left lower lobe pulmonary arteries but not in upper lobe pulmonary arteries or segmental branches (N.K., S.W., O.M.H.). Thrombectomy was discontinued as soon as the mean aortic pressure increased to more than 70 mm Hg or the mean pulmonary artery pressure decreased to less than 25 mm Hg, regardless of the angiographic result. In one animal, the right lung was left untreated to investigate macro- and microscopic changes due to embolization; the left lung was treated with the thrombectomy catheter.
Angiographic procedure and hemodynamic measurements.—Pulmonary angiography was performed, and hemodynamic measurements were obtained at baseline, 4 minutes ± 2 after embolization, and 3 minutes ± 1 after thrombectomy. Angiography was performed by using biplanar radiographic imaging equipment (Poly C-Larc; Philips, Eindhoven, the Netherlands). Digital images were acquired at a rate of 12.5 frames per second by using frontal and posterior oblique views. A 5-F pigtail catheter was positioned in the main pulmonary artery, and 30 mL of low-osmolar nonionic contrast material (Optiray; Guerbet, Zurich, Switzerland) was injected with a power injector (Mallinckrodt, Hazelwood, Mo) at 15 mL per second.
Continuous and simultaneous aortic and pulmonary artery pressure recordings were obtained with a physiologic monitor and recording system (Cardis; Schwarzer, Munich, Germany) by using fluid-filled 5-F pigtail catheters connected to a pressure transducer placed at the midchest level. Oxygen saturation was analyzed by using blood samples from the aortic and pulmonary arteries (mixed venous saturation). Rhythm monitoring was performed with three surface extremity leads; rhythm was displayed continuously on a physiologic monitor.
Necropsy.—The mean time from thrombectomy to euthanasia was 26 minutes ± 15, and the mean time from thrombectomy to necropsy was 45 minutes ± 16. After en bloc resection of the heart and lungs (D.M.), all cardiac structures were examined macroscopically, including the right atrium, tricuspid valve, right ventricle, and pulmonic valve. In addition, the main pulmonary artery and right and left pulmonary arteries were evaluated for rupture, perforation, dissection, or hemorrhage (Y.B.). Lung specimens were examined macroscopically for hemorrhage, edema, or atelectasis. After partial fixation in a 4% formaldehyde solution, lung specimens were cut transversely into 1-cm-thick sections and evaluated macroscopically for perforation and dissection of treated and untreated pulmonary artery segments. After complete fixation, representative samples (eight to 10 per lung) were embedded in paraffin and cut into 3-mm-thick sections. The sections were stained with hematoxylin-eosin and van Gieson stains by using the Weigert method for elastic fiber staining (Weigert–van Gieson staining) for histologic evaluation of vessel wall integrity. The microscopic end points included perforation, dissection, or hemorrhage of treated vascular segments. A pathologist with more than 2 decades of experience performed microscopic interpretations (T.S.).
Statistical Analysis
Continuous in vitro and in vivo measurements are given as mean ± standard deviations. For in vitro tests, we compared the thrombus extraction rate, aspirated fluid volume, aspirated fluid volume rate, and macro- and microembolization between thrombus and blood sausage tests, respectively, by using a two-sample t test. A paired t test was used to compare differences in mean plasma-free hemoglobin levels before and after catheter aspiration. We used one-way repeated-measures analysis of variance to compare differences in mean aortic pressure, mean pulmonary artery pressure, heart rate, and mixed venous oxygen saturation at baseline, after embolization, and after thrombectomy. We used the Bonferroni correction for multiple comparisons, and a P value of less than .004 was indicative of a statistically significant difference. All analyses were performed by using STATA software, version 8.0 (STATA, College Station, Tex).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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In Vivo Tests
Thrombus injection was angiographically successful, with obstruction of both main pulmonary arteries in all 13 pigs (Fig 3). In 10 surviving animals, thrombus injection was associated with a decrease in mean aortic pressure (Fig 4) and mixed venous oxygen saturation and an increase in mean pulmonary artery pressure and heart rate (Table 3, Fig 4).
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Angiography showed improved flow in all treated main and lobar pulmonary arteries. The mean procedure time was 32 minutes ± 10 (range, 20–55 minutes), including thrombectomy and angiographic or hemodynamic documentation before and after thrombectomy.
At necropsy, partial lower-lobe atelectasis without substantial edema was present in all animals. In addition, residual thrombi were confirmed in segmental branches. In the animal with an embolized but untreated right lung, thrombi were present in the main lower lobe pulmonary artery and all segmental pulmonary arteries. The left treated lung showed thrombi in only the lower lobe segmental branches. In that animal, both lungs showed lower lobe atelectasis. None of the 10 animals had pulmonary hemorrhage, hemothorax, or pericardial bleeding. Cardiac structures, including the right atrium and ventricle and the tricuspid and pulmonic valves, were intact. In none of the 10 animals was perforation or dissection of treated and untreated pulmonary artery branches noticed.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Because the distal catheter shaft (length, 41 cm) of the Aspirex (Straub Medical) PE catheter thrombectomy device is highly flexible, we did not experience difficulties in approaching main and lobar pulmonary arteries by using a long exchange guidewire. The PE thrombectomy device was highly effective in vitro and in vivo, enabling rapid and complete thrombus removal from 14-mm test tubes and from main and lobar pulmonary arteries in 10 animals. The device facilitated rapid reversal of cardiogenic shock, with a substantial increase in systemic arterial pressure and cardiac output and a decrease in mean pulmonary artery pressure. In patients with massive PE, older organized thrombi may obstruct main or lobar pulmonary arteries. Although not tested in vivo, the aspiration capacity of the thrombectomy device was efficient for breaking down and removing a firm substance (ie, blood sausage) in vitro with an extraction rate of 2.1 g/min.
In patients with recurrent PE, large emboli may be adherent to the vessel wall of main and lobar pulmonary arteries. No conclusion can be drawn with regard to device effectiveness in this situation because, in our in vitro and in vivo tests, thrombi did not adhere to test tubes or pulmonary arteries. The thrombectomy device, however, was developed for patients with acute massive PE in whom recently embolized thrombi are usually not attached to the vessel wall.
In the 10 pigs, the thrombectomy catheter device was used in the main pulmonary artery and the left and right main and lobar arteries but not in segmental pulmonary arteries. Catheter thrombectomy was not associated with macroscopic or microscopic damage to treated and untreated pulmonary artery segments or to cardiac structures (eg, the right ventricle or tricuspid valve). Although we did not observe damage to vascular structures, we cannot exclude the possibility of vascular injury, particularly when this device is used in segmental branches with calibers smaller than 6 mm.
One disadvantage of the Aspirex device (Straub Medical) is that blood is extracted during thrombectomy. Prolonged aspiration may potentially cause hemodynamic deterioration in patients with PE-related shock. We limited the thrombectomy time and discontinued the use of the device immediately after hemodynamic improvement was achieved, regardless of the angiographic findings, which resulted in an average aspirated blood volume of 137 mL. Blood is also extracted with other mechanical thrombectomy catheters, including Angiojet (Possis, Minneapolis, Minn), Hydrolyzer (Cordis, Warren, NJ), or Oasis (Medi-Tech/Boston Scientific) (23). In patients with a massive thrombus load, prolonged thrombectomy may be necessary to reverse cardiogenic shock but may result in substantial blood loss. In this situation, transfusion of 1 or 2 U of packed red blood cells may be necessary.
In some situations, simple thrombus fragmentation with a balloon or pigtail rotational catheter may be sufficient to improve hemodynamics in patients with massive PE (23). Macroembolization, however, may cause further deterioration of hemodynamics when a large centrally located thrombus breaks and embolizes into a previously unobstructed lobar branch (17). Microembolization with a substantial amount of macerated clot fragments may further increase pulmonary vascular resistance and worsen hemodynamics. The risk of in vitro macroembolization with the thrombectomy device was negligible for both fresh thrombus and firm thrombus equivalent. In vitro microembolization occurred during thrombectomy of fresh thrombi (approximately 10% of baseline thrombus weight) but was negligible during thrombectomy of the firm substance.
Transient mechanical hemolysis of 24–48 hours duration has been reported after catheter thrombectomy, particularly with the Amplatz device (Bard-Microvena, White Bear Lake, Minn) and with hydrodynamic devices, such as the Angiojet catheter (Possis) (23). Mechanical hemolysis occurs when macerated blood or thrombus is not removed with the catheter. The design of the Aspirex catheter (Straub Medical) does not enable recirculation of aspirated blood. The occurrence of hemolysis is also dependent on the blood vortex created at the catheter tip. In static in vitro tests with human blood samples, aspiration with the thrombectomy device was not associated with an increase in plasma-free hemoglobin. In a study of 10 patients (25), catheter thrombectomy of occluded femoral arteries with the Rotarex catheter (Straub Medical), a catheter device in which the technology is similar to that of the Aspirex catheter (Straub Medical), was not associated with an increase in plasma-free hemoglobin. Further investigation is required to ensure that the thrombectomy device does not cause mechanical hemolysis in the treatment of massive PE.
There are some limitations to our study. The consistency of in vitro generated thrombi may not reflect that of in vivo thrombi. Thus, we also tested a firm substance that was intended to mimic the consistency of older organized thrombi. The lack of in vivo plasma-free hemoglobin measurements after thrombectomy is another limitation of our study.
Practical applications: The main application of the thrombectomy device is in massive PE. A phase I study is being planned to investigate device safety in a cohort of patients with massive PE in whom thrombolysis or surgical embolectomy is not suitable. Another potential application of the thrombectomy device encompasses acute symptomatic proximal deep vein thrombosis.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: PE = pulmonary embolism
See Material and Methods for pertinent disclosures.
Author contributions: Guarantor of integrity of entire study, N.K.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; literature research, N.K., O.M.H.; experimental studies, N.K., S.W., Y.B., T.S., D.M., O.M.H.; statistical analysis, N.K., S.W.; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript editing, N.K., S.W., T.S., D.M., B.M., O.M.H.; manuscript revision/review, all authors; approval of final version of submitted manuscript, all authors
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References |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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