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UDC 616.131-005.6-08:615.273
COMPARATIVE EVALUATION OF THE EFFECTIVENESS OF METHODS OF CONSERVATIVE TREATMENT OF PULMONARY ARTERY THROMBEMBOLIA
Altai State Medical University, Barnaul Neimark M.I., Akatov A.B.
The article presents the validation of an essential new method of implying thrombolytic in patients with pulmonary artery thrombembolia. The authors have elaborated and registered the method "Local thrombolysis by obstructive thrombus" (RF patent №2376042). There were examined 217 patients with angiographically confirmed thromboembolia of the pulmonary artery. The results of the conducted research showed, that the method of local thrombolysis provides the full lysis of thrombus in the pulmonary artery and the normalization of hemodynamic parameters.
Key words: thrombembolia, pulmonary artery, thrombolysis, hemodynamics.
Despite the existence of pulmonary artery thromboembolia (PATE) prevention pattern, the frequency of its occurrence at present time is 0,50,7 per 1000 population. As a rule, the main cause of PATE is phlebothrombosis or thrombosis of lesser pelvis or lower limbs. According to different authors, morbidity by PATE right after the undergone episode reaches 60%. Till the present day the administration of patients with PATE has presented a number of difficulties. The severity of the condition is determined by the ventilationperfusion imbalance as the result of the exclusion of pulmonary vessels out of blood circulation, growth of dead space, spasm of vessels of lesser circulation and pulmonary hypertension.
This determines the formation of firstly right and then left ventricular failure. There exists only one way to provide aid to a patient with PATE - to restore the lesser circulation by excision of thrombus out of pulmonary artery. In case of symptomatic therapy the patients are bound to chronic pulmonary hypertension with further advance of concomitant right and left ventricular failure. According to a number of authors, the lethal outcome in such cases occurs during five years [1,2,3,4].
At the present time, such patients can be exposed to surgical treatment. Thrombectomy of pulmonary artery is a radical method allowing to influence directly the cause of the critical condition. However, this operation requires adherence to a number of conditions - implementation of artificial circulation, high qualification of the surgeon and anesthesiologist, which can be realized only in advanced medical centers. Technical complexity of the operation and initially severe state of patients precondition a considerable number of complications and further mortality up to 60-70% [4,5].
The development of interventional radiology and also appearance of various intravascular devices and catheters allowed to carry thrombus fragmentation. Thrombus is split into small
parts, although these fragments embolize minor arteries with the blood flow, meaning that there occurs recanalization of large arteries due to the embolization of the small ones. Since the total transection of small arteries is several times bigger that the transection of large ones, this technology is accompanied by further reduction of pulmonary circulation [5].
Thrombolysis is an alternative method. Due to technical simplicity it is the most common one and consists in the implementation of thrombolytic drug. It can be intravenous infusion (systemic thrombolysis), selective thrombolysis - injection of drug through a catheter leading directly to the thrombus and intrathrombus lysis - the injection of drug into catheter, inserted into the thrombus with continuous advance inside the thrombus [6,7].
Despite the commonness of thromboembolytic therapy and a considerable number of articles presenting relevant clinical success in patients with PATE, in the world literature there appears more and more criticism on the effectiveness of the stated method. In 2006 the Chest journal published an article proving that even by an effective clinical thrombolysis thrombi retain in the pulmonary artery, which causes the formation of pulmonary hypertension. It is explained by the fact, that by the vessel thrombosis there appears the Bernoulli effect due to the acceleration of blood circulation through collaterals. In consequence, in the area of thrombus there is created depression, due to which even by catheter-directed selective thrombolysis the drug is washed out through collaterals into the systemic blood flow. At the first stage of intrathrombus lysis the bigger amount of the drug contacts the thrombus, but further the thrombolytic begins to wash out into the systemic blood flow into the lumen between the catheter wall and thrombus. It explains a considerable number of hemorrhagic complications of thrombolytic therapy connected with systemic influence of the drug on hemostasis [8, 9].
By thrombolytic therapy it is necessary to consider, that a considerable part of the drug will be spent on the lysis of parent thrombus in the circulation of lower hollow vein, which reduces the effectiveness of thrombolysis in the pulmonary artery [10].
In print media appear more and more publications recommending to refuse of thrombolytic therapy by PATE and use it only by life-threatening conditions of patients - reduction of systemic blood flow under 80 mm hg, decrease of saturation of blood lower than 80%. The reason -low effectiveness of thrombolytic therapy and high risk of hemorrhagic complications [11,12,13,14,15].
The necessity of carrying out thrombolytic therapy on the one hand, its low efficiency and large number of complications made us to review ultimately the approaches to the method of thrombolytic drug infusion.
It is logical to assume, that the effectiveness of thrombolytic therapy will be determined by the concentration of this drug in thrombus. On the other hand, it is necessary to reduce the concentration of thrombolytic in the systemic blood flow to the maximum for the prevention of hemorrhagic complications.
The research objective was to justify a principally new method of thrombolytic implementation in patients with PATE.
Materials and methods
In our hospital there was elaborated the methodic called "Local thrombolysis by obstructive thrombus" (RF patent №2376042), which consists in the following.
Swan-Ganz catheter is inserted into the pulmonary artery and lead to the thrombus in such a way, that the distal end of the catheter is situated between the thrombus and catheter balloon. The balloon is blown until fool obstruction of the artery, after which there is obtained a space, "blocked" from the one side by a balloon and by thrombus from the other side. Through the distal passage of the catheter the fibrinolytic drug begins to be delivered in the "blocked" space. The mechanism of the method consists in the following - the blown balloon of the catheter obstructs the pulmonary artery and does not let the drug into systemic blood flow. Due to the lack of opening in the "blocked" space the maximum concentration of drug is reached. The drug is delivered under pressure, which allows it to quickly get inside the thrombus, and also spreads along the thrombus in the space between the artery wall and thrombus, which makes lysis more effective. The lack of linear blood flow does not allow the fragmented segments of thrombus to embolize smaller arteries. All parts of thrombus are constantly present in the zone of fibrinolytic drug influence.
The most suitable drug for local thrombolisys is the recombinant tissue plasminogen activator - alteplase. It is destructed under the influence of enzyme blood systems during 20-40 minutes after the injection. Consequently, the catheter balloon can be blown off and the blood flow can be restored maximum in two hours after the start of thrombolysis. By this time the drug reservoir will be inactivated. All other drugs for thrombolytic therapy act much longer, which requires long-term obstruction of the pulmonary artery by the balloon.
There were examined 217 patients with angiographically confirmed thromboembolia of the pulmonary artery. The patients were divided into three groups. The first group consisted of 88 people with stable hemodynamics, who had underwent heparin therapy through Swan-Ganz catheter, inserted into the pulmonary artery. This method of treatment was chosen, because from the moment of PATE episode till the start of therapy there had passed more than 72 hours, the thrombus was organized, and the implementation of thrombolytic therapy in this group of patients was a priori ineffective. The other two groups were randomized by means of enevelope method. The second group consisted of 79 people, who were exposed to selective thrombolytic therapy through Swan-Ganz catheter lead to the thrombus. The third group consisted of 50 people, who underwent local thrombolysis be means of Swan-Ganz catheter.
The measurement of the parameters of hemodynamics was registered by the monitor of «Hewlett Packard 56S» company. The parameters of central and pulmonary hemodynamics were examined in the pulmonary artery free of thrombotic masses. With the monitor software there were calculated indexed parameters of the blood circulations system. The location of catheter in the pulmonary artery was evaluated angiographically. The hemodynamic parameters were measured in dynamics from the start of thromboembolic and heparin therapy right after thrombolysis and in 2, 12, 24 hours. In patients of the second and third groups there was measured the concentration of alteplase in the blood plasma by means of liquid chromatography.
Results and discussion
The evaluation of the hemodynamic parameters of patients, who were exposed to heparin therapy, showed, that during 24 hours from the moment of therapy start there was registered a stably high level of cardiac output in comparison with the control parameters, high pressure in the pulmonary artery and high indexes of total peripheral and pulmonary resistance.
In patients, who had been exposed to the selective thrombolysis for 24 hours, there was registered a progressive decrease of pressure in
the pulmonary artery, however, by the end of the research it statistically exceeded the control parameters. The initially lowered heart index grew statistically during the treatment, but was still lower than the control level. Total peripheral resistance did not change significantly, the index of pulmonary vascular resistance had been decreasing during 24 hours, but did not reach the control value (Table 1).
Under the influence of local thrombolysis the average pressure in the pulmonary artery decreased right after the procedure and reached control values. The same occurred to the heart index. Total peripheral and pulmonary resistance normalized since two hours after thrombolysis.
Consequently, the conducted research showed, that heparin therapy does not influence pulmonary hemodynamics and cardiac output, since it does not lyse thrombi, but only prevents the progression of the process. Selective thrombolysis has a positive influence on the hemodynamic shifts, although it does not eliminate them fully, which is connected with insufficiently effective thrombolysis. The best therapeutic effect was reached by local thrombolysis, when already in two hours after the procedure all studied parameters normalized, which confirms the elimination of obstruction in the minor blood flow. For the determination of causes of this condition we had conducted the following research aimed at the determination of concentration of the drug in blood out of the pulmonary artery and peripheral vein by both methods of thrombolysis.
The drug concentration at the moment of test dose injection into the pulmonary artery by local thrombolysis exceeded the concentration of alteplase by 930 times at the same stage of the study by selective thrombolysis (P<0,001). In 30 minutes after the injection of the test dose the concentration of alteplase by local thrombolysis exceeded the concentration of drug by selective thrombolysis by 100 times (P<0,001). By the moment of the end of thrombolytic therapy the concentration of alteplase became significantly lower by local thrombolysis that by the selective one (P<0,001), (Table 2), which is connected with the utilization of fibrinolytic by thrombus. Further the significant difference between the concentration of actilise in the pulmonary artery by local and selective thrombolysis was not revealed.
By the comparison of alteplase concentration in the blood plasma out of the peripheral vein by the injection of test dose and in 30 minutes after the start of injection of the main dose there was registered significantly lower concentration by local thrombolysis than by selective. By the end of thrombolytic therapy the difference of alteplase concentration in the cubital vein by local and selective thrombolysis was not observed.
The comparison of actilise concentration in the pulmonary artery and peripheral vein by selective thrombolysis showed, that until the moment of thrombolytic therapy termination the significant difference in the drug concentration stayed lacked. At the moment of thrombolytic therapy termination the concentration of drug in the pulmonary artery more than two times exceeded this parameter in the peripheral vein, which seems to be conected with low utilization of the drug by thrombus. In 15 and 60 minutes after the end of thrombolytic therapy the concentration of fibrinolytic drug both in the pulmonary artery and the cubital vein occurred statistically non-significant.
Consequently, the effectiveness of local thrombolysis is determined by high concentration of thrombolytic in the area of thrombus in the pulmonary artery. Its low content in the peripheral vein explains the lack of hemorrhagic complications by the performance of this technology.
By the analysis of complications of the methods of thrombolytic therapy there was considered the failure of method - the occurrence of thrombi in the pulmonary artery after thrombolysis according to angiopneumography or computer tomography, occurrence of hemorrhagic complications in the form of hematomas in the area of vascular puncture, nasal, gastric bleedings. By the method of local thrombolysis there were no complications registered. (Diagram 1)
Conclusions:
The method of local thrombosis provides the full lysis of thrombus in the pulmonary artery and the normalization of hemodynamic parameters.
The effectiveness of local thrombosis is conditioned by high concentration of fibrinolytic in the area of thrombus in the pulmonary artery.
The lack of hemorrhagic complications by the local method is determined by low concentration of fibrinolytic in the peripheral blood flow.
Diagram 1
Frequency of complications by selective thrombolysis
Selective thrombolysis
10,00% 2,0p% ■Hematoma
Nasal bleedings
Gastric bleedings
Method failure
The method failure consists in the ineffective thrombolysis with preservation of thrombotic masses in the pulmonary artery according to angiopulmonography or computer tomography
Table 1
Comparative evaluation of hemodynamic parameters in patients receiving selective and local thrombolytic therapy
Statistical significance Units of measure-men t Befóte thrombolysis After thrombolysis In 2 hours In 12 hours In 24 hours
M m M m M m M m M m
Average pressure in the pulmonary artery Selective mmHg 48,96 8,37 33,56 5,55 22,50 3,15 20,04 2,99 19,55 3,11
Local mmHg 47,89 5,04 15/19 1,07 11,07 1,11 7,98 0,76 10,11 0,94
tip P 0,11 p>0,05 3,20 p<0,005 3,42 p<0,005 3,91 p<0,001 2,91 p<0,005
Heart index Selective l/min/m? 1,06 1,12 0,16 1,28 0,18 1,31 0,14 1,32 0,12
Local 1/min/m2 1,13 0,28 1,94 0,09 2,09 0,08 2,02 0,09 2,01 0,09
up P 0,24 0,08 4,47 p<0,001 4,11 p<0,001 4,27 p<0,001 4,60 p<0,001
Index of peripheral vascular resistance Selective DSmVcm" 5532,00 p>0,05 5201,00 205,11 5612,00 212,25 5325,44 215,21 5239,01 234,15
Local DSmVcm' 5432,89 211,01 5987,65 254,55 4298,66 225ft» 4219,30 247,59 4192^1 235,55
tip P 0,32 223,36 2,41 p<0,05 4,25 p<0,001 3,37 p<0,005 3,15 p<0,005
of pulmonary vascular resistance Selective DSmVcm' 720,11 p>0,05 601,00 69,54 451,11 68,88 401,94 21,33 399,56 19,48
Local DSmVcm' 641,54 56,35 325,11 39,88 312,69 44,11 324^0 52,04 319,54 54,22
fp P 1,00 54,25p>0,05 3,44 p<0,005 1,69 p>0,05 1,38 p>0,05 1,39 p>0,05
p - statistical significance of the parameter differences.
Table 2
Comparison of the changes parameters of actilise concentration in the pulmonary artery and cubital vein by selective and local thrombolytic therapy
Parameter Units of measure-men t Test dose 30 min End of thrombolysis 15 min 60 min
M m M m M m M m M m
Pulmonary artery locally mkt/m a 42,910 9,752 0,576 0,018 0,039 0,005 0,029 0,008 0,010 0,006
Pulmonary artery selectively mkt/ma 0,046 0,006 0,058 0,005 0,078 0,006 0,023 0,004 0,016 0,003
P p<0,001 p<0,001 p<0,001 p>0,05 p>0,05
Cubital vein locally mkt/ma 0,017 0,003 0,020 0,004 0,018 0,007 0,018 0,006 0,018 0,006
Cubital vein selectively mkt/ma 0,043 0,006 0,047 0,008 0,036 0,007 0,029 0,006 0,021 0,005
P p<0,005 p<0,05 p>0,05 p>0,05 p>0,05
p - statistical significance of the parameter differences.
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Altai State Medical University.
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