Pulmonary Thromboembolism

Definition

Aetiology

Pathogenesis
Clinical manifestations
Diagnosis
Treatment
Prevention

Epidemiology

§  The third leading cause of death in the US

§  Every year about 600000 patients are admitted with PE  ( 30% with mortality!)

§   60% of patients who died in hospitals, show signs of thromboembolic disease

§   5 out of 1000 patients who died after large operations, their cause of death was PE

In Russia

•       about 240 000 cases of venous thrombosis is reported every year

•       PE has affected more than 100 000 people

Risk factors

•       Prolonged bed rest;

•       The postoperative period;

•       Heart failure;

•       Obesity;

•       Malignant tumors of internal organs ;

•       Estrogen;

•       Pregnancy;

•       Hypercoagulability
(Antithrombin III deficiency, protein C and protein S, erythremias, dysfibrinogenemias);

•       Thrombocytosis after splenectomy;

•       Age 

•       Thromboembolic disease in history

The pathogenesis of venous thrombosis
(Triad R. Virchow (1856) *)

•       increase blood clotting.
(Hypercoagulable state)

•       vascular wall injury (Endothelial damage)

•       decrease rate of blood flow (blood stasis)

 Types of venous thrombosis

          Occlusive thrombosis                    Mural thrombosis
Floating or axial clots

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Aetiology and pathogenesis

• General overview.

The most common cause and source of embolisation of branches of the pulmonary artery is a blood clot originating from the phlebothrombosis in the basin of the inferior vena cava (90%) or in the right heart (heart failure with dilatation of the right ventricle, in patients with atrial fibrillation).

The composition and morphology of venous blood clots (emboli) change over time. After blood clots is formed, it detaches from its origin. This clots is composed of plasma proteins and fibrin filaments. In the process of passing through the vessel by squeezing and mechanical compression, clots loose about 90% of the initial content of plasminogen. The remaining 10% of the clots is fibrin filaments. This portion of the clots become resistant to thrombolytic therapy, and has the tendency to occult small or large vessel. The pulmonary veins are very small and are susceptible to obturation by a thromb. 
The most typical location of pulmonary thromboembolism is at the lower lobes of the lungs, especially the right. This is because of the smallness of the pulmonary vessel supplying this region. As a result, contact embolus in pulmonary circulation can cause obstruction of the vessel, resulting in haemodynamic and respiratory disorders.

Pathogenesis of pulmonary embolism. 
Any obstruction in the heart vessels, pulmonary vessels, the lung parenchyma, pleura can lead to disorder of pulmonary blood sypply and can trigger complex cellular, humoral and reflex reactions.  
The pathogenesis of thromboembolism is inflieuced by many factors (size, origin, and "age", thromboembolic recurrence, activity of the fibrinolytic system, the initial state of the lungs and heart, concomitant diseases, therapeutic measures elapsed since embolism time).  Note that pulmonary embolism is a rapidly growing and dynamic disease with varying functional, clinical, radiological and laboratory data. This partly explains the difficulty of diagnosis.

Figure 3. Pathophysiology  PE.

• Ethology (risk factors)

The outstanding pathologist in the XIX century, Rudolph Virchow first showed that  blood clots in the pulmonary arteries originate from venous thrombi. He wrote: "More or less large fragments of thromb detached from the soft thrombus and move int bloodstream. So the developing part of the process, which I called "embolism".

• clotting cascade

Thrombus formation process is a cascade of enzymatic reactions resulting in the formation of fibrin strands, which are the basis of the thrombus. By addition of homeostatic coagulation factors including natural anticoagulants operate at preventing thrombosis and fibrinolytic system providing restoring vascular potency after clot formation.

Fundamentally, coagulation cascade is a chain of reaction of activate or inactive precursors (zymogens), resulting in the formation a insoluble fibrin strand. Cascade consists of external and internal coagulation paths. Both pathways converge at the activation of factor X, which results in the conversion of prothrombin to thrombin,  thrombin then converts fibrinogen from the soluble plasma fraction into  insoluble fibrin strands.

The diagram shows coagulation cascade, coagulation relationship, anticoagulants, fibrinolytic systems and inflammatory mediators. In the diagram, the coagulation factor VIIa formed complex with tissue factor (FVIIa / TF) resulting in the activation of factor X.  Factor X can be activated to factor IXa cofactor, in combination with factor VIIIa ( X+VIIIa). Activated factor Xa, together with factor Va converted prothrombin (FII) into thrombin FIIa (Xa+Va+FII). Then, thrombin converts fibrinogen to fibrin. Thrombin also activates both protein C and factors V and VIII through binding to endothelial thrombomodulin receptor (not shown on the diagram). In the presence of a cofactor, protein S activates protein C (aPC) and  proteolytically inactivates Factors Va and VIIIa, thus blocking thrombin formation. Thrombin also binds coagulation cascade factors and inflammatory mediators by activating endothelial cells, monocytes and neutrophils, which then act as adhesion molecules and release pro-inflammatory mediators: NK - high molecular weight kininogen, PK - prekallikrein, PL - phospholipids, PT - prothrombin.

Coagulation cascade that start in the veins and arteries run factors VII and tissue factor which is the cellular receptor for activated factor VII (VIIa factor). Most non-vascular cells constantly express tissue factor, while the synthesis of tissue factor de novo can be run in monocytes. Damage to the arterial or venous wall leads to a transition of tissue factor in the blood stream. Factor VIIa, in small amounts detectable in normal plasma, binds to tissue factor. Contacting the tissue factor, it catalyzes the activation of factor VII, which is also associated with tissue factor. Complex factor VIIa / tissue factor activates factors IX and X, which leads to the formation of factor Xa and factor IXa, respectively. Factor IXa binds to factor VIIIa in the surface of a phospholipid membrane.

On the surface of a phospholipid membrane factor Xa binds factor Va, forming a prothrombinase complex. As part of this complex factor Xa converts prothrombin to thrombin, which in turn, dissociates from the membrane surface and converts fibrinogen into fibrin monomer. Fibrin momomers polymerize to form fibrin strands that bind to and stabilize factor XIIIa. Thrombin amplifies its own formation through a feedback mechanism, by activating factors V and VIII, cofactors and prothrombinase complex, respectively. Thrombin can also activate factor XI, thus leading to further formation of factor Xa.

Locally formed fibrin wraps and secures the platelet plug. The complex coagulation factors and cofactors on the platelet surface with a plurality of feedback loops enhance this process. The increasing number of activated platelets adhere to the sub-endothelial matrix and aggregation to other platelets and erythrocytes. The platelets granular protein having procoagulant activity which enhance formation of thrombin. Once the thrombus reaches a certain size, it can break under the action of internal fibrinolytic system which ends in the separation of thrombus  and development of thromboembolism.

• sources of embolism

Thrombi formed in arteries and veins differ substantially. While arterial thrombi are composed mainly of platelet thrombi, and in the venous thrombi comprise mainly of fibrin and erythrocytes. Venous thrombosis usually develops in the muscle veins of the legs and  deep vein valves, characterise by a slow blood flow.

Principally, venous thrombosis of any location can be complicated by the development of pulmonary embolism (PE). Most life threatening emboli are formed from the inferior vena cava, which is associated with approximately 90% of PE. In most cases, the primary thrombus is located in the ilio-caval segments or proximal veins of the legs (femoral-popliteal segment). Such location of venous thrombosis can lead to pulmonary embolism in 50% of cases. Venous thrombosis located in the distal deep vein can cause  PE from 1 to 5%. Symptoms of deep vein thrombosis (DVT) detected in 70% of pulmonary embolism. In other words, when a blood clot in the veins cannot be detected, it is necessary to think that its all gone into the lungs.The source of emboli from iliac, renal vein, vein of upper limbs (resulting formulation venous catheters) and the right heart (atrial fibrillation, dilation chambers) are rare.

The most dangerous pulmonary embolisms are caused by the"floating thrombi"  that are fixed in the distal venous bed.  "Floating thrombi" typically formed in veins of smaller caliber and can move proximally into larger veins : deep vein of  shin- the popliteal vein-and then in a deep common femoral vein - in the common iliac- the inferior vena cava.

Figure 5. Sources of embolism and embolus migration path. Embolical clots usually form in deep veins of the lower limbs, often - the shins. Normally, thrombus formation begins on the venous valves. When thrombosis reaching  above the knee joint space (or initial proximal   location)  it increases significantly in size. 

• Risk factors for venous thromboembolism (VTE)

Pathogenesis of deep venous thrombosis (DVT) always begins with a reference triad Virchow. 

• Venous stasis is considered an important factor contributing to the development of pulmonary embolism. The role of its has been proven in studies on patients with spinal cord injury, and the various forms of paralysis. These studies have shown that blood clots are formed mainly in areas with slow blood flow, such as large venous collectors, hip and thigh, valves and vein bifurcation. Especially significant blood flow slows down in situations where there is no physical activity, such as bed rest or during long travels, when the activity is considerably reduced musculovenous pump and the blood flow is slowed down to stasis.

It is shown that blood stagnation leads to activation of coagulation system, leading to a state of local hypercoagulability. Moreover, possible damage to the endothelium due to tension of the vascular wall, which also contributes to a hypercoagulable. stage products of coagulation and fibrinolysis may also damage the endothelium that, in turn, reinforces the tendency to hypercoagulability.

• Increased tendency to clotting (hypercoagulable)                

The risk of venous thrombosis increases when there is a shift in the hemostatic system in the direction of hypercoagulation (procoagulants activity predominance of anticoagulant). When this

imbalance develops as a result of hereditary factors, thrombophilic condition persists throughout life. 
In most cases, disbalance of the coagulation cascade occurs as a result of  hereditary abnormality of  hemostastis. While every genetic defect is an independent factor in the risk of thrombosis, people with several types of thrombophilia have a substantially greater risk. Sufficiently high prevalence factor V Leiden mutation and prothrombin G20210A mutation of the gene, so that a combination of these defects is relatively frequent in the general population. Currently, diagnostic features allow you to confirm the hereditary abnormalities of the hemostatic system in more than 50% of the patients  with venous thromboembolism (VTE).

• Damage to the vascular wall               

Damage to the vascular wall is an important predisposing factor for thrombosis after major surgery on the hip and knee joints. After vessel injuries, hemostasis develops a number of changes, in particular increased levels of von Willebrand factor and platelet aggregation, which further promotes thrombosis.
Factors that predispose to venous thromboembolism

• Strong predisposing factors ( vessel wall injury)
• Fractures of the lower extremities (leg bones, the femur)
• Prosthetic hip or knee joints                
• Major surgery             
• seriously injured                     
• Spinal cord injury                   
• Arthroscopic knee surgery                  
• venous catheters                     
• chemotherapy             
• Chronic cardiac or respiratory failure    
• Hormone Replacement Therapy
• malignancies               
• Receiving oral contraceptives   
• Strokes with the development of paralysis         
• postpartum                 
• Previous episodes of VTE        
• hereditary thrombophilia
• Weaknesses predisposing factors (hazard ratio <1)
• Bed rest for more than 3 days              
• Prolonged stay in the sitting position (e.g., in an airplane, a car)            
• Age (risk increases with age)    
• Laparoscopic surgery (e.g., cholecystectomy)               
• Obesity
• Pregnancy                   
• varicose veins

Clinic and complications

• The clinical picture of deep vein thrombosis (DVT)

The source of emboli with pulmonary embolism are almost always from the veins, especially veins of the lower extremities. Suspected DVT is possible in the presence of the following clinical symptoms:

• Spontaneous pain in the feet and legs, worse when walking.
• The occurrence of pain in the calf muscles, especially in dorsiflexion of the foot (Homans' sign), when the anteroposterior compression of the lower leg (the calf muscles; Moses symptom).
• Local tenderness veins.
• Change the colour of the skin.
• Soreness in the course of vascular bundle.
• Visible leg and foot edema or asymmetry detection shin and thigh circumference (1.5 cm). For suspected PE to identify asymmetric edema measurement is necessarily lower leg circumference (10 cm below the knee caps) and hips (15-20 cm above the kneecaps).

However, in half of the cases are asymptomatic phlebothrombosis. Development of clinical DVT thrombosis varies with the length, degree of occlusion and the presence of inflammation. Most of clinically overt venous thrombosis begins with deep vein thrombosis shin, but the clinical picture appears only in the propagation of thrombosis in the proximal veins is the cause of asymptomatic phlebothrombosis should first mention the possibility of an incomplete obturation thrombosed veins. Another reason may be insignificant influence on thrombosed vein blood flow, such as deep vein thrombosis isolated reed. Finally, perhaps one of the doubled clotting superficial femoral or popliteal veins.

The clinical picture of pulmonary embolism (PE)

• symptoms of pulmonary embolism

Supporting complaints were forced to make a PE in the differential diagnoses, are shortness of breath, pain (pain in the chest of various kinds, and sometimes - abdominal), frequent palpitations. Often marked drop in blood pressure (possibly with loss of consciousness). Other symptoms include cough, hemoptysis, low-grade fever, symptoms of cerebral blood flow and organ failure.

• Dyspnea 

Shortness of breath is mainly inspiratory character (the patient, like a fish, "catch air" mouth). For her peculiar sudden development, synchronized with popadanieem emboli in the pulmonary artery, as well as variability in the severity of respiratory failure.

In patients with pulmonary embolism dyspnea quiet (without distant wheezing), independent of the body position. Patients lie - orthopnea uncharacteristically! (Position orthopnea accept patients who have already had to PE or joined left ventricular heart failure).

bronchospasm element may complement the clinical picture in any patient, not only suffering from chronic disorders of the respiratory tract.

If dyspnea is not possible to link to the existing pathology or she is threatening the growth of their character (in the form of attacks of breathlessness), that is, nothing definite can be motivated, then the suspicion of pulmonary embolism with good reason.

• hypotension  

Another starting symptom is detected in a patient hypotension, especially if its tendency to the appearance not previously observed.

Properties hypotension with PE: variation in depth from a minor reduction in blood pressure to the degree of shock; parallel hypotension increased central venous pressure (at this time, you can catch the jugular veins, or notice them ripple).

There is not always a direct correlation severity of hypotension on the caliber of the affected vessel 

• Tachycardia 

As already mentioned, tachycardia - obligate symptom of pulmonary embolism. The severity of sinus tachycardia depends on the severity of the pulmonary artery. But it is worth considering that the continuity of this nonspecific symptom becomes a valuable contribution to the diagnosis only in combination with other manifestations.

• Pain syndrome

Pain syndrome makes the time mask, which requires differential diagnosis, without which it can mislead a physician and cause loss of time and incorrect choice of tactics.

On chest pain patients often complain of a young age, still has not suffered cardiorespiratory pathology. Typically, this contingent formed patients who had undergone surgery, trauma. Attention is drawn to the sudden appearance of this symptom. Usually the pain is not clear localization, although it is enough intense.

The pain can wear coronary similar character, no different from its expression of pain in angina, and occur at the beginning of pulmonary embolism, clinically resembling myocardial infarction . It is believed that in the genesis of the pain acts as a dramatic expansion of the mouth of the pulmonary artery in its massive thrombotic occlusion masses.

The name of another embodiment of the pain syndrome, pulmonary, pleural, carries with it an explanation of its origin - the defeat of the pleura in the development of myocardial infarction, lung or pneumonia. Patients worried about a sharp pain, worse when breathing (especially severe), cough, change of body position.

In the case involving the diaphragmatic pleura is formed abdominal pain option. It may also participate genesis acute swelling of the liver, and the swelling wall gallbladder bed (through the development of right heart failure). In these patients, pain is identical manifestations of hepatic colic (spasmodic pain in the right upper quadrant, often with vomiting, persistent hiccups, icteric sclera and skin) may be accompanied by intestinal paresis. In some patients the symptoms of peritoneal irritation (case 6). Patients do not always accurately localize the pain. This is due to different reasons: the status severity, various pain sensitivity threshold, combining one pain syndrome (mixed type)

Weakness  

Patients suffering from pulmonary embolism, usually develops weakness, which is the manifestation of cardiovascular disease. It can also be observed in the development of heart attacks, pneumonia and pleurisy, and be the result of intoxication. Additionally, general weakness may be the main clinical sign occlusion of small branches of the pulmonary artery.

• Cough 

Cough, hemoptysis, low-grade fever, and a syndrome of laboratory changes not only specific, but are not mandatory, their presence and severity depends largely on the severity of the injury. Among them, perhaps only the cough is very common. However, cough and expectoration of sputum - the later symptoms appear within a few days after the occurrence of pulmonary embolism.

• hemoptysis 

Hemoptysis usually is of great importance in the diagnosis of pulmonary embolism. But this feature is not early: it appears 2-3 days PE and found only 30% of patients as a result of heart attack lung . Hemoptysis rarely massive, often only an admixture of blood is observed in the form of streaks or small clots.

• Manifestations of multiple organ failure 

Manifestation of ischemia and hypoxia are the appearance of cerebral organs (most often in the elderly, loss of consciousness, convulsions and paresis) and renal syndromes (anuria, usually after removing the patient from shock, pulmonary embolism).

Clinical forms of PE

PE classification, taking into account the current embodiment and massiveness vascular lesion.

option PE	Anamnesis	LA volume% obstruction	clinical manifestation	typical pressure
				PAP	RAP
acute non massive	A short, sudden onset of	< 50	Shortness of breath, possibly in combination with pleural pain, and haemoptysis	normal	normal
acute Massive	A short, sudden onset of	> 50	Right heart failure, hemodynamic instability and possible loss of consciousness	45/20	12
subacute massive	Few weeks	> 50	Shortness of breath, and right ventricular failure	70/35	8
PAP, pulmonary artery pressure; RAP, mean right atrial pressure.

• Acute massive pulmonary embolism
•  Sub-acute massive pulmonary embolism
•  Acute PE

 Clinical syndromes in PE

Acute no massive.

In acute PE, the most frequent clinical syndromes are:

Acute vascular (shock collapse) or acute cardiovascular (cardiogenic collapse) failure 

Acute coronary insufficiency 

Anginal pain in nature and ischemic ECG changes, due to a sharp decrease in blood supply to the coronary arteries and fall in blood flowing to the left heart and the pressure drop in the aorta, and the resulting pressure increase in cavities of the right heart. Obstruction in the coronary circulation leads to heart muscle ischemic, mainly in the subendocardial regions. Chest pain, apparently, can be conditioned and acute dilation of the initial division of the pulmonary artery with irritation embedded in its wall of nerve receptors,

  

Acute asphyxia syndrome 

Asphyxia syndrome often develop during the first moments after the occlusion and combines with cardio-vascular collapse and cerebral disorders. The origin of it must also take into account several factors:

• ·         Disorder of intrapulmonary circulation with an increase in capillary permeability and the           development of pulmonary edema.
• ·         Generalized reflex constriction of the bronchial tree, greatly disturbed bronchial patency.
• ·         Hypoxia (anoxia) of brain centers that regulate breathing.

 The main symptoms of asphyxia syndrome are:  cyanosis of the face, chest, neck, feeling of choking, shortness of breath at the beginning of the inspiratory and expiratory, dilated pupils, involuntary urination and defecation. Subsequently rapid breathing or is replaced by a rare Cheyne-Stokes breathing, and finally respiratory arrest occurs. 

 Acute cerebral disorder syndrome 

Acute cerebral disorders in pulmonary embolism can cause brain tissue hypoxia or haemorrhages of the brain membranes. This can lead to a sudden loss of consciousness, pale skin, vomiting, spasms of the facial muscles and limbs, confusion, coma, pupillary constriction and sometimes can lead to the death of patient.

Acute renal failure 

Due to the pressure drop in the renal vessels with reduced glomerular filtration and dystrophic changes in the tubular epithelium lead to the renal hypoxia. It is usually manifested by a sharp decrease in diuresis (up to anuria) and the appearance of mild uremic symptoms (moderate azotaemia, chloropenia), albuminuria and cylindruria

Acute abdominal syndrome

Pain and muscle tension in the upper right quadrant of the abdomen (or epigastric pain) due to acute congestive swelling of the liver with the development of acute pulmonary heart disease. In such cases, patients manifest clinical signs of mild jaundice and vomiting and often gives erroneous diagnosis of acute pancreatitis or cholecystitis. 

Laboratory and instrumental methods of diagnosis.

The diagnostic procedures for suspected pulmonary embolism include chest X-ray, blood gas analysis and an electrocardiogram, D-dimer, echocardiography, spiral computed tomography, contrast-enhanced (CT angiography) of the chest, ventilation-perfusion lung scintigraphy, angiography, and other methods of diagnosis of thrombosis of deep lower limbs (ultrasound, CT venography).

 Electrocardiography (ECG)

This is most widely available method of investigation. When PE may reveal arrhythmias, conductivity, voltage and complex ventricular repolarization process, signs of overload of the right heart.

• Acute pulmonary embolism leads to the sudden appearance of pulmonary hypertension and development of acute pulmonary heart. Signs of PE in electrocardiographic:
• Symptom Q _III -S _I (QR _III -RS _I).
• Hoisting ST segment in leads III, aVF, V _1.2 and discordant reduction ST segment in leads I, aVL, V _5.6.
• Appearance of negative T waves in leads III, aVF, V _1.2.
• Complete or incomplete right bundle branch block.
• Signs of overload right atrial (P-pulmonale) in leads II, III, aVF.
• Rapid positive dynamics of these changes while improving the patient's condition.

These ECG changes occur only in 15-40% of cases and more common with occlusion of the lumen of the pulmonary artery by half or more, however ECG remained normal in more than 27% cases of pulmonary embolism.

One of the major signs of acute pulmonary heart disease is the electrocardiographic Mc Jin-White syndrome (S _I Q _III T _III ): sudden appearance of deep dents S _I and Q _III , negative T _III . 

Chest X-ray

Chest X-ray - method has low sensitivity and specificity for the diagnosis of pulmonary embolism.  The main aim of radiography without contrast is to exclude other conditions that are similar to the clinical picture of pulmonary embolism (pneumonia, cancer, pneumothorax, pulmonary edema, and others). 

Radiological signs: high standing dome diaphragm on the affected side; infiltration of the lung tissue (after 12-36 hours from onset); bulging of pulmonary artery; increase in right heart; expansion of the superior vena cava and others. These symptoms only with a certain degree of probability may be associated with the occurrence of pulmonary embolism, and only in cases where they are combined with the described clinical symptoms of embolism (shortness of breath, chest pain, etc.).

                                                        

Radiographic signs of pulmonary embolism (Scheme Heinrich F., 1981): 1 - high standing dome of diaphragm; 2 - pleural effusion; 3 - lung infarction; 4 - "open" vessels at the root of lung contours; 5 - contralateral lung congestion; 6 - dilatation of the right ventricle; 7 - dilatation unpaired veins and the superior vena

symptoms of pulmonary embolism:

• Symptoms of acute pulmonary heart disease.
• The symptoms of impaired blood flow in the pulmonary artery (changes roots, pulmonary drawing).
• Symptoms of pulmonary infarction.

 Laboratories indicators

Among the laboratory parameters in the diagnosis of pulmonary embolism significant place is occupied by the level of D-dimer . In the analysis of blood gas most common symptom of pulmonary embolism is a drop in oxygen partial pressure in arterial blood, which is observed at 13% occlusion of the pulmonary vascular bed, hypocapnia and respiratory alkalosis due to compensatory hyperventilation. Hypercapnia (increased PaCO2) is possible in extremely severe cases, due to pulmonary edema. Note Normal blood gas levels do not exempt diagnosis of pulmonary embolism

The occurrence of pulmonary infarction may will to mild hyperbilirubinemia, leukocytosis and increased ESR. Transaminases and creatine phosphokinase usually not changed, which is of great important in the differential diagnosis of PE with myocardial infarction, but the levels of LDH, alkaline phosphatase may increase. The appearance of proteinuria and microscopic haematuria may be caused by hypoxia and impaired renal hemodynamic 

D-Dimer

D-dimer is a fibrin degradation product. Its plasma level is increased by thrombus formation, since it is always simultaneously activated by fibrinolytic system. Thus, a normal level of D-dimer makes the diagnosis of pulmonary embolism or deep vein thrombosis (DVT) is unlikely. Alternatively, fibrin can be formed by a number of other pathological conditions such as malignant tumors, inflammation, necrosis, dissecting aortic aneurysm et al., I.e.  D-dimer is not specific for PE, and a positive result has a low predictive value in its diagnosis. In addition, increasing the specificity of D-dimer for PE decreased during pregnancy and with age, accounting for <10% of patients older than 80 years.

Diagnosis of deep vein thrombosis (DVT) (US deep venous with compression tests, CT venography, MR venography)

In 90% of cases of pulmonary embolism are the source of blood clots in the deep veins of the lower extremities.  

Treatment

General overview, aims and objectives of the treatment

The aim of therapeutic measures in PE is to normalize or improve lungs perfusion, preventing the development of severe chronic pulmonary hypertension.

This can be achieved by:

• Suppression of thrombosis.
• Activating lysis of thromboembolism.
• Preventing further thrombus formation.
• Post syndrome treatment.

 Tactical measures on the acute phase PE.

5.                   Strict bed rest for the prevention of recurrence of pulmonary embolism.

6.                   Catheterization of central vein for infusions and determining the central venous pressure CVP.

7.                   Immediate bolus heparin to prevent further thrombogenesis

8.                   Inhalation oxygen-air mixture.

9.                   The struggle with the shock (hemodynamic support).

10.               thrombolysis or embolectomy .

11.               When complications of a heart attack, pneumonia antibiotic therapy appointment.

treatment embolism also aims at:

• Normalizing hemodynamic parameters (including infusion therapy, administration of positive inotropic drugs).
• Restoring the permeability of pulmonary artery (thrombolysis or embolectomy).

Pain relief

• Intravenously:
• Fentanyl 1-2 ml of 0.005% solution with 2.1 ml of 0.25% solution of droperidol .
• Or 0.5-1 ml of a 1% solution of morphine with 0.4-0.7 ml of 0.1% solution of atropine .
• Or other analgesics

Morphine 1% - 1 ml with diluted solution of 0.9% sodium chloride and 20 ml (1 ml of the resulting solution contains 0.5 mg of active substance) and administered intravenously by fractional 4-10 ml (2.5 mg or ) every 5-15 minutes to eliminate pain and shortness of breath or until there are side effects (hypotension, respiratory depression, vomiting).

We must remember that opioids are contraindicated in acute abdominal pain, convulsive disorders, heart failure due to chronic lung disease.

 Hemodynamic and respiratory support

Acute right ventricular failure, leading to a decrease in cardiac output, is the main cause of death from pulmonary embolism at high risk . Thus, maintenance therapy is essential component for the treatment of pulmonary embolism. 

In PE patients with decreased cardiac index, but with normal BP, moderate infusion of (500 mL rheopolyglucin and dextran) can improve hemodynamic. Note that massive fluid therapy can deteriorate the function of the right ventricle due to mechanical distension and also through reflex mechanisms.

If arterial hypotension develops, immediately administer  Dexamethasone (4-8 mg),  Rheopolyglucin 400 ml with introduction rate of 20-25 ml / min; this is important to correct the electrolytes balance. Positive inotropic preparates  ( dopamine , Korotrop); the rate of administration of dopamine depends on the degree of cardiovascular system insufficiency and ranges from 3 to 15 ug / kg / min.

Contraindications of the use of dopamine: pheochromocytoma, ventricular fibrillation. Dopamine should not be mixed with a solution of sodium hydrogen carbonate 

If hypotension remains persistent,  dopamine and noradrenaline can be administered (Risk: cardiac arrhythmias, renal and mesenteric vasoconstriction, decrease blood flow into the internal organs; kidneys and liver

Possible alternative to dopamine administration are the sympathomimetic preparats,  Angiotensin Amide . 

If there is bronchospasm. 

Slowly administer 10 ml of 2.4% solution of aminophylline ( aminophylline ) intravenously; inhalation of salbutamol 2.5 mg (1 Nebula) through nebulizer for 5-10 min and repeat after 20 minutes if there no positive effect is in the first inhalation.  Aminophylline decreases total peripheral vascular resistance and pressure in the pulmonary circulation, increases the sensitivity of the respiratory centres to the stimulating influence of carbon dioxide. Common side effects include tachycardia, tremor, irritability, nausea and / or vomiting. There have been cases of hypotension and heart failure after rapid administration of aminophylline. Overdose can lead to death due to the development of cardiac arrhythmias or seizures. When to administer aminophylline?  When systolic blood pressure SBP> 100 mmHg, excluding myocardial infarction, absence epilepsy, severe hypertension and paroxysmal tachycardia.

Isoproterenol - inotropes. It also has vasodilatation effect on blood vessels of the lungs, but this not advantageous as it also has effect on peripheral vasodilatation. A decrease in blood pressure of the right ventricle may lead to its ischemia.

Norepinephrine directly exerts a positive inotropic effect in the right ventricle. Increase in blood pressure due to the stimulation of peripheral alpha-adrenergic receptors also improve blood flow to the right ventricle. Don’t us norepinephrine in hypotensive patients.

Dobutamine has been effective in patients with pulmonary embolism requiring hospitalization in the intensive therapy, dobutamine increased cardiac output, improved tissue oxygenation, increase cardiac index without any significant changes in heart rate, systemic and pulmonary arterial pressure. NOTE -increase in cardiac index may cause ventilation-perfusion mismatch
Adrenalin  combines the advantages of norepinephrine and dobutamine without expanding system vessels. In shock in patients with pulmonary embolism the use of adrenaline can give very good results.

Levosimendan could improve the function of the right ventricle by improving its contractility and pulmonary vasodilation.

 Thrombolysis

Thrombolytic therapy is of first-line treatment in patients with cardiogenic shock and constant arterial hypotension, i.e. patients with pulmonary embolism at high risk . Contraindications to the use of thrombolysis:  myocardial infarction, severe gastrointestinal bleeding

 (e.g., surgery within the last 3 weeks or gastrointestinal bleeding notice less than one month), in patients with life-threatening pulmonary embolism considered as relative

Absolute contraindications to thrombolytic therapy are only two: severe internal bleeding or recent spontaneous intracranial haemorrhage.

Thrombolytic ( streptokinase or urokinase or recombinant tissue plasminogen activator) are administered intravenously. The method of administration through a catheter into the pulmonary artery has no advantages.

The thrombolytic treatment should be started within 48 hours of the onset of symptoms, but can also be given to patients who have showed symptoms of PE for 6-14 days.

Table below shows the standard use of thrombolytic therapy with streptokinase, urokinase and recombinant tissue plasminogen activator (alteplase).

Heparin should not be administered at the same time  with streptokinase or urokinase, however  alteplase infusion combination is possible.

Thrombolytic treatment is associated with a high risk of bleeding, especially in the presence of concomitant diseases predisposing. Pooled data from a number of randomized studies, the incidence of major bleeding - fatal intracranial hemorrhage and bleeding - 13% and 1.8%. When using non-invasive diagnostic methods PE thrombolytic frequency-associated bleeding is reduced. 

 Approved thrombolytic therapy regimes PE

A drug	mode of administration
streptokinase	250 thousand units’ dose within 30 minutes at a rate of 100 thousand Units / h for 12-24 hours. Fast mode of administration: 1.5 million units within 2 hours.
urokinase	4400 U / kg dose for 10 minutes, followed by administration of 4400 U / kg per hour for 12-24 hours. Fast mode of administration: 3 million units within 2 hours.
Recombinant tissue plasminogen activator	100 mg for 2 hours or 0.6 mg / kg for 15 minutes (maximum dose - 50 mg).