INTRODUCTION

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Pulmonary thromboembolism (PTE) is a common cardiovascular disease. Acute PTE is categorized as either massive PTE (obstructions or filling defects involving two or more lobar arteries or the equivalent) or submassive PTE (obstructions or significant filling defects involving at least one segmental pulmonary artery) (1, 2). Recently, tissue-type plasminogen activator (tPA), which induces thrombolysis in the absence of systemic fibrinolytic activation, has been used for the PTE. However, detailed studies regarding regional pulmonary hemodynamics in thrombolytic therapy are rare, particularly the relationship between regional hemodynamics and expired CO₂. We used a canine model of unilobar PTE to measure blood flow quantitatively at an embolized pulmonary artery. Moreover, we used expiratory CO₂ concentration to detect changes in gas exchange indirectly (3) and examined the correlation between regional pulmonary hemodynamics and regional pulmonary gas exchange.

	METHODS

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Ten beagle dogs were randomly divided into two groups5 animals received tPA (tPA group, body weight from 10.9 to 13.2 kg), and five control subjects received vehicle only (control group, body weight from 11 to 12.8 kg). All animals were anesthetized by intravenous injection of thiopental (30 mg/kg), intubated, and mechanically ventilated with a tidal volume of 20 ml/kg and a respiratory rate of 15 cycles/min. Spontaneous respiration and secretions of the respiratory tract were inhibited by intramuscular injections of pancuronium bromide (4 mg) and atropine sulfate (0.5 mg).

Under bronchofiberscopic observation, two CO₂ sampling tubes were positioned at the trachea and the left lower lobe of each animal, and CO₂ concentrations were measured by two infrared CO₂ sensors (1H type; Nippon-Denki Sanei Co., Japan). The flow rate of CO₂ sampling was 20 ml/min. This flow ensured that the sampling line was not drawing significant gas from points proximal to the segment (4). A polyethylene catheter was inserted into the right femoral artery, and mean arterial pressure (MAP) was measured. MAP was maintained by an infusion of hydroxyethylated starch through a line into the left femoral vein. A 7-Fr Swan-Ganz catheter was introduced into the right femoral artery and positioned in the right pulmonary artery to measure mean pulmonary arterial pressure (mPAP).

A left thoracotomy was performed, and after an intravenous injection of heparin (1,000 IU), an artificial blood circuit (ABC) consisting of a silicone tube (length, 10 cm and inner diameter, 2.6 mm) and a cannulation-type electromagnetic blood flowmeter probe (FF-type, inner diameter, 3 mm; Nihon-Kohden Co., Japan) was placed at the left lower pulmonary artery (Figure 1a). Blood flow at the left lower pulmonary artery (LL-flow) was measured with an electromagnetic blood flowmeter (MFV-3100; Nihon-Kohden Co.). All operations were performed during LL-flow standstill time which was less than 10 min.

View larger version (17K): [in this window] [in a new window]   Figure 1.   (A) Schema of the artificial blood circuit (ABC). (B) Scheme of the unilobar PTE model. PTE = pulmonary thromboembolism.

LL-flow, expiratory CO₂ concentration waves at the trachea and the left lower lobe, arterial pressure (AP), pulmonary arterial pressure (PAP), and ECG were monitored on a physiologic recorder (Polygraph System; Nihon-Koden Co.).

Autologous blood clots were formed by slowly dripping 50 ml of freshly drawn unheparinized dog blood and 5,000 U of thrombin into a glass beaker. The mixture was allowed to stand for at least 90 min until the clot had a gelatin-like consistency (5). The clots were stuffed into a metallic coil basket (length, 8 mm and inner diameter, 3 mm) and inserted into the ABC to create a submassive PTE model in the left lower pulmonary artery (Figure 1b).

In the tPA group, tPA (Alteplace) at 1 mg/kg (580,000 IU/kg) dissolved in 100 ml of saline was administered; 10% was injected as a single bolus, and the remainder was infused over a period of 30 min. Administration of tPA was started from a point in time in which complete cessation of LL-flow was confirmed. In the control group 100 ml of saline were administered in the same way. In both groups, just prior to measurement, 1,000 IU of heparin were added to prevent the formation of new thrombi.

The following physiologic parameters, LL-flow, end-expiratory CO₂ partial pressure at the trachea (Tr-PET_CO2), PET_CO2 at the left lower lobe (LL-PET_CO2), MAP, mPAP, and pulse rate, were followed continuously at baseline (before insertion of clot-stuffed metallic coil into the ABC) and every 10 min after embolization for 90 min.

The wet weight of clots was measured at baseline and after 90 min. Necropsy was performed to exclude heartworms and to assess the histologic changes in the left lower lobes.

Data are reported as mean ± SD. The paired t-test was performed for statistical analysis, and differences were considered significant for p < 0.05.

	RESULTS

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After creation of the ABC, LL-flow was regulated from 181.1 ± 32.5 ml/min to 91.9 ± 14.3 ml/min (approximately 50% of the original flow volume), and LL-PET_CO2 decreased from 36.8 ± 2.9 mm Hg to 33.1 ± 2.7 mm Hg (approximately 90% of the original value). However, CO₂ waves measured at the left lower lobe on the recorder showed the normal pattern and were identical to those at the trachea. LL-PET_CO2 was almost identical to Tr-PET_CO2 (Figure 2).

View larger version (65K): [in this window] [in a new window]   Figure 2.   Recorded waves after creation of the ABC at the left lower lobe (10 mm/s). ABC = artificial blood circuit.

After embolization, Tr-PET_CO2 did not change. However, LL-flow and LL-PET_CO2 clearly decreased, and CO₂ waves at the left lower lobe showed flattening with a peak at the early inspiratory phase (a peak-tail shape) (Figure 3). The peak was thought to have been due to inspiration of gas with a high CO₂ concentration in the central airway expired from other intact lobes. Therefore, when measuring LL-PET_CO2, it was necessary to exclude the value of the peak (6).

View larger version (52K): [in this window] [in a new window]   Figure 3.   Recorded waves after insertion of the metallic coil with autologous clots (10 mm/s).

In the tPA group, increases of LL-flow and LL-PET_CO2 are shown on the recorded waves (Figure 4). LL-flow in the tPA group was 92.3 ± 16.2 ml/min at baseline and decreased to 5.4 ± 3.4 ml/min just after insertion of the clot. Flow increased significantly to 61.0 ± 26.3 ml/min at 20 min after the onset of the drug infusion, and at 30 min it approached baseline values. In the control group LL-flow was 91.3 ± 7.5 ml/min at baseline, decreased to 10.5 ± 7.1 ml/min after insertion of the clot, and did not increase significantly during the study period (Figure 5). Similarly LL-PET_CO2 decreased after embolization and increased after tPA administration (Figure 6). Tr-PET_CO2 did not change significantly in either group. Moreover, MAP, mPAP, and pulse rate remained unchanged (Table 1).

View larger version (80K): [in this window] [in a new window]   Figure 4.   Recorded waves during thrombolytic process in the tPA group. tPA = tissue-type plasminogen activator.

View larger version (24K): [in this window] [in a new window]   Figure 5.   Time course of LL-flow (mean ± SD). LL-flow = blood flow of the left lower lobe.

View larger version (23K): [in this window] [in a new window]   Figure 6.   Time course of LL-PETCO2 (mean ± SD). LL-PETCO2 = end-expiratory CO2 partial pressure of the left lower lobe.

LL-flow as a percentage of its pre-embolization baseline (%LL-flow) correlated very well with LL-PET_CO2 as a percentage of its pre-embolization baseline (%LL-PET_CO2) (r = 0.929, p = 0.0001;) (Figure 7).

View larger version (21K): [in this window] [in a new window]   Figure 7.   Correlation between LL-flow as a percentage of baseline before embolization (%LL-flow) and LL-PETCO2 as a percentage of baseline before embolization (%LL-PETCO2). Data points were obtained at 10-min intervals in all animals for a total of 90 min. LL-flow = blood flow of the left lower lobe. LL-PETCO2 = end-expiratory CO2 partial pressure of the left lower lobe.

The wet weight of clots at baseline was 313.6 ± 39.0 mg in the tPA group and 293.4 ± 41.8 mg in the control group. After 90 min within the metallic coil in the ABC, the clots had disappeared in the tPA group. A white fibrin mass (139 ± 23.3 mg) remained in the control group. No correlation was observed between the weight of the remaining white clot and either LL-flow or LL-PET_CO2.

Histologic findings in the control group showed dilation of capillaries, thickening of alveolar walls with invasion of RBCs and macrophages, and RBCs and macrophages in alveolar spaces. In the tPA group, histologic findings were normal.

	DISCUSSION

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It has been shown that CO₂ partial pressure at a regional lobe is essentially unchanged when blood flow is reduced to 40% to 50% of original value. However, when blood flow is reduced to less than 30% of original value, CO₂ partial pressure rapidly decreases and a peak appears (6). Therefore in this study, blood flow at the ABC was regulated to approximately 50% of original value. After forming the ABC, it was shown that gas exchange at the left lower lobe was still relatively normal.

We used a metallic coil to hold a clot inside the ABC. Van de Werf and coworkers used a similar method in a canine model of coronary infraction (7). In their method, heparin was not administered, and the thrombus formed naturally inside a coil. The quantity of blood in the clot was unknown. Our method, however, allowed control of the weight of the clot. The changes in CO₂ waves at the left lower lobe following insertion of a clot-stuffed coil into the ABC were identical to those observed in clinical cases of submassive PTE (4, 6).

Our study showed that in the control group, despite reduction of the clot weight by approximately 50%, regional pulmonary blood flow did not increase in parallel with the reduction. We speculated that shape and position of the clot in the ABC were the reason for incorrelation between clot weight and blood flow. It was suggested that changes in physiologic conditions in PTE were not determined by clot quantity alone.

In the tPA group, clots disappeared completely in all animals. By evaluating the improvement in blood flow, thrombolysis appeared to have been completed after 30 min of tPA infusion. Blood flow at the embolized pulmonary artery improved, and expired CO₂ concentration from the affected lobe increased in correlation with blood flow. However, CO₂ concentration in the trachea did not reflect the tPA effect. Therefore, measurement of expired CO₂ from an affected lobe is considered to allow estimation of the regional pulmonary hemodynamics at the embolized pulmonary artery with tPA therapy.

Histologic examination showed RBCs in alveolar spaces in the control group within 90 min of PTE. The rapid bronchial arterial flow into the isolated segment may cause extravasation of RBCs into the alveoli (8), and prolongation of these conditions may cause pulmonary infarction. The histologic results suggested that thrombolytic therapy might be performed before significant pulmonary hemorrhage can occur.

Measurement of regional expired CO₂ is an easy technique which can be performed at bedside by using a flexible bronchofiberscope. Therefore, it could be applied for clinical PTE cases. Regional pulmonary hemodynamic and gas exchange data such as ours should help to refine thrombolytic therapy.