Fig. 7.1
Modified of C Jerjes Sanchez y cols. Ischemic cascade that are generated from a massive PE over the right ventricle, and the phenomena that can increase or reduce the degree of ischemia. Myocarditis as an important trigger to RV failure; and potential importance of greater obstruction of 50 % of the corresponding coronary artery. *Begieneman MVP, et al. Pulmonary embolism causes endomyocarditis in the human heart. Heart 2008; 94:450-456
In our case, transthoracic echocardiogram was an important tool in diagnosis and stratification. Considering the age, clinical presentation, and ST dynamic changes on electrocardiograms, a suspicion of acute coronary syndrome was considered. However, transthoracic echocardiogram showed right ventricular dysfunction with severe global hypokinesis excluding this possibility. Severe right ventricular dysfunction could explain the lack of correlation between pulmonary artery pressure and pulmonary resistance. Electrocardiogram in this context could be another important tool in the setting of PE risk, not only as an early indicator of pulmonary reperfusion, also through ST dynamic changes high-risk PE could be identified [3]. Necessarily, we need to change our traditional way to analyzing electrocardiogram changes; persistent or transitory ST-elevation or depression have to be considered as severe myocardial ischemia expression and jeopardized right ventricular mass. Both conditions required a fast-track therapeutic approach to establish a thrombus lysis to preserve right ventricular viability, through reducing right ventricular dysfunction avoiding right ventricular myocardial infarction, a mortality determinant.
Both cases were the beginning of the series of studies that tested the safety and effectiveness of high dose in short-term (one-hour) streptokinase infusion.
Streptokinase and Heparin Versus Heparin Alone in Massive Pulmonary Embolism: A Randomized Controlled Trial
Study No. 1
Background
In 1977, streptokinase was approved by the FDA for the treatment of PE (250,000 IU/30 min and then 100,000 IU/h/24 h). Recently, we reported the successful use of 1,500,000 IU of streptokinase over 1 h in one patient with massive PE and cardiogenic shock [1]. We subsequently undertook a trial of eight patients with PE who were randomized to high dose, short infusion of streptokinase followed by heparin versus heparin alone. When all four heparin alone patients died compared with none in the streptokinase group, we terminated the trial [5].
Methodology
Inclusion criteria: (a) patients aged 15 years or more; (b) previously healthy; (c) PE diagnosis sustained by high clinical suspicion (one or more major risk factors and clinical, ECG, chest X-ray, blood gas findings; (d) PE proven by: high probability V/Q lung scan, suggestive echocardiogram, or DVT (5) by radiovenogram; (e) massive PE defined: >9 obstructed segments on V/Q lung scan with or without cardiogenic shock (systolic blood pressure <90 mmHg); (f) <9 obstructed segments on V/Q lung scan but with right ventricular dysfunction and or extensive DVT; g) symptoms or signs of PE within 14 days after onset symptoms [5].
Exclusion criteria: (a) previous PE; (b) patients with <3 segmental defects on V/Q lung scan, with normal echocardiogram and without DVT; (c) absolute contraindication for thrombolytic therapy: active or recent hemorrhage, intracranial disease, head trauma, neurologic or major surgery within previous 6 weeks, or any concurrent condition considered to limit survival to a few months [5].
Patients were randomized to streptokinase followed by heparin or to heparin alone.
Streptokinase group: received 1,500,000 IU of streptokinase over 1 h by peripheral vein, followed by a bolus of 10,000 U of heparin and then a constant infusion of 1000 U/h of heparin titrated to PTT of 2–2.5 times control. Heparin group: followed the same regimen, without streptokinase. In the survivors of the acute phase, on the fifth day, heparin was overlapped with coumadin and was stopped on day 7. Patients were kept on coumadin, aiming for an INR between 2.0 and 3.0 for 3 months or more, depending on the presence of major risk factors [5].
V/Q Lung scans were performed in anterior, posterior, and lateral and oblique views. Echocardiograms required measurements of right and left ventricular size and motion, ejection fraction, abnormal septal position, paradoxical systolic motion, tricuspid, and/or pulmonary regurgitation. Parasternal long axis, apical four chambers, and subcostal four chambers view were performed. Pulmonary arterial pressure was determined with the modified Bernoulli formula. Static and dynamic venograms with 99 technetium-labeled albumin macroaggregates were performed.
Results
Eight patients were enrolled, four in each group, all with massive PE and cardiogenic shock. The mortality in the streptokinase group was 0 % compared to 100 % (p = 0.02) in the heparin group. Therefore, after discussion with the ethics committee, the trial was terminated [5].
The characteristic of this study, main target, fibrinolytic regimens and hospital type is shown in Table 7.1. In Table 7.2, all demographic variables related with age, acute and chronic inflammation, as well as, acute venous thrombosis incidence and triggers were described. In Table 7.3, it is possible to observe the main variables related with clinical, echocardiographic, and VQ lung scan findings. Mortality and recurrence incidence, residual thrombus and rescue therapeutic approach are shown in Table 7.4. Table 7.5 was designed to fibrinolytic regimens, adjunctive treatment, and bleeding complications. Also, 289 patients with proven PE treated in almost 20 years period have been included.
Table 7.1
Studies characteristics of 289 patients with proven pulmonary embolisms
Variable | 1992 | 1992–1994 | 1996–2002 | 2002–2004 | 2009–2011 |
|---|---|---|---|---|---|
Number of patients | 8 | 40 | 131 | 80 | 30 |
Randomized | Yes | No | No | Yes | No |
Controlled | UFH | No | NBP with or without RVH | UFH | No |
Open | Yes | Yes | Yes | Yes | Yes |
Multicenter trial | No | No | No | Yes | No |
Objective | Efficacy | Safety | NBP with or without RVH | Evolution | Security |
60 min regimen | 1,500,000 UI SK | 1,500,000 UI SK | 1,500,000 UI SK | 100 mg rt-PA, alteplase | TNK-t-PA/10 s mg/kg |
Hospital | Cardiology | Cardiology | Cardiology | Cardiology/Community | Cardiology |
Table 7.2
Demographic characteristics for 289 patients with pulmonary embolism
Variable | 1992 | 1992–1994 | 1996–2002 | 2002–2004 | 2009–2011 |
|---|---|---|---|---|---|
Number of patients | 8 = N | 40 = % | 131 = % | 80 = % | 30 = % |
Age/gender female | 51 ± 23/1 % | 47 ± 15/25 % | 61 ± 18/41 % | 52 ± 16/56 % | 58 ± 6/73 % |
Health | 100 (%) | 100 | 37 | 34 | 33 |
Age >65 | 1 | – | 34 | 34 | 53 |
Chronic inflamación | 8 | 48 | 74 | 83 | 83 |
Acute deep venous thrombosis | 0 | 85 | 23 | 80 | 44 |
Triggers: stasis | 8 | 85 | 48 | 73 | 26 |
Acute inflamación | – | – | 68 | 55 | 44 |
Table 7.3
Clinical, echocardiographic, and VQ lung scan findings in 289 patients with pulmonary embolism
Variable | 1992 | 1992–1994 | 1996–2002 | 2002–2004 | 2009–2011 |
|---|---|---|---|---|---|
Number of patients | 8 = N | 40 = % | 131 = % | 80 = % | 30 = % |
High-risk PET | 8 | 100 | 100 | 100 | 100 |
Dyspnea and/or angina | 7/8 | 83/80 | 79/86 | 85/73 | 93/59 |
Third sound right ventricular | 8 | 95 | 92 | 96 | 97 |
Cardiogenic shock | 8 | 40 | Low BP 28 | 16 | 3 |
RVD (mm) | 40.5 ± 2.8 | 40.7 ± 2.5 | 39.8 ± 3.70 | 43.9 ± 4.4 | 39 ± 4.3 |
RV/LV ≥ 2:1 | 8 | 100 | 100 | 100 | 100 |
RVHK % | 8 | 67 | 47 | 75 | 86 |
PSD before thrombolysis | – | 9.69 ± 1.16 (29) | 9.35 ± 3.42 (79) | 10.7 ± 1.7 (32) | 12 ± 4.2 (17) |
Table 7.4
Cardiovascular adverse events and therapeutic rescue approaches
Variable | 1992 | 1992–1994 | 1996–2002 | 2002–2004 | 2009–2011 |
|---|---|---|---|---|---|
60 min regimen | SK 1,500,000 | SK 1,500,000 | SK 1,500,000 | rt-PA 100 mg | TNK-t-PA/10 seg mg/kg |
Number of patients | 8 = N | 40 = % | 131 = % | 80 = % | 30 = % |
Mortality | T 0/4 H p = 0.02 | 12 | 28/61 RVHK | T 3–25 H | 13 |
Recurrence | 0 | 18 | 11 | T10–H 20 | 3 |
Rescue thrombolysis | 0 | 10 | 5 | 10 | 0 |
Rethrombolysis | 0 | – | 7 | 0 | 0 |
Residual thrombus | 2 | 18 | 26 | 10 | 7 |
P. pulmonary intervention | 0 | – | 16 | 5 | 7 |
Surgical embolectomy | 0 | – | 2 | 0 | 0 |
Table 7.5
Fibrinolytic regimen bolus, adjunctive treatment and bleeding complication findings in 289 patients with pulmonary embolism
Variable | 1992 | 1992–1994 | 1996–2002 | 2002–2004 | 2009–2011 |
|---|---|---|---|---|---|
60 min regimen | SK 1,500,000 | SK 1,500,000 | SK 1,500,000 | rT-PA 100 mg | TNK-t-PA/10 s mg/kg |
Number of patients | 8 | 40 | 131 | 80 | 30 |
Bolus | No | No | No | 20 mg <65 years | Yes |
15 mg >65 years | |||||
Unfractionated heparin | Bolus 10,000/1000/h | Bolus 10,000/1000/h | Bolus 5000/1000/h | Bolus 60 U/kg or 12 U/kg | Bolus 60 U/kg or 12 U/kg |
Low-molecular-weight heparin | No | No | No | 1 mg/kg/12 h 24–48 h/7 days | 1 mg/kg/12 h 24–48 h/7 days |
Intracranial hemorrhage (%) | 0 | 0 | 2 | 0 | 0 |
Major hemorrhage (%) | 0 | 2 | 8 | 8 | 3 |
Minor hemorrhage (%) | 0 | 0 | 5 | 5 | 10 |
These eight patients had similar baseline characteristics, except in time elapsed from onset of symptoms of the first event of PE before randomization, which occurred by chance. Patients in streptokinase group arrived to the Emergency Department from 1 to 4 h after onset symptoms of PE, whereas patients in heparin group had a first PE in other hospitals. In this first pulmonary event, they had minor PE by 1, 2, 2 and 3 occluded segments on V/Q lung scan, with hemodynamic stability, without any evidence of acute pulmonary arterial hypertension and with therapeutic PTTs [5].
There, they were asymptomatic and suddenly had recurrences of massive PE, with severe respiratory failure and were transferred to our hospital 2–4 h after onset symptoms of a new event. The time elapsed from onset of cardiogenic shock was comparable in both groups. All patients had similar clinical characteristics and echocardiographic abnormalities. The patients who were randomized to receive streptokinase plus heparin improved their clinical and echocardiographic findings in the first hour after treatment. The V/Q lungs scan postthrombolytic therapy showed 3, 4, 4, and 5 segments perfusion defects and DVT were proved [5].
All patients in heparin group died despite endotracheal intubation, mechanical ventilation, and Swan-Ganz catheterization. Necropsy was performed in three patients, all had massive PE and, both macroscopically and histologically, the presence of right ventricle acute myocardial infarction, two were subendocardial and one transmural, in all cases without significant coronary arterial obstruction. The four patients who lived were discharged in good conditions. After 2 years follow-up, all are in functional class I, without pulmonary arterial hypertension, and without recurrent PE [5].
Lessons Learned for This Study
We present the first randomized clinical trial that demonstrates a decreased mortality rate with thrombolysis compared with heparin alone among patients with massive PE [5].
Because of their grave clinical condition, in the acute phase the diagnosis of PE was sustained by high clinical suspicion and bedside echocardiogram only. Later, diagnosis of PE was confirmed by means of high probability V/Q lung scans and proven DVT on streptokinase group and through high probability V/Q lung scan in two patients of heparin group and by necropsy in three of them. On admission, the baseline clinical and echocardiographic data showed severe right ventricular dysfunction and cardiogenic shock. However, after treatment, the patients who received streptokinase plus heparin had earlier reversal of hemodynamic disturbances than patients who received only heparin, who deteriorated and died [5].
We did not observe major or minor hemorrhagic complications possibly due to the patient’s young age, because the streptokinase was used through a peripheral vein, and because of a diagnostic strategy which avoided vascular puncture [5].
The role of echocardiography was to establish bedside diagnosis of massive PE, to ascertain the severity of pulmonary arterial hypertension, and to document abnormalities of motion and geometry of the right ventricle. The findings in the necropsy studies have been previously reported [3] and suggest that right ventricular myocardial infarction could cause irreversible right ventricular dysfunction and mortality [5].
The patients who received thrombolysis had reductions in pulmonary arterial hypertension, right ventricular dysfunction, and preservation of ventricular myocardial viability. Rapid reversal of right ventricular failure, noted previously in recombinant human tissue-type plasminogen activator, alteplase patients who compared with heparin alone patients, is the likely mechanism that prevented death from acute PE [5].
There were two limitations of study: (1) small sample size, and (2) gross imbalance in the onset of the first PE, however, at that moment, patients in heparin group did not have right ventricular dysfunction. The observations from this randomized controlled clinical trial indicate that among patients with massive PE and cardiogenic shock, prompt administration of thrombolytic therapy can be lifesaving compared with heparin alone [5].
Additionally, the results reproduce in terms of safety and effectivity, our previous clinical observations [1, 3] with the streptokinase regimen proposed. Furthermore, in-hospital results were extended in 2-year follow-up in which no recurrence, no PE mortality was observed. This study has been criticized for two reasons: first, because patients in heparin group had had a first PE in other hospitals inducing gross imbalance in onset of the first PE. However, they had basal echocardiogram evaluations proving normal right ventricular function; second, the small sample size; if the study had not been suspended it is possible a major number of patients with acute PE could have been saved. However, for our clinical research group, four patients with PE and severe right ventricular dysfunction on heparin alone who died compared with four streptokinase patients who alive, was sufficient to suspend the clinical trial. Additionally, three new right ventricular myocardial infarction cases were identified.
High Dose and Short-Term Thrombolytic Regimen in Pulmonary Embolism Patients: Prospective with 7-Year Follow-Up Trial
Study No. 2
Background
Thrombolysis in PE accelerates reversal of right ventricular dysfunction and reduces recurrent PE rate and mortality, among proper selected patients. Infusions of short duration and high concentration act most rapidly and enhance safety. The sole investigation demonstrating that thrombolysis reduces mortality from PE has been our previous randomized controlled trial, in which 1,500,000 IU in one-hour streptokinase infusion followed by heparin compares with heparin alone improved survival in patients with massive PE, severe right ventricular dysfunction and cardiogenic shock [5]. Nevertheless, it was a small trial and more evidence needs to consider this accessible thrombolytic regimen as an effective and safety alternative. In addition, there is little evidence that assesses the long-term benefits of thrombolytic therapy after initial PE event [6].
Now, we present the results of a subsequent prospective trial in 40 consecutive new patients with PE, in whom a high dose and short-term streptokinase regimen through peripheral vein reversed acute pulmonary arterial hypertension, clinical and echocardiographic evidence of right ventricular dysfunction and improved pulmonary perfusion without increasing hemorrhagic complications. In a 7-year follow-up, evidence suggests that this streptokinase regimen preserves functional class, without recurrence or chronic pulmonary arterial hypertension [6].
Methodology
In our previous randomized controlled trial [5], originally we intended to enroll 40 patients, however, the study had early stopped for ethical reasons after the first 8 patients had dramatic differences in terms of mortality (p = 0.02). This result provides reasonably strong evidence to design a new prospective, noncomparative, open label with a long follow-up trial [6].
Primary end points: In acute phase, baseline and post thrombolytic characteristics were analyzed to know the efficacy and safety of a high dose and short-term streptokinase infusion in terms of pulmonary arterial hypertension, right ventricular dysfunction, perfusion abnormalities, recurrence, mortality, and hemorrhagic complications. In long-term follow-up, we assessed functional class, recurrence, chronic pulmonary arterial hypertension, postthrombotic-syndrome and mortality.
Secondary end point: Identify right ventricular hypokinesis as major risk factor to recurrence and mortality [6].
Patients were considered for the study if they had: (a) age 15 years or more, (b) previously healthy, (c) clinical suspicion of PE: one or more major risk factors (prolonged bed rest, major surgery, obesity, trauma, puerperium, smoking, estrogens, and long travel) and clinical (sudden dyspnea, angina-like pain, S3 gallop, syncope, shock or cardiac arrest), ECG (new ST segment depression or T wave inversion in leads V1–V4, new right bundle branch block or new right axis deviation), chest X-ray, (band atelectasis, focal oligemia, pulmonary artery enlargement, elevated hemidiaphragm) blood gas (hypoxemia and hypocapnia) findings, (d) PE proven (high clinical suspicion plus suggestive echocardiogram), plus high probability V/Q lung scan and deep venous thrombosis by radiovenogram, (e) massive PE defined as >9 obstructed segments on V/Q lung scan with cardiogenic shock (systolic blood pressure <90 mmHg), (f) large PE defined as >7 obstructed segments on V/Q lung scan without cardiogenic shock with or without right ventricular dysfunction and/or extensive deep venous thrombosis, (g) patients referred within 14 days after onset of symptoms [6].
Conditions to excluded patients: (a) previous PE, (b) V/Q lung scan with normal, near normal or medium perfusion abnormalities without right ventricular dysfunction and without extensive deep venous thrombosis, (c) absolute contraindication for thrombolytic therapy as active or recent hemorrhage, intracranial disease, head trauma, neurologic or major surgery within previous 6 weeks, or any concurrent condition limiting survival to a few months [6].
All patients received a bolus of 10,000 U of heparin and then 1,500,000 IU of streptokinase over one-hour by peripheral vein, followed by a constant infusion of 1000 U/h of heparin titrated to PTT of 2–2.5 times control. In the survivors of the acute phase, on the first to third day, heparin was overlapped with coumadin and was stopped on day 7. The patients were kept on coumadin, aiming for an INR between 2.0 and 3.0 for 6 months or more, depending on the presence of major risk factors [6].
All patients with high clinical suspicion of PE (major risk factors, clinical manifestations, and chest X-ray, ECG and blood gases) were under a 24-h “fast-track” echocardiography evaluation and treatment within the Emergency Department. Patients with clinical, ECG and echocardiographic findings of severe pulmonary arterial hypertension and right ventricular dysfunction with normal blood pressure (impending hemodynamic instability) [7] or cardiogenic shock, were considered at highest risk and an experienced physician administered thrombolytic therapy by peripheral vein, as soon as possible [6].
These were the only patients in whom V/Q lung scan was performed after starting treatment. Twenty-four hours after thrombolytic therapy, all patients had lung scan evaluation and deep venous thrombosis search. When severe pulmonary arterial hypertension and right ventricular dysfunction were excluded, lung scan was performed before starting streptokinase regimen [6].
Baseline, 1, 24 h, at discharge and follow-up echocardiograms were done. The echocardiographic examination and interpretation were performed before and after starting thrombolytic therapy by one experienced echocardiographer. Qualitative evaluation: (a) right ventricular end diastolic diameter/left ventricular end diastolic diameter ratio (RVEDD/LVEDD) was considered normal when LVEDD was larger than RVEDD and abnormal if RVEDD was equal or larger than LVEDD [6].
Right ventricular wall abnormalities were assessed as follows: normal, moderate regional hypokinesis, severe regional hypokinesis, regional akinesis, global hypokinesis, (b) left ventricular motion, (c) abnormal septal position, (d) paradoxical systolic motion, (e) loss of inspiratory collapse of the inferior cava vein. The qualitative evaluation of right ventricular wall motion was considered as follows: Quantitative evaluation: (a) pulmonary artery systolic pressure determined with the modified Bernoulli formula, (b) measurements of right and left ventricular size, (c) ejection fraction, (d) tricuspid and pulmonary regurgitation, (e) right ventricular wall thickness. Echocardiography was standardized using the apical four chambers, parasternal long and short axis. When these positions were not appropriate, a subcostal four-chamber view was used [6].
Baseline, 24 h and at discharge perfusion scan with intravenously injected 99mTC/DTPA in anterior, posterior, lateral and oblique views were performed. Ventilation lung scan was done with 99mTC/MAA aerosol inhalation. The scans were scored through a segmental method that includes all views. A search for deep venous thrombosis with static and dynamic venograms with 99 technetium-labeled albumin macroaggregates was performed. One experienced nuclear medicine specialist analyzed all studies [6].
Analysis of efficacy: Baseline and 24 h clinical evaluation included: clinical, ECG, chest X-ray, PaO2, pulmonary arterial hypertension improvement. Pre- and post-treatment lung scans and echocardiograms were analyzed regarding perfusion abnormalities, pulmonary artery systolic pressure, and right ventricular dysfunction behavior. In-patient recurrence and mortality were evaluated. Follow-up evaluation included functional class, recurrent PE, chronic pulmonary arterial hypertension, post-postthrombotic syndrome, and mortality [6].
Major hemorrhages were defined as: stroke (confirmed by computed tomography), hematomas >5 cm, prolonged external bleeding at puncture site, oral or gastrointestinal bleeding, hematuria or another bleeding with concomitant hypotension that required treatment with intravenous fluids, blood transfusion, surgical control, discontinuation of thrombolytic regimen, decrease >15 % points in hematocrit or >5 g/dL in hemoglobin. Minor hemorrhage was defined as: decrease between 10 and 15 % points in hematocrit or 3–5 g/dL in hemoglobin reduction [6].
All surviving patients were educated regarding symptoms and signs of recurrent PE after hospital discharge and had follow-up by the Principal Investigator (CJS). All patients had monthly visit, during the first 3 months and then every 3 months. In each visit clinical and echocardiographic evaluations were done. V/Q lung scan and venogram were performed at the third month and every 6 months up to January 1996. Then, direct telephone contact follow-up was done until September 1999 [6].
Results
From February 1992 until April 1994, 40 consecutive patients with high clinical suspicion and highest risk PE (right ventricular dysfunction and normal blood pressure—impending hemodynamic instability—and cardiogenic shock) were enrolled. In all, PE was proved by high probability V/Q lung scan and necropsy (four patients). In 33 patients, long follow-up was obtained. Patients were young predominantly females. All patients had a recent acute PE event, diagnosed through a noninvasive workup strategy; 60 % of the patients had normal blood pressure and 40 % had cardiogenic shock. At beginning, all patients had severe acute pulmonary arterial hypertension and in 29 patients baseline V/Q lung scan showed extensive perfusion abnormalities (Table 7.6) [6].
Table 7.6
Baseline characteristics of patients and assessment streptokinase regimen
Variable | Streptokinase 1,500,000 IU/1 h infusion | |
|---|---|---|
n = 40 | % | |
Age (years) | 47.3 ± 15.3 | |
Female | 25 | 62 |
Male | 15 | 37 |
Deep venous thrombosis | 34 | 85 |
Prolonged bed rest | 18 | 45 |
Obesity | 13 | 32 |
Lower extremity trauma | 11 | 27 |
Puerperium | 7 | 17 |
Smoking | 6 | 15 |
Estrogen | 6 | 15 |
Surgery | 5 | 12 |
Long travel in sitting position | 4 | 10 |
Onset symptoms (days) | ||
0–5 | 34 | 85 |
6–10 | 4 | 10 |
11–14 | 2 | 5 |
Diagnostic workup | ||
ECG | 40 | 100 |
Echocardiogram | 40 | 100 |
Lung scan | 40 | 100 |
Radionuclide venogram | 40 | 100 |
Normal blood pressure | 24 | 60 |
Cardiogenic shock | 16 | 40 |
Pulmonary artery systolic pressure | 60.37 ± 6.43 | |
No. of segmental perfusion defects | 9.69 ± 1.16 | |
Right ventricular hypokinesia | 28 | 67 |
As has been previously proved, 11 ill patients received streptokinase regimen without V/Q lung scan. In the next 24 h all patients had a high probability V/Q lung scan. Right ventricular hypokinesis on echocardiography was recognized in a high percent of the patients. Patients referred between 10 and 14 days after onset symptoms received heparin in secondary hospitals. After patients arrival in the Emergency Department, mean time to starting streptokinase infusion was 1.88 ± 0.71 (range 45 min to 3 h) [6].
Streptokinase efficacy. Pre- and postthrombolytic improvement on severe acute right ventricular dysfunction, perfusion abnormalities, and pulmonary arterial hypertension through clinical, V/Q lung scan and echocardiography baseline and 24 h assessment is shown in Table 7.6.
In the acute phase, five patients died (12 %), all had severe pulmonary arterial hypertension and severe right ventricle dysfunction. Four had cardiogenic shock and a remarkable characteristic was a longer time between onset symptoms and starting thrombolysis (mean 40.60 ± 33.13, range 12–79 h) regarding 35 patients who survived (mean 1.88 ± 0.71, range 45 min to 3 h). After treatment, all of these patients died within 72 h [6].
Three patients suffering cardiogenic shock improved after thrombolysis, however, they had early recurrence in the next hours, hemodynamic instability and died. Two of them received nonsuccessful rescue thrombolysis with the same regimen due to nonaccess to another thrombolytic regimen or surgical embolectomy. Three other patients had recurrence, two had critically ill conditions and successful rescue thrombolysis was performed. In another patient, recurrent left upper lung PE was observed on V/Q lung scan after successful streptokinase regimen. Neither signs nor symptoms were identified and possible fragmentation, thrombosis, or silent PE was considered [6].
The diagnosis of recurrent PE was established through high clinical suspicion and new evidence of pulmonary arterial hypertension and right ventricular dysfunction and/or new perfusion abnormalities on V/Q lung scan. The streptokinase role on the lysis of lower extremity thrombi and recurrent PE event cannot be excluded [6]. Postmortem study was performed in four patients, in which massive PE with right ventricle subendocardial acute myocardial infarction and normal coronary arteries were proved. CK-MB or troponin measurements were not done [6].
When patients who died were compared with patients who survived, right ventricular global hypokinesis was identified as independent risk factor for mortality before thrombolytic therapy (p < 0.0001). Risk factors for mortality after thrombolytic therapy were: 6 h or over between onset symptoms and streptokinase regimen (p = 0.02), severe and sustained systolic pulmonary arterial hypertension (p = 0.001) in association with right ventricular hypokinesis (p = 0.001), hypoxemia (p = 0.02) and right ventricular acute myocardial infarction (p < 0.0001). Right ventricular hypokinesis on echocardiography (p = 0.02) was the only independent risk factor for recurrence [6].
Only one major hemorrhage was identified (2 %). A 66-year old woman arrived with massive PE, severe acute right ventricular dysfunction, cardiogenic shock and tracheal intubation and mechanical ventilation were considered. The patient had oral hemorrhage secondary to traumatic intubation and received 2 U of packed red blood cells. She received mechanical ventilation more than 48 h and was eventually discharged. In this trial, no intracranial hemorrhage was observed. Four patients (10 %) had immediate reactions characterized by transient hypotension, two of them had skin rashes and rigors. The streptokinase infusions were never stopped, and improvement was obtained with intravenous fluids. (250 mL in 30 min) In patients with allergic reactions, intravenous diphenhydramine (0.5–1 g) and intravenous hydrocortisone (100 mg) were effective [6].
Transthoracic echocardiogram was performed and was considered technically adequate in 100 % of the cases; however, none of the patients had COPD or comorbid obesity. Right and left ventricular abnormalities were often present in patients with acute PE. Right ventricular wall motion abnormalities recognized were: (a) right ventricular hyperkinesia (base, mid-right ventricular free wall and apex) (12/40), (b) moderate or severe regional hypokinesis (24/40), and (c) severe global hypokinesis (4/40). The qualitative RVEDD/LVEDD analysis showed an abnormal ratio in all patients, being 2:1 in 36 patients (12 with hyperkinesia alone and 24 with hypokinesis) and >2:1 in four patients (global hypokinesis). All had similar degree of pulmonary arterial hypertension and in 29 patients in which lung scans were performed, there were extensive perfusion abnormalities. Only one patient had a right ventricular thrombus in-transit and none had right ventricular hypertrophy [6].
After thrombolytic therapy, despite clinical, pulmonary artery systolic pressure and perfusion abnormalities improvement, nine patients had persistent right ventricle regional hypokinesis. In four, these wall motion abnormalities persisted for the next 3 or 4 months and then right ventricular function normalized. In the other five patients, right ventricular hypokinesis was a remarkable characteristic in the follow-up and the possibility of right ventricle acute myocardial infarction was considered. In two, coronary angiography was performed, and no coronary lesions were detected [6].
In 35 patients that survived acute phase, a follow-up was achieved in 33 patients (94 %). During the follow-up period, six patients were lost for a few months and later on four were recovered. In the two lost patients, 1 year and 15 days follow-up was obtained. In 33 patients, mean follow-up was 5.32 ± 2.57 (range 5 years, 1 month to 7 years, 7 months). All patients were asymptomatic, without recurrent PE, chronic pulmonary arterial hypertension or death. In the later years, four patients had postthrombotic syndrome [6].
Related posts:
Current Guidelines and Recommendations for Thrombolysis Use in Pulmonary Embolism
Thrombolytic Therapy: Evidence-Based Results from Multicenter Control Trials
Anticoagulation as Adjunctive Treatment and One-Hour Alteplase Infusion
Mechanisms of Thrombosis
Pharmacokinetics and Pharmacodynamics of Fibrinolytic Agents
Thrombolysis in Special Situations
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