small IVC with respirophasic variation), give fluid judiciously and in small amounts. Kearon C., Akl E.A., Ornelas J., Blaivas A., Jimenez D., Bounameaux H., Huisman M., King C.S., Morris T.A., Sood N., et al. Grifoni S., Olivotto I., Cecchini P., Pieralli F., Camaiti A., Santoro G., Conti A., Agnelli G., Berni G. Short-Term Clinical Outcome of Patients with Acute Pulmonary Embolism, Normal Blood Pressure, and Echocardiographic Right Ventricular Dysfunction. Vasopressin causes systemic vasoconstriction, while simultaneously causing pulmonary. Furthermore, systematic reviews (SRs) have encouraged confusion by reaching different conclusions [8]. Goldhaber S.Z. By definition, patients with submassive PE have a worse outcome than the majority of those with standard-risk PE, who are hemodynamically stable and lack imaging or laboratory features of cardiac dysfunction. Chatterjee et al. J Am Coll Cardiol. Lots of unstable patients have PE, but in some cases they may have multifactorial instability (e.g. Background Acute pulmonary thromboembolism is the most dangerous presentation of venous thromboembolic disease. Background: Massive and submassive pulmonary embolism (PE) can be life-threatening. Pulmonary embolism is a known cause of ST elevation. More on the EKG manifestations of PE here. Patient with mild tachycardia (HR > 110 b/m) and elevated troponin would be classified as intermediate-risk (7% risk of PE-related mortality), even with a completely normal right ventricle. No high-level evidence exists regarding VA-ECMO in PE, nor is such evidence likely to emerge in the near future (given how rare this situation is). No significant differences were found between the two groups in terms of recurrent embolism and pulmonary hypertension at 6-month follow-up (p=1.000 and p=0.778). Likewise, hemoptysis is only a relative contraindication to thrombolysis. Consequently, there remains significant interest in whether lowering the dose of thrombolysis may widen the therapeutic window by affording the same benefit without a prohibitive increase in bleeding [50,71]. These factors are essential for thrombus propagation but have little role in haemostasis. The review by Riva et al. Whilst these approaches have demonstrated efficacy in preclinical animal models [92], they are yet to enter clinical trials and therefore are unlikely to be part of the therapeutic armament in the immediate future. There is little theoretical or evidentiary support for why catheter-directed thrombolysis should be superior to administration of an identical dose of tPA via peripheral circulation (all tPA infused peripherally will be transported directly to the pulmonary circulation). Relative contraindication & stabilized: may start with 50 mg alteplase. Korin N., Kanapathipillai M., Matthews B.D., Crescente M., Brill A., Mammoto T., Ghosh K., Jurek S., Bencherif S.A., Bhatta D., et al. Binding of Tissue-Plasminogen Activator to Fibrin: Effect of Ultrasound. RV/LV ratios and modified Miller scores were significantly reduced in all groups at 48 h. Major bleeding occurred in four patients (4%), two of whom were in the highest dose group. Konstantinides S.V., Vicaut E., Danays T., Becattini C., Bertoletti L., Beyer-Westendorf J., Bouvaist H., Couturaud F., Dellas C., Duerschmied D., et al. The differential diagnosis here is pretty short. ~10% of clots will not respond to thrombolysis (perhaps because they are chronic and have undergone organization). By definition, patients with submassive PE have a worse outcome than the majority . This is a well-known problem with the score. Another area of significant interest is the development of targeted thrombolysis strategies [92]. P.C.N. no significant difference demonstrated between the types of reperfusion treatment regarding 30-day mortality (15 and 13%, respectively). The conclusion regarding favourable outcomes with thrombolysis is questionable with small patient numbers, convoluted composite endpoints, and the combination of early outcomes. The code dose of alteplase which is best evidence-supported seems to be a. Tenecteplase may be faster to mix up, so that is another option. The risk of intracranial hemorrhage due to alteplase in prospective RCTs is shown in the table below. This is. To illustrate, Grifoni et al. Weitz J.I., Bauersachs R., Becker B., Berkowitz S.D., Freitas M.C.S., Lassen M.R., Metzig C., Raskob G.E. Erkens P.M.G., Prins M.H. The colour: risk stratification. Recent-onset or accelerating symptoms are worrisome. However, high-quality RCTs are needed. There were no statistically significant differences between the two groups in terms of major or minor bleeding complications. If the patient is actively dying from PE and there aren't good options, it may be necessary to use thrombolysis despite the presence of an absolute contraindication. As discussed, the major benefit of thrombolysis in the context of submassive PE is a reduction in the rate of hemodynamic deterioration. Acute pulmonary embolism (PE) is a common and life-threatening disease, affecting up to 900,000 individuals per year in the US. Kucher N., Boekstegers P., Mller O.J., Kupatt C., Beyer-Westendorf J., Heitzer T., Tebbe U., Horstkotte J., Mller R., Blessing E., et al. . For patients with (sub)massive PE who are receiving tPA or who will immediately receive tPA, heparin increases the risk of bleeding without providing any proven benefit. Being thorough is good, but it is also important to avoid counting the same risk factor multiple times (e.g., if the right ventricle is severely dilated on CT and also dilated on echocardiogram, then echocardiogram doesn't provide any new information). CDT involves positioning catheters directly into thrombi and delivering local thrombolysis. Clinical success (defined as hemodynamic stabilization, improved pulmonary hypertension or RVD, and survival to hospital discharge) occurred in 85.7% and 97.3% of patients with massive and submassive PE, respectively. Further evidence is needed to see how this device will work outside the confines of a clinical trial. Has earned a black box warning from the FDA by causing numerous adverse events (including bradycardia, massive hemoptysis, and renal failure). For a while, it was believed that thrombolysis would reduce the risk of chronic thromboembolic pulmonary hypertension and thereby improve long-term functional endpoints. Retrospective studies suggest an improved survival among patients treated with systemic thrombolysis. However, there was no difference between thrombolysis and placebo in the individual components of the 90 day composite outcome, and patients that received thrombolysis had a similar proportion of NYHA class 3 (p = 0.051), RVD (p = 0.64), and 6MWT distance < 330 m (p = 0.19) compared to placebo. Thrombolysis has been shown in several studies to cause an immediate reduction in pulmonary vascular resistance and thus an immediate improvement in right ventricular function. For a patient undergoing systemic thrombolysis, heparin increases the risk of bleeding without providing any proven additional benefit. In a study of 779 patients with a sPESI score of zero, an RV/LV 0.9 or 1.0 was not associated with worse outcomes [18]. (1) High-flow nasal cannulae with 100% FiO2 is generally the first thing to try. Gali N., Kim N.H.S. Klok E., Mos I.C.M., Huisman M.V. . Moreover, whether the use of these novel antithrombotic approaches are safe in conjunction with thrombolysis is a question unlikely to be addressed in the short-term. The MOPETT trial evaluated low-dose thrombolysis compared to anticoagulation alone in 121 patients with moderate PE, defined as CTPA involvement of >70% thrombi in 2 lobar or left or right main pulmonary arteries, with at least two clinical signs or symptoms of acute PE [50]. Bajaj A., Saleeb M., Rathor P., Sehgal V., Kabak B., Hosur S. Prognostic value of troponins in acute nonmassive pulmonary embolism: A meta-analysis. Crossref Medline Google Scholar; 23 Fava M, Loyola S, Huete I. See, Fall in systolic Bp by >40 mm for 15 minutes, comparison should be made to prior echocardiography, CT scans, and/or EKGs, step #3/4: thrombolytic contraindications, fluid only if clear evidence of hypovolemia, resume heparin (without a bolus) when the PTT is below 1.5-2 times normal, Clot-in-transit which is lying across a patent foramen ovale (PFO), (sub)massive PE in a patient with hemoptysis, (sub)massive PE in a patient with ST elevation, If the inferior vena cava and right ventricle aren't dilated, another process is probably causing the patient's instability, : JACC Focus Seminar. Advances in catheter embolectomy (e.g. Konstantinides S.V., Meyer G., Becattini C., Bueno H., Geersing G.J., Harjola V.P., Huisman M.V., Humbert M., Jennings C.S., Jimnez D., et al. The difference in size of the embolus is an important factor in determining the best treatment option for each patient. included eight additional RCTs in the submassive PE meta-analysis that were ineligible in the Nakamura et al. The BOVA score doesn't ensure that instability is due to pulmonary embolism (specifically, it doesn't require RV dysfunction). An ABG or VBG is exceedingly unlikely to change management. Currently no high-level evidence exists comparing these modalities. Nassiri N., Jain A., McPhee D., Mina B., Rosen R.J., Giangola G., Carroccio A., Green R.M. DOACs are safer when compared to warfarin, but they still carry an approximate 3% annual rate of major bleeding [76]. The cyclical nature of this explains why patients may be stable one minute, but crash the next minute. Greineder C., Howard M.D., Carnemolla R., Cines D., Muzykantov V.R. In this group of patients, it remains appropriate to initiate treatment with LMWH for 12 days before switching to a DOAC. In a study of 411 patients with hemodynamically stable PE, the hazard ratio (HR) for 30 day PE-related mortality or rescue thrombolysis was increased with both elevated RV/LV ratio (HR 7.3, 95% CI 2.027.3, p = 0.003) and TAPSE (HR 27.9, 95% CI 6.2124, p < 0.0001) [11]. ketamine). and transmitted securely. Attempts to improve outcomes in those with submassive PE, also called intermediate-risk PE, have been disappointing [7]. fever. Treatment should generally focus on management of the PE. Submassive PE patients (n = 101) were randomised into one of four groups (2 h 2 mg/h/catheter, 4 h 1 mg/h/catheter, 6 h 1 mg/h/catheter, and 6 h 2 mg/h/catheter). ST elevation in inferior leads (especially III, aVF). In this article, we hope to clarify the current evidence and inform clinical practice. This is usually an incidental finding in a patient who is otherwise doing OK. The PEITHO trial is the largest randomised controlled trial (RCT) to date and constitutes a major landmark in the field [36]. There is no good evidentiary support for the IVC filter (previously discussed here). Impact of Thrombolytic Therapy on the Long-Term Outcome of Intermediate-Risk Pulmonary Embolism. Submassive Pulmonary Embolism | American Journal of Respiratory and In another meta-analysis, short-term mortality was increased in unselected PE patients with either elevated BNP (OR 6.5, 95% CI 2.021) or NT-proBNP (OR 8.7, 95% CI 2.827) [26]. is supported by an NHMRC Senior Principal Research Fellowship. Aspiration thrombectomy for acute pulmonary embolism with an Since bleeding doesn't originate from the pulmonary arteries, the bleeding is generally minor. Submassive pulmonary embolism (PE) lies on a spectrum of disease severity between standard and high-risk disease. Engelberger R.P., Moschovitis A., Fahrni J., Willenberg T., Baumann F., Diehm N., Do D.-D., Baumgartner I., Kucher N. Fixed low-dose ultrasound-assisted catheter-directed thrombolysis for intermediate and high-risk pulmonary embolism. J.D.M. Overall, if the patient has a favorable response to thrombolysis (clinical improvement, weaning off vasopressors), then waiting, (1) Studies usually include a heterogeneous group of patients with a. Kiser T.H., Burnham E.L., Clark B., Ho P.M., Allen R.R., Moss M., Vandivier R.W. A clinically significant clot-in-transit is generally fairly unmistakable (as a large, thick, highly mobile snake-like structure). A large meta-analysis evaluated the predictive value of several CTPA parameters [16]. This is a four-component risk-stratification system for PE. The Tenecteplase Italian Pulmonary Embolism Study (TIPES) enrolled 51 patients with normal blood pressure and echocardiographic RVD [43]. Marti C., John G., Konstantinides S., Combescure C., Sanchez O., Lankeit M., Meyer G., Perrier A. Don't delay thrombolysis if this is an option. However, several situations may warrant careful deliberation of the risks and benefits. Might increase stasis of blood in the legs (thereby increasing the risk of deep vein thrombosis). CTPA can also assess RV dysfunction and is more readily available than echocardiography. is supported by the Monash University RTP Scholarship, the Wheaton Family Scholarship and the HSANZ New Investigator Scholarship. Notably, the association between RVD and the presence of symptoms was not reported. Clinical outcomes of acute pulmonary embolectomy as the first-line In the case of progressive hemodynamic deterioration, rescue thrombolysis is often performed as salvage therapy. Challenges include variable definitions of submassive PE, non-standardised criteria of right ventricular dysfunction (RVD), underpowered studies, and lack of all-cause mortality as a primary endpoint. The diagnostic work-up for CTEPH was performed according to standard medical care and occurred in only 2.6% of patients overall. Alteplase versus heparin in acute pulmonary embolism: Randomised trial assessing right-ventricular function and pulmonary perfusion. The role of thrombolysis in submassive pulmonary embolism (PE) is controversial due to the high risk of hemorrhage. The Management Strategies and Prognosis of Pulmonary Embolism (MAPPET-3) trial was larger and randomised 256 submassive PE patients to receive thrombolysis plus heparin or heparin alone [46]. This involves placement of bilateral catheters into the pulmonary arteries to directly infuse tPA in close proximity to the clot. Pulmonary embolism response to fragmentation, embolectomy, and catheter thrombolysis (PERFECT): Initial results from a prospective multicenter registry. There was a reduction in the mean RV/LV ratio (1.55 vs. 1.13, p < 0.0001), mean PASP (51.4 mm Hg vs. 36.9 mm Hg, p < 0.0001), and modified Miller Index score (22.5 vs. 15.8, p < 0.0001) within 48 h compared to baseline. (b) Can be paused or down-titrated in anticipation of thrombolysis or procedures. Systemic thrombolytic . Vasopressin may be a reasonable second-line agent. This topic review focuses upon PE due to thrombus. What Is The Difference Between Massive And Submassive Pulmonary Embolism 2020 Nov 3;76(18):2117-2127. doi: 10.1016/j.jacc.2020.05.028 [, Crashing patient: Massive PE resuscitation guide , cardiac arrest (how to code a PE patient), http://traffic.libsyn.com/ibccpodcast/IBCC_Episode_53_Submassive__Massive_Pulmonary_Embolism.mp3, Challenging situations: Submassive/massive PE plus. However, this procedure has made a resurgence over the past decade. Prior cerebrovascular accident with residual deficit = 5 points. Half dose tPA: 0.5 mg/kg tPA up to a max of 50 mg tPA. The question of whether thrombolysis with thrombotic agents is effective for submassive pulmonary embolism stems from the cumulative data regarding systemic thrombolytic versus SA. Becattini C., Vedovati M.C., Agnelli G. Prognostic Value of Troponins in Acute Pulmonary Embolism. This site represents our opinions only. The benefits of reduced hemodynamic deterioration are outweighed by increased rates of major bleeding, although it is likely a subgroup of patients with severe submassive PE may still derive net gain. Attempts to develop the holy grail of anticoagulation therapy, a drug that does not cause bleeding, has led to the rational targeting of factor XI (FXI) and XII (FXII). It encompasses mild dyspnoea to the severe CTEPH. Indeed, the presence of syncope has been associated with an increased prevalence of hemodynamic instability and RV dysfunction [52]. One explanation for the discordant results is the inclusion of different primary studies. CTEPH was suspected in only three patients (based on echocardiography), none of whom underwent confirmatory right heart catheterisation due to medical comorbidities. In a prospective, non-randomized, open-label, single-center . As such, significant interest remains in optimising thrombolysis, with recent efforts in catheter-based delivery as well as upcoming studies on reduced systemic dosing. Goldhaber S.Z., Agnelli G., Levine M.N. Brain or spinal surgery (absolute if recent). (28123984) Prolonged filter implantation increases the risk of retrieval failure, filter migration, IVC perforation, filter embolization, or filter thrombosis. Hemoptysis is usually seen during a recovery phase, at which point the patient no longer has a large central clot burden. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (, {"type":"clinical-trial","attrs":{"text":"NCT02923115","term_id":"NCT02923115"}}. Catheter-directed thrombolysis versus suction thrombectomy in the Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension. By comparison, these results are drastically different to the more contemporary PEITHO study [36]. Similarly, the ACCP definition of intermediate-risk PE is met if either RVD or abnormal cardiac biomarkers are present, but also includes abnormal BNP in addition to elevated troponins [28]. Several limitations are notable. Definition Pulmonary embolus (PE) refers to obstruction of the pulmonary artery or one of its branches by material (eg, thrombus, tumor, air, or fat) that originated elsewhere in the body. Recent puncture of non-compressible vessel (relative). Eid-Lidt G., Gaspar J., Sandoval J., Santos F.D.D.L., Pulido T., Pacheco H.G., Martnez-Snchez C. Combined Clot Fragmentation and Aspiration in Patients with Acute Pulmonary Embolism*. Fibrinogen <150 mg/dL (relative; usually don't delay treatment in massive PE if fibrinogen is unknown). Patients with contraindications to thrombolysis might benefit from IR clot extraction. Risk stratification - primary factors General schema for stratification Prognostic factors which don't add much Risk stratification & lysis without a CT scan Physiology of the PE death spiral Resuscitation Rotational embolectomy, using the Aspirex aspirating spiral catheter (Straub Medical), was performed in 11 of 18 patients with massive PE who did not improve after initial thrombus fragmentation using a routine pigtail catheter [62]. This should be removed at the first available opportunity. Prandoni P., Siragusa S., Girolami B., Fabris F., BELZONI Investigators Group The incidence of heparin-induced thrombocytopenia in medical patients treated with low-molecular-weight heparin: A prospective cohort study. Therefore, if you are unsure about whether there is a clot in transit, be suspicious about whether this is a real finding and seek expert advice. PE treatment ranges from anticoagulation, and systemic thrombolysis to surgical embolectomy and catheter embolectomy. Large (22F) catheter that removes emboli through a centrifugal pump with blood return (similar to cardiopulmonary bypass). Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis. Additionally, NT-BNP is elevated in renal dysfunction. Patients were randomised to two doses of FXI-ASO (200 mg or 300 mg) or enoxaparin 40 mg daily. Systemic Thrombolysis for Pulmonary Embolism: A Review 100 mg IV alteplase (tPA) over 2 hours has traditionally been considered as full dose thrombolysis, for use in massive pulmonary embolism. Note that a small IVC should rarely or almost never occur in massive PE. Patients with submassive PE will be randomised to a reduced dose of alteplase (0.6 mg/kg to maximum of 50 mg) or placebo. However, one possible explanation is the early intervention and favourable outcomes of patients who suffered hemodynamic deterioration in the anticoagulation arm. Refractory hypoxemia always reflects some sort of shunt. The placement of thousands of IVC filters over decades is a case study in fear-based medical practice, reinforced by eminence-based guidelines. Bridge to intervention: ECMO could be used as a bridge to other definitive therapies (e.g. Definitions of submassive/intermediate-risk PE demonstrating the variable inclusion of RVD and cardiac biomarkers. Pulmonary embolism (PE) presents a spectrum of hemodynamic consequences, ranging from being asymptomatic to a life-threatening medical emergency. Additionally, the rate of pulmonary hypertension was drastically higher compared to other studies. Kuo W.T., Banerjee A., Kim P.S., De Marco F.J., Levy J.R., Facchini F.R., Unver K., Bertini M.J., Sista A.K., Hall M.J., et al. The subsequent conclusions regarding the net clinical value of thrombolysis therefore varied between SRs, ranging from strongly positive to strongly negative. JCM | Free Full-Text | Submassive Pulmonary Embolism: Current - MDPI For (sub)massive PE, unfractionated heparin is generally preferred for the following reasons: (a) Can be stopped if the patient begins hemorrhaging. By definition, patients with submassive PE have a worse outcome than the majority of those with standard-risk PE, who are hemodynamically stable and lack imaging or laboratory features of cardiac dysfunction. FLARE study: Single-arm trial involving 106 patients with submassive PE treated with the FlowTriever. Advanced PE therapies are beneficial only if PE is causing the patient's instability. Vasopressin is generally used as a second-line agent because it's not tremendously powerful and it is difficult to titrate (with a half-life of ~20 minutes, its onset and offset are sluggish). The initial choice of anticoagulation in patients with submassive PE is generally between low-molecular weight heparin (LMWH) and a direct oral anticoagulant (DOAC). Quezada C.A., Bikdeli B., Barrios D., Barbero E., Chiluiza D., Muriel A., Casazza F., Monreal M., Yusen R.D., Jimnez D. Meta-Analysis of Prevalence and Short-Term Prognosis of Hemodynamically Unstable Patients with Symptomatic Acute Pulmonary Embolism. Kucher N., Rossi E., De Rosa M., Goldhaber S.Z. RVD is often combined with abnormal cardiac biomarkers in defining submassive PE. Patients with submassive PE, defined by both RVD and elevated troponins, had a mortality rate of only 1.2%.
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