Management of Pulmonary Embolism:

The prophylaxis and therapy of DVT as prevention of massive pulmonary embolism (MPE), optimization of ventricular preload and the amplification of RV myocardial blood flow; and approach to life-threatening MPE.

Filip A. Konecny Msc., DVM, CRTC, CCRA 1 2.

1 University of Veterinary Medicine and Pharmaceutical Sciences Brno, Czech
Republic.


2 McMaster University, Ontario, Canada L8S 4L8.Address correspondence to:
Dr. Filip A. Konecny, CTRC, CCRA, Department of Physiology , University of Veterinary Medicine and Pharmaceutical Sciences, Czech Republic. Palackeho 1-3, 6120 42 Brno, Czech Republic, Ph. +420 541562301, E-mail:. filkon@post.cz

Abstract

The most traditional definition of shock in the massive pulmonary embolism (MPE) literature is the life-threatening presence of hemodynamic instability, followed by the critical reduction of organ perfusion. During this condition heart cannot drive blood from the systemic circulation into pulmonary, since it is obstructed by an embolus or multiple emboli. On many occasions, liberating of an obstruction is impossible, thus embolism is deadly. Over the decades of MPE study, it becomes more evident that treatment should start with a prevention of (DVT), since more than twenty percent proven patients with MPE have signs and symptoms suggesting leg vein thrombosis and seventy percent of them have venographic evidence of venous thrombosis. Physician responsibility is to successfully avert this circulation collapse by preventing DVT.


This article discusses the prevention and treatment options that clinician can implement, and outlines current prevention and medication strategies of DVT/MPE.

 

Key words: Massive Pulmonary embolism; medical prophylaxis of DVT and MPE, supportive and thrombolytic management.
Abbreviations: APTT activated partial thromboplastin time; AT III antithrombin; CO cardiac output; COPD Chronic obstructive pulmonary disease; CPR cardiopulmonary resuscitation; CT Computed Tomography; CTPAV Computer Tomography Pulmonary Angiography Venography; CTPE Chronic pulmonary thromboembolism; CXR chest radiograph; DVT deep vein thrombosis; ECG Electrocardiography; GES graded elastic stocking; HC II heparin cofactor II; HIT heparin induced thrombocytopenia; IPC intermittent pneumatic compression devices; IVC inferior vena cava; INR the international normalization ratio; LDUH low dose unfractionated heparin; LMWH low molecular weight heparin; LV left ventricle; MAP mean arterial pressure; METRO study Melagatran for THRombin inhibition in Orthtopedic surgery; MRA Magnetic resonance angiography; MPE massive pulmonary embolism; NO Nitrous Oxide; NSAID non steroid anti inflammatory drugs; PA pulmonary artery; PAI-1 plasminogen activator inhibitor; PAP pulmonary artery pressure; PCV packed cell volume; PE pulmonary embolism; PEP Pulmonary Embolism Prevention trial; PF platelet factor; PGI Prostaglandins; PIOPED Prospective Investigation of Pulmonary Embolism Diagnosis; PPH primary pulmonary hypertension; PT prothrombin time; rt-PA recombinant tissue plasminogen activator; RA right atrium; RBC red blood cell; RV right venttricle; RAP right atrial pressure; rt-PA recombinant tissue plasminogen activator; RV right ventricle, ventricular; RVCPP Right ventricle coronary perfusion pressure; SK Streptokinase; t-Pa tissue plasminogen activator; TF tissue factor; TR tricuspid regurgitation; UK urokinase; USET Urokinase Streptokinase Embolism Trial; V/Q ventilation/perfusion ratio; VDUS Leg venous duplex sonography; VR venous return; VTE venous thromboembolism.


Venous thrombosis and thromboembolic syndrome is always a severe illness with often fatal end. Thrombi fragments may detach and occlude branches of the pulmonary artery. Occlusion of the main branches of the pulmonary artery causes a substantial blood pressure increase. Blood pressure increase cause the right ventricle (RV) to generate higher pulmonary arterial pressure to maintain its normal output in order to ensure circulation. When occlusion reaches more than 50 % of pulmonary arterial tree, RV is restricted from such generation. This leads to a severe hypotension where non-principally muscular RV is capable to respond to an immediate increase of after-load and experiences diastolic and systolic failure with a stern tricuspid regurgitation. As a result, RV myocardial ischemia is followed by an ischemia-induced RV failure. Fatalities can be prevented by early physical exam followed by planned prophylaxis.
The prophylaxis of PE started preoperatively and continued for 35 days, after the orthopedic surgery in the Pulmonary Embolism Prevention (PEP) trial, where the dose of aspirin helped to reduce PE in about 43% of patients (1). Platelet inhibition was a major achievement in this prophylaxis, which considered patients that survive either surgery for hip fracture and were assigned for the treatment with aspirin 160 mg daily or to a placebo. Data showed a reduction of PE and DVT vs. placebo in about one–third of assigned patients throughout the period of increased risk (1). New tested Aspirin NCX 4016, with nitric oxide (NO) release, was shown in mouse and rabbit model, that NO could add to inhibition and accumulation of platelets in pulmonary vasculature. The (NO) aspirin role was tested as it is a powerful vasodilatator and inhibitor of platelet aggregation in vitro as well. NCX 4016 manifest better antithrombotic activity compared to regular aspirin mainly because of direct effect of NO on platelets (2, 3).


Use of the low dose of unfractioned heparin (LDUH) as prophylactic approach to the DVT/PE is effective in reducing incidence of DVT, calf thrombosis and PE in the patients undergoing a variety of elective surgical procedures. Heparin catalyzes effect of antithrombin III that sufficiently inhibits factor IXa and Xa, which are required to convert prothrombin to thrombin at early stage of coagulation sequence. This action prevents clot formation, but is ineffective once factor Xa was activated and the process started (4). This could be overcome by use of the LMWH, which in addition has a greater inhibitory effect of factor Xa. Advantage of clinical use of LMWH is based on longer half-life and reduced need for a laboratory monitoring compared to the LDUH that are difficult to titrate and the dosage has to be adjusted precisely to the patient weight. The difficulties of using LDUH are further derived from a directly testing heparin levels that was not established for the routine monitoring. Measuring of a direct plasma heparin levels, rather the APTT, has to be implemented because APTT does not always correlate with a plasma heparin levels.


LDUH is usually given preoperatively (5000 UI sc.), and then given post operation at the dose of 5000 UI every 8-12 h to, and then for 7 –10 days or until the patient is fully ambulatory. Hazard of LDUH might not be appreciated and the administration of a continuous infusion in the hospital setting is often not entirely valued due to the need of monitoring and dosage adjustment that could be inadequate to administered doses (5). The administration of LMWH’s is highly appreciated and advantageous in that respect, because of no need of monitoring and it’s subcutaneous instead of intravenous injection. Other differences that favor use of a LMWH over the LDUH are the metabolism and the elimination. LDUH is cleared through liver rather then kidneys; moreover some of the LMWH’s are eliminated unchanged in urine (fondaparinux sodium).


In the prospective randomized study the LDUH and LMWH enoxaparin were compared in the treatment of an acute PE. Results demonstrated that no statistical significant differences in terms of recurrent thromboembolism, major bleeding and death after 8 and 90 days were found (6).
LMWH was proven as safe as effective for the prevention and treatment of DVT in many trials and demonstrated an alternative for LDUH. Enoxaparin, Dalteparin, Ardeparin are licensed for the treatment of DVT, with Tinzaparin additionally licensed for the treatment and prevention of DVT and PE. Many different LMWH are offered worldwide, therefore the prescribed amount is highly clinical specific; however some similarities in terms of its use exists.
Enoxaparin (Lovenox) was marketed for both the prevention and the treatment of the DVT/PE. The treatment dose for DVT with or without PE was established to the 1.5-mg/kg sc per day, or 1mg/kg sc per 12h. The dose 1.5mg/kg body weight is dosing equivalent of the150 IU/kg and should be given once daily at the same time. The common use of the Lovenox is the prophylaxis of DVT/PE after the orthopedic surgery, such is knee arthroplasty, where is usually initiated 12 to 24 h postoperatively 40mg sc, and continued typically 7-14 days until patient is released from the hospital. In the studies made by Planes (7) and Bergqist (8) was documented that prevention with enoxaparin after the total hip replacement surgery have to be longer than only within post surgical hospitalization. Planes (7) showed that at the day 21 the incidence of DVT was lower for the enoxaparin group than a placebo, while Berquist (8) further prolonged its use for one month with 40mg q.d.sc after the surgery. Need for an early initiation of anticoagulant therapy after total knee arthroplasty (30 mg of enoxaparin sc twice daily for 4 to 14 days) was recommended in the study made by Fitzgerald et al (9).


Lovenox was recommended after the abdominal and the colorectal surgery. For the prevention of the DVT/PE after the abdominal surgery, it was optional to use 40mg sc, once a day initiated 2 h preoperatively and followed for the total of 7-10 days. The dose of 40 mg of enoxaparin, injected sc. was more successful in prevention of VTE in emergency or an acute medical illness during 6-14 days compared to 20mg or placebo (10).
Another LMWH that used in patients undergoing the abdominal surgery is Dalteparin (Fragmin). The dose of the 2500UI sc is usually initiated one to two hours prior the surgery and repeated daily for 5 to 10 days. For the patient undergoing an orthopedic surgery, for example the hip replacement surgery, it is recommended to use 2500UI sc within 2 h before the surgery and from 4 to 8 hours after, he may be given the 2500 UI sc and then the 5000 UI, once daily for the period 5 to 10 days. Additionally in the orthopedic setting use of Dalteparin was compared with the direct thrombin inhibitor Melagatran in METRO study (Melagatran for THRombin inhibition in Orthtopedic surgery, which documented the same efficacy and the safety for venous thromboembolism (VTE) and PE. Dalteparin, in the dose of the 5000IU sc once daily, started evening before the surgery and followed up for 8-11 days (11) was found successful.
Another LMWH that is used mainly after the orthopedic surgery for the prophylaxis of PE is Ardeparin (Normiflo). This LMWH is administered in the dose of the 50 anti Xa IU/kg postoperatively, twice daily, Normiflo was proved to be effective and safe in VTE (DVT/PE) prevention in patients undergoing a major knee surgery (12,13).
The last LMWH’s discussed is Tinzaparin (Innohep), which is used for the treatment and the prevention of DVT and additionally is licensed in dose 175 antiXa IU/kg sc, administered once daily at the same time every day, for the treatment of PE. The average duration of the administration is 7 days after the hip and the knee surgery. Postoperative prevention of DVT is accomplished by the dose of 75 anti Xa UI/kg. In general surgery 3500anti, Xa UI/kg is given 2 hours before the surgery and then followed for 7-10 days with the same dose. In Canadian study 97 patients with the high probability of lung scan findings were treated with Tinzaparin, none of them had repeated episode of VTE, respectively PE (14).
Numerous well-designed clinical trials have demonstrated that LMWH’s are as effective and safe as LDUH. No laboratory control is needed for LMWH’s; therefore they could serve as an initial treatment for an out-of hospital DVT patients. For patients with pulmonary embolism, LMWH’s are the potential alternative for LDUH (6, 14, and 15).
Complications with LDUH anticoagulant treatment include heparin induced thrombocytopenia (HIT), inability of heparin to access platelets bound factor X and clot bound thrombin. Heparin induced thrombocytopenia type I. is characteristic by a mild thrombocytopenia caused by direct interaction between platelets and heparin developed within 1-4 days of Heparin treatment, Type II is a severe thrombocytopenia immunologicaly mediated. In the literature is documented that (HIT) leads to an abnormal activation of the coagulation system and the platelets. Formation of platelet-derived micro particles caused (pseudo-PE) (16-18).
Other limitation of heparin in PE prophylaxis is the inability to access clot bound thrombin. An effort was made to develop a direct thrombin inhibitors that could directly access thrombin bound in clot. Currently, three drugs were approved for the clinical use (lepirudin, bivalirudin, and argatroban) other drugs are in an advanced clinical testing such is (melagatran/ ximelagatran). Comparison of these agents and its role in the clinical prophylaxes of VTE/PE is in progress (11). Direct thrombin inhibitors compared to heparin inhibit thrombin without cofactor action of (AT III, HC II); eliminate HIT I, II as a side effect and inhibit thrombin already bound on fibrin in clot. Direct thrombin inhibitors are not inactivated by platelet (PF 4) or plasma proteins.

DVT and PE patients that developed immunogical hysensitivity to heparin could benefit from use of Warfarin (Coumadine). Warfarin, inhibits vitamin K coagulation factors (II, VI, IX and X) and anticoagulant proteins C and S and therefore prevents further clot growth. Warfarin does not affect already created thrombus, but prevents further expansion of clot. When Warfarin is administered, it reduces the activity of anticoagulant proteins C and S, therefore for a short period of time cause to hypercoagulable state to occur. During the first 2 to 5 days of Warfarin treatment, prolongation of extrinsic coagulation pathway measured by prothrombin time (PT) occurs, mostly because of decrement of factor VII and factor X. During the longer-term anticoagulation, PT reflects decrease of factors II, VII, X and IX. DVT/PE prophylaxis could be done with moderate dose of Warfarin, 2 mg/day, with dose adjusted to mildly prolong PT to the international normalization ratio (INR) to 1.5 to 2. Warfarin could be started between the first and the third day of LMWH or LDUH therapy, given for at least three months (15, 19, 20).

Another approach to prevent VTE and PE, after the surgery (e.g. orthopedic surgery), is to decrease an amount of blood loss. Results with the use of a crystalloids such as ringer lactate, used regularly to reinstate volume of blood loss, demonstrated a need for more potent volume plasma expander such as polysaccharide Dextran (21). Dextran used to restore plasma volume had positive effect on hemodynamic status (increasing right atrial pressure and RV end volume) of patients suffered with acute massive PE (21). Role of colloids rather then ringer lactate, per operative administration, trend to reduction of fibrinogen concentration with sufficient impair of the fibrinogen polymerization (22). Result further showed that clot strength and its elasticity reduction were observed more using colloids rather then ringer lactate (22). Colloid solute as Dextran therefore play positive supplementary role in the prevention of massive PE after blood loss in the orthopedic surgery.
Orthopedic mechanical devices used in DVT therapy and in the prevention of PE and post-thrombotic syndrome has not been validated by the same amount of studies for PE prophylaxis as for DVT. After orthopedic surgery (total hip arthroplasty) the use of graded elastic stocking (GES) as a prophylactic measurement for PE and reduction of VTE is suggested. Sarmiento et al. found no significant difference between the use of GES and the intermittent compression devices in fatal or non-fatal PE (23). The meta-analysis made by Wells et al. compared 11 studies, where the surgery of abdomen, gynecologic and neurosurgery had a moderate-risk for developing of VTE. GES in that study significantly (68%) reduced the risk of VTE after performed surgeries (24). However, if GES produce a limited compression, it becomes inadequate and non-effective in prevention of DVT and correspondingly PE. Effective drainage compression gradient for vein from ankles to mid calf position should not be less than 30-40% in order to effectively improve venous drainage. That is why in venogram-proven DVT patients, the size to fit compression reduced the rate of thromboembolism about 50% in the patients developed their first postrombotic DVT event (25). Stannard et al. had recently compared the thigh calf compression device as a low-pressure device with the intermittent pneumatic compression (IPC) high pulsatile device, and illustrated that use of IPC is less associated with DVT and that none of the patient from IPC developed PE compared to one that had PE documented (26). In the conclusion, art of the technology in this field of research and development lies in studying how frequent and potent compression has to be performed, to prevent blood stasis in deep veins of lower limb. In addition, the sleeve of reasonable length and its positioning has to be re-examined (27).


In the group of patients with the high risk of the lower extremity DVT with anticoagulant complication, and possibility of PE development, interventional methods are frequently applied as DVT prevention. Situate an intravenous filter are one of the options how to protect thrombi traveling towards the heart and lungs. Before the placement, vena cavography or other image technique should be used to fully obtain parameters of the site of final filter placement (28). Most filters are placed in the infrarenal vena cava. Filters could be placed in veins other than vena cava, such as the iliacs or the subclavian veins. Implantation site used for deploy of the filter could vary, based on the patient clinical conditions and the type of the filter. Each filter has to possess certain qualities before the placement; such is ability to trap emboli while maintaining its patency, no sharp surfaces and structures such as the attachment hooks, non-thrombogenic surface, biocompatibility, non-corrosiveness, structural integrity, maintainability, and non-ferromagnetivity for MRI checks. Filters can be used as a permanent or retrievable. Current filters FDA approved for clinical use include following (stainless steel Greenfield and titanium Greenfield, Vena Tech-LGM, 12F SGF, Simon nitinol filter, Bird’s nest and TrapEase filter). New devices are currently tested, for example Gunter Tulip, Tempofilter or Amplatz.
Lastly, prophylaxes of DVT and PE have to cover the plans for the blood loss reduction with an appropriate fluid replacement. Patient after the surgery, if there are no complications, should be advised to start movement of the lower limbs. Pre-induction of the antithrombotic therapy is advisable. Change of the life style habits such as reduction of sedentary behavior, dietary changes, stop smoking and others can be recommended.

The supportive treatment in PE plays a substantial role. Pathophysiological origin and the clinical cases showed that the PE shocked patients need an urgent hemodynamic life support. When PE due to the occupancy of the systemic vessels by thrombus occurs, heart is unable to compensate, and hemodynamic shock develop. In that case the resuscitation of the circulation must be immediate. Since the removal or dissolution of emboli is the principle method of improving hemodynamics, excellent supportive therapy has to be instituted in meantime. Any PE hypotensive or these who has significant RV dysfunction should be treated as hemodynamically unstable. The methods that are available include the optimalization of the ventricular preload and the amplification of RV myocardial blood flow. Analgesics and anti-anxiety treatment is reflecting on the patient anxiety and the chest pain.
The optimization of ventricular preload and the amplification of RV myocardial blood flow
In patient with moderate or severe PE, plasma volume expansion has a negative effect on RV performance. When (RV) after load rises, RV function worsens with the additional volume, because of the pericardial constraint. If hypotension is present, administration of excess volume can cause profound worsening of ventricular function. Decrease of coronary perfusion in overloaded heart causing RV myocardial ischemia because of inadequate RV coronary perfusion pressure (RVCPP) (less than 30 mm Hg) and start an acute RV failure. Coronary constriction is usually followed by worsening of cardiac contractile performance, RV hypertension, elevated systemic blood pressure and (RVCPP) (29). Through ventricular interdependence and decreased left ventricular filling, the cardiac output and systemic circulation is compromised. This downhill cycle of RV progress in infarction, circulatory arrest or death. Dschietzig recently illustrated that peptides endothelins playing the important role in decreasing of coronary arterial perfusion and heart contractility after severe PE (30).
Patients with clinical findings of pulmonary hypertension and decreased heart contractility with signs of the RV failure could benefit from the beta-adrenergic stimulators. Beta-adrenergic stimulators help to maintain tissue perfusion due to its cardio- tonic effect and vasodilatation. The use of noradrenaline, explored in the dog PE model, is preferred over isoproterenol, because of a sudden increase of RV myocardial blood flow and RVCPP and as well for its better cardiac output values. This suggests that the ability of beta-adrenergic stimulation is important in improving of the ventricular contractility, ventricular hemodymamics, and coronary vasodilatation (31, 32). There appear to be other mechanisms, which may explain animal survival, using beta-blockers in experimental models of the RV heart failure. Catecholamines are postulated to be cardiotoxic when levels are excessive, as they rise in RV failure. Injected beta-blockers may then provide a direct cardioprotection, blocking catecholamine receptors, and consequently the cardiotoxic effects of released catecholamines (19).
Variety of adverse effects caused by delayed exposure of noradrenaline limit its use. Noradrenaline causes a peripheral vasoconstriction, exacerbate myocardial ischemia, increase pulmonary hypertension, provoke ventricular arrhythmias, product a state of relative energy deficiency, or lead to calcium overload of the failing heart. Furthermore it may provoke apoptosis, either by promoting cell growth in cells capable of division or by increasing the activity of inducible nitrous oxide synthase, a major source of oxidative stress in the failing heart.


Other catecholamines Dopamine and Dobutamine could also improve the cardiac output in hypotensive PE patient, but like noradrenaline they may increase the pulmonary hypertension.


Prostaglandins (PGI) are vascular mediators that can reduce pulmonary arterial pressure and restore cardiac output. They appear to have a preferential pulmonary vasodilatation action. In the study completed by Derwin et al, prostaglandin I-2 (PGI-2) in adequate dose had minimal impact on systemic vasodilatation; reduced the pulmonary artery pressure and the cardiac output (33). Long therapy of primary pulmonary hypertension with the intravenous injection of PGI-2 improved pulmonary hemodynamics. The use of PGI-2 is considered advantageous in pulmonary hypertension therapy (34).
Amrinone and Milrinone are ionotropes with vasodilatation qualities that were used in PE animal models to study pulmonary artery pressure reduction. Both agents belong into a group of phospho-diesterase inhibitors. Amrinone was shown, in a canine model of PE, to raise cardiac output and systemic arterial pressure while in the same time lower pulmonary arterial pressure (35). Milrinone demonstrated equally inspiring results. There is however lack of human data to recommend this therapy for PE, since systemic hypotensive state were observed (36). Recently treatment of pulmonary hypertension was proposed by the other phospho-diesterase inhibitor sildenafil. Sildenafil was compared to nitric oxide and epoprostenol (prostacyclin), to assess its pulmonary vasodilatative potency. Results using sildenafil demonstrated the reduction of pulmonary vascular resistance (37). However, more data is necessary to evaluate sidelafnil, before its use in PE. Nitrous Oxide (NO) in piglet model of PE (38) caused selective dilatation of pulmonary vessels while systemic mean arterial pressure remained unchanged. Significant reduction of pulmonary arterial pressure was observed with inhalation 40 ppm and 80ppm of NO (38). The use of NO has an inhibitory effect on platelets, and restrains platelet aggregation and accumulation in the lung vasculature (4,39). There have been recent reports of haemodynamic and gas exchange improvements in PE patients administered NO or prostacyclin by inhalation. More data are considered necessary to determine position of NO in the reduction of the pulmonary vascular resistance and in the prophylaxis of PE.
Analgesia of patient with suspected PE
Analgesics are given to pulmonary embolism suffering patients when they experience pleuritic chest discomfort and pain (4). The anti anxiety drug such is barbiturates can be used as well but with caution.
The life-threatening MPE treatment is oriented to cease RV failure with signs of cor pulmonare, concurrently with low cardiac output and hypotension with signs of the hemodynamic shock. The methods employed include A/ fulminative fibrinolytic therapy B/ pulmonary embolectomy and C/ partial interruption of v.cava caudalis with the filter placement and the extra corporeal membrane oxygenation (40,41,42), and the extra corporeal circulation (43).
Thrombolytics in massive life- threatening PE play major role in decreasing of the size of obstruction. While anticoagulation with heparins only prevents extension and restrains the new clot accretion, thrombolytics selectively dissolve and remove clot from the site where it cause the resistance. Rapid fibrinolytic therapy, now alternative to pulmonary embolectomy, is less invasive, and is the primary method of the treatment of hemodynamically unstable PE patients. Groups of hemodynamically unstable patients with the severe pulmonary artery resistance and RV dysfunction, as well as those with the prior history of PE and expected to have PE recurrences, and those with the prior history of DVT/PE that experienced recent hypercoagulable event, has to be mandatory for fibrinolytic treatment.

Amid the predominant side effect of the fibrinolytic therapy belongs the antigenicity of some of these agents such is for example Streptokinase (SK). Other side effect that can be the life threatening is the presence of intracranial hemorrhage that is observed with the use of for example urokinase u-PA, tissue plasminogen activator t-Pa and a variety of recombinant tissue plasminogen activators rt-Pa. Effort is made to develop and research the most desirable thrombolytic agent with the qualities such is for example a rapid reperfusion, higher fibrin specificity (minimizing systemic plasminogen activation), lower incidence of bleeding, higher resistance to plasminogen activator inhibitor PAI-1, low re-occlusion speed, longer half-life, no antigenicity and realistic costs. These and other characteristics can advance thrombolysis in PE. There is number of agents that are in progress of the clinical testing and development including Saruplase (pro-urokinase), Staphylokinase, mutants of t-PA (TNKase-tenecteplase, Retavase, Lanoteplase) and Vampire Bat PA that are reflecting some of the desired qualities.


The least popular fibrinolytic agent for the treatment of PE is (a) Streptokinase SK (Kabikinase, Streptase). One of the first trials was done by Ly et al. (44) and Tibbutt et al. (45) in the early eighties. Streptokinase was compared to the heparin in the treatment of PE, with the final endpoint represented by the pulmonary perfusion, controlled by the angiography. SK had better efficacy and showed great improvement in pulmonary perfusion over heparin, with no significant different mortality. Today SK is recommended in dose 250 000 UI i.v over the period of 30 min, followed by continuous infusion of 100 000 UI /h for 24 –48 h (46). Pre-medication with hydrocortisone sodium succinate 100mg i.v can minimize its allergic reaction potential (4). Recent streptococcal infection, exposure to SK in the past 4-years, aneurysm, recent intracranial bleeding limits use of SK.


The other thrombolytic agent that was tested in early eighties for the use in PE is (b) Urokinase (UK). In the largest trial that compared UK and SK (Urokinase Streptokinase Embolism Trial-USET), angiography proven 167 PE patients were randomized, to receive either 12h of UK, 24h of UK or 24h of SK treatment. Similar improvement in perfusion scans were observed between the test groups, some patients having massive embolism had however greater resolution using UK instead of SK (47). There were no statistical significant differences in mortality, recurrent embolism or major hemorrhage in the treated groups. The recommended dose of UK was established and adjusted for an adults 250 000 UI over 30min and maintenance dose 100 000 UI/h for 12-72 hours. Pediatric dose was accustomed to 4400UI /Kg IV over 10 min period, followed by 4400 UI /Kg for 12-72 h.


The major safety veto came later from the office of FDA. In 1999 inspection of the production of Abbokinase revealed deficiencies in procedures used by the Abbot Company. UK was harvested from the post mortem human neonate’s kidneys. Prior to the inspection, neither mothers nor the neonate was tested for example for Hepatitis C virus, which may have permitted the contamination.
Until today, there is a deficit of the results using UK, which correlates clot fibrinolysis with coagulation. The serum half-life is about 20 min, with major liver clearance accompanied by bile and urine. The history of cerebrovascular accident, intracranial neoplasm, arteriovenous malformation or intraspinal surgery limits the use of UK.
The last member of fibrinolytics with the ability of conversion of plasminogen to plasmin used for the massive PE treatment is (c) Alteplase, the recombinant tissue plasminogen activator (rt-PA, Activase). Like UK, rt-Pa is non-antigenic. Injected into the systemic circulation produces minimal alteration of plasminogen in absence of fibrin, binds to preferentially to fibrin in thrombus, and converts thrombus plasminogen into plasmin. Alteplase is rapidly cleared from plasma with half-life less than 5 min. Clearance is preferentially mediated by the liver. As a portion of (PIOPED) study, thirteen patients were randomized to receive either i.v dose of heparin or Alteplase. There was no significant difference in angiographic observation at 2 hours after the injection, but slight decrease in pulmonary vascular resistance was observed in the Alteplase group (1). Pulmonary artery perfusion using rt-Pa over heparin treatment showed improvement only within minutes and hours; while at the day 7, the result of perfusion ventilation scans (V/Q) demonstrated no difference (46,48,49).


Hemorrhage using Alteplase, in a randomized controlled study, was moderate when PE patients were administrated either regular dose of Alteplase100mg over 2hours or the weight adjusted dose of 0.6mg/kg, with maximum dose 50mg over 15 min. In both groups the excessive bleeding and intracranial hemorrhage was not observed. The reduction of fibrinogen and fibrin degradation products was higher in the group treated with high dose (50). It is not clear, whether the low dose or patient adjusted dose can produce significant results that will lead to the quick and stable thrombi dissolution. It is indispensable to revise and re-evaluate whether patient- adjusted dose could brink some benefits into massive PE therapy.


Interventional therapy is a method of emergency management of PE. Candidates for the interventional procedure are those that were angiographically determined as PE positive, those with the unsuccessful fibrinolytic therapy and those heparin-treated, where the resuscitation of hemodynamic instability was not achieved. The methods of the interventional PE therapy include percutaneous embolectomy, catheter directed thrombolysis, and recently percutaneous fragmentation techniques.
Pulmonary embolectomy and thrombo-fragmentation technique involve an introduction of a suction catheter through femoral or jugular venotomy. Catheter is under the fluoroscopic guidance aimed through the patient right heart and inserted into pulmonary artery. Success depends on the detailed understanding of devices used for the embolectomy and the thrombo-fragmentation (51). In general, success rate of the catheter technique varies with different devices. The overall rate is about 76 % with the mortality rate about 25% of cases (52). After the procedure, emboli fragments size varies based on the selected catheter and the method of destruction. Generally, the Hydrolyser catheter or the modified Hydrolyser catheter had the best results in the clot removal (51). Hydrolyser catheter was well documented in the experimental animal study, where the percutaneous technique was used (53). This technique enabled partial elimination of the central emboli and flow restoration; though peripheral pulmonary emboli remained intact (53). Interventional therapy and research technology in the last couple of years brought into play devices such for example the catheter with high pressure saline jet. This catheter generates high force velocity in the proximity of the clot, which cause thrombi to break. Fragmented pieces are then easily evacuated under the negative pressure from the arteries (54).
Many randomized and controlled clinical trials were performed during the last tree decades. Fibrinolytic treatment in massive PE was compared to other treatment and the results showed need of fibrinolytics for the early reperfusion life-threatening therapy. The invasive patient care however was not translated into a reduction in morbidity and mortality caused by PE.


Diagnostic approaches have to be performed directly from the start, including methodical and systematic physical exam done by physician by adspection, auscultation, palpation and percussion Test as CXR and ECG can be done concurrently. Thus majority of PE suspected patient do not have this condition it is better to react on presence of a sign specific to PE. Then more detailed visualization test (V/Q scan, pulmonary angiography, computed tomography or magnetic resonance angiography) can be provided.


Treatment of MPE in the future has to be coordinated through the prevention of VTE and DVT, because major reported source of PE is its occurrence as a complication of DVT . Despite of the fact that potential advantage was achieved in research and development of the thrombolytics, additional information is required for treatment (e.g. use of patient adjusted dose, pulse or sprayed fibrinolysis). In addition, MPE is dominated by the pathophysiology of the disease, which often labels outcome in the very important first hour of its presentation. Similar to the shock or myocardial trauma, MPE requires time-aptness. An instant recognition, resuscitation, and treatment provides the greatest opportunity to optimally undertake on this lethal disease.

 

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