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Management of intermediate and high risk pulmonary embolism (aka submassive/massive PE)

Justin Morgenstern
Managing High Risk pulmonary embolism
Cite this article as:
Morgenstern, J. Management of intermediate and high risk pulmonary embolism (aka submassive/massive PE), First10EM, April 1, 2025. Available at:
https://doi.org/10.51684/FIRS.140873

Pulmonary embolism is probably discussed far more than is truly necessary. It receives more attention than almost any other pathology. We endlessly debate the best algorithms for diagnosis. We add new decision tools almost yearly. However, if there is one aspect of pulmonary embolism that might be under-discussed it is the management of massive and submissive PEs. After being asked to participate in an Emergency Medicine Cases podcast on the subject, I spent a lot of time on PubMed trying to fill gaps in my knowledge. These are the notes that I made for that podcast. 

When should we be using thrombolysis?

There is general agreement that thrombolysis should be used in patients with massive PE, which is defined as patients having hypotension. As a whole the data is not strong, and there is definitely remaining uncertainty, but the absolute benefit in massive PE looks large enough to drive clinical practice. For example, in one systematic review and meta-analysis that includes 748 patient from 11 trials, although there was no overall statistical benefit from thrombolytics, the subgroup of massive (or hemodynamically unstable) PE demonstrated a 10% absolute reduction in mortality (9.4% versus 19.0%; OR 0.45, 95% CI 0.22 to 0.92; number needed to treat=10). (Wan 2004) 

Reading through some of these early trials, “life threatening” or “hemodynamically unstable” PE was often left undefined. Clinically, the working definition seems to be focused on hypotension, although even the exact definition of hypotension is somewhat unclear (especially in the initial chaos of an emergency resuscitation). Consensus definitions of massive PE, and therefore clear indications for thrombolysis, usually include: (Jaff 2011; Konstantinides 2014; Kearon 2016)

Thrombolysis as first line therapy for massive PE is supported by several international guidelines, including those from the ACCP, AHA, ESC, and ACEP. (Jaff 2011; Kearon 2016; Konstantinides 2020)

“Submassive PE” encompasses a much larger and much more heterogeneous group of patients, which probably explains why there is still so much confusion and debate about the best approach to these patients. Hopefully future research will do a better job risk stratifying within this group, because they are not all created equal. For now, management will require a lot of clinical judgment, based on a number of factors. 

A quick aside: why are we giving thrombolytics?

As emergency and critical care physicians, we are often focused on the immediate question of whether a patient is going to live or die. Unfortunately, even when our patients survive the initial insult, there are often long term consequences of their pathology. For DVT, a significant minority of patients have chronic symptoms from post-thrombotic syndrome. Similarly, after pulmonary embolism, many patients have significant long term pulmonary hypertension and persistent dyspnea reducing their quality of life. 

There was some thought that thrombolysis might improve the long term outcomes after PE, but long term follow-up of the PEITHO trial (discussed more below) demonstrated no change in mortality, functional limitations, or pulmonary hypertension at 3 year follow up. Therefore, for the time being, if we are considering thrombolysis in the setting of PE, we are doing so to prevent short term clinical deterioration or death. (Konstantinides 2017)

Back to the main question: which submassive PEs should be treated with thrombolysis? (The evidence)

As of 2024, there is no definitive answer to which submissive PE patients (if any) will benefit from thrombolysis. There are conflicting meta-analyses and conflicting points of view. For the most part, we just don’t have enough studies focused on differentiating this very heterogeneous group.

There are 4 main RCTs to know about: MAPPET-3, TIPES, TOPCOAT, and PEITHO. 

The MAPPET-3 trial is a multicenter double blind RCT that randomized 256 patients with acute PE and RV dysfunction (based on echo, ECG, or cardiac catheterization) to alteplase (10 mg bolus then 90 mg over 2 hours) or placebo. There was an improvement in their composite primary outcome of in-hospital mortality or clinical deterioration requiring escalation of care (11% vs 25%). However, the difference was essentially entirely from escalation of care, and almost all the escalation of care was providing thrombolytics. That outcome is very circular. “We saw a benefit from giving everybody thrombolytics because a few patients didn’t need thrombolytics later.” The drug company was involved in this trial, and it was stopped early, among other shortcomings. (Konstantinides  2002)

TIPES is a small multicenter RCT in which 58 patients with acute PE, normal blood pressure, and RV dysfunction on echo were randomized to tenecteplase (standard 30-50mg dose) or placebo. Their primary outcome was an improvement in RV function on echo. The right ventricle looked better on echocardiography at 24 hours, with a borderline p value of 0.04, but there was no difference at 7 days. It is unclear to me whether the differences they are measuring had any clinical significance, and there were just a handful of clinical events, and so you can’t really comment further. (Becattini 2009) 

TOPCOAT is a small double blind multicenter RCT that randomized 83 patients with submassive PE (normal blood pressure but RV strain based on echo, troponin, or BNP) to standard dose tenecteplase or placebo.  (Kline 2014) Based on a very broad composite outcome, the study was positive, with fewer adverse events with thrombolysis (15% vs 37%). However, the vast majority of these events were patient perceived quality of life. Based on the demographic numbers provided I think these patients are probably at the very low end of the submassive risk spectrum (i.e. only 25% of patients had a heart rate over 110).  

PEITHO is the largest trial we have, enrolling 1005 patients with PE, RV dysfunction, and an elevated troponin, in a multicenter RCT comparing standard dose tenecteplase (30-50 mg) to placebo. Although this is a statistically positive trial, the results do not convincingly demonstrate net benefit. The primary outcome was a composite of death and hemodynamic decompensation, and was improved with tenecteplase (2.6% vs 5.6%). However, mortality was unchanged (1.2% vs 1.8%), and although there was less hemodynamic decompensation (1.6% vs 5.0%), less than half of these patients were even started on vasopressors, making the clinical relevance questionable. This questionable benefit was balanced by a significant increase in both extracranial major bleeding (6.3% vs 1.2%) and hemorrhagic stroke (2% vs 0.2%). The primary issue with this study may be that it included patients who were too healthy, given that the mean heart rate at enrollment was below 100, and only about 4% had any bad outcomes. (Meyer 2014)

There are multiple meta-analyses that look at thrombolysis in the intermediate risk group of patients. The conclusions of these papers vary, and there is a ton of uncertainty, but I think they are mostly telling us the same thing (within a huge veil of uncertainty). One meta-analysis reported an improvement in all cause mortality (2.2% vs 3.9%), but an increase in major bleeding (9.2% vs 3.4%) and ICH (1.5% vs 0.2%). (Chatterjee 2014) A second meta-analysis by Marti and colleagues (2015) demonstrates a statistical improvement in all cause mortality, as well as a decrease in need for ‘treatment escalation’, but again at the cost of increased bleeding. Xu and colleagues (2015) report no statistical difference in all cause mortality (although with a p value of 0.08), but a decrease in recurrent PE and clinical deterioration, and strangely no increase in major bleeding.

At the end of the day, these meta-analyses are just taking the same data and slicing it up in different ways to say slightly different things. We clearly need more data. There are clear risks from using thrombolysis, and we should therefore be very cautious with this choice. However, it also seems very likely that there are going to be benefits, including a potential to save lives. The big problem is the incredibly broad and non-specific “intermediate” risk group. It seems pretty clear that this group will contain higher risk patients that will benefit and lower risk patients who will be harmed, and we need a lot more research separating those groups out. 

So, at the end of the day, the primary scientific answer is obviously that “more research is needed”. Clinically, that doesn’t help us much, as we still need to make treatment decisions for these patients today.

So who do I actually treat?

The intermediate or submissive group of patients is incredibly variable, and specific evidence to guide treatment is still mostly lacking. This group is defined differently in different guidelines, with the key features usually being either evidence or right ventricular dysfunction and/or changes in biomarkers such as troponin or BNP. Most publications lump all the patients together, but some try to stratify them further. For example, the ESC guidelines call patients “intermediate low risk” if they have either right ventricular dysfunction or positive biomarkers, and “intermediate high risk” if they have both. (Machanahalli Balakrishna 2022)

Within this intermediate group, there are almost certainly high risk patients, closer to the “massive” group, who warrant thrombolysis, while there are other patients who are much lower risk and would be harmed by thrombolysis. Unfortunately, within the intermediate risk or “submassive” group, there is no single variable that will make this decision for you. You are going to have to make a judgment call that incorporates many clinical variables. 

A history of syncope, presyncope, or severe dyspnea increases risk. Physical exam features such as the patient’s general appearance (are they diaphoretic and anxious) and vital signs are important. (However, don’t allow yourself to be overly reassured by a normal blood pressure, especially in young patients, as intrinsic catecholamines can often support a blood pressure even when there is clear clinical shock). A shock index greater than 1 (i.e. a heart rate greater than the systolic blood pressure) is associated with increased short term mortality, and is probably more sensitive (but less specific) than just looking at the blood pressure alone. (Ozsu 2017; Tapson 2017)

A history of syncope always concerns me, and it is strongly associated with hemodynamic instability, RV dysfunction, and mortality. (Barco 2018) However, the association with death disappears when you focus only on normotensive patients, and so syncope may not be an independent risk factor. 

The ECG can give some important insight into what is going on with the heart, and any abnormality should increase your concern. ECG abnormalities specifically associated with increased in hospital mortality include S1Q3T3 (OR 3.3), right bundle branch block (OR 3.9), T wave inversions (OR 1.6), right axis deviation (OR 3.2), and atrial fibrillation (OR 2). (Qaddoura 2017)

There are a number of laboratory markers that are associated with increased risk. An elevated troponin is associated with a significant increase in short term mortality (odds ratio of about 5). (Bajaj 2015) An elevated lactate is also associated with short term mortality (hazard ratio 11). (Vanni 2013) Some people add BNP to their risk stratification tools, but I doubt it adds much in addition to everything else considered here. (The patients with elevated BNP will almost certainly have an abnormal ECG and/or echocardiogram and/or physical exam findings and/or troponin elevation.) 

Obviously, emergency medicine loves ultrasound, and a bedside echocardiogram can add a lot of prognostic information. The classic signs of RV strain are an RV that as equal to or larger in size than the LV, and flattened interventricular septum (or the “D” sign), or if you have some expert level skills, a TAPSE (tricuspid valvular annular systolic excursion) reduction <18 mm. There is mixed evidence on the prognostic value of echocardiogram. One of the big issues is trying to distinguish acute from chronic changes.  

Although they are static images, the CT scan can provide clues about function. A significantly enlarged RV on CT is believable, and if there is reflux of contrast into the IVC/ hepatic veins that is a hint of RV failure.

Note: One caution found in the ESC guidelines is that even patients classified as low risk by clinical scores can have RV dysfunction, and are still considered higher risk. They suggest some assessment of the right ventricle in every patient. That obviously complicates the concept of outpatient management, unless you are very comfortable with bedside ultrasound. However, they suggest CT is an OK alternative, but that does rely on your radiology department consistently commenting on signs of RV dysfunction when reporting PE scans. (Konstantinides 2019) However, CT has an abysmal specificity for RV dysfunction (4% as compared to TTE), and so experts outside of ESC would strongly advise against using CT as additional risk stratification in patients already stratified as low risk.

When reviewing these numbers, it is important to keep in mind that these are not likely to be independent variables. For example, right axis deviation on ECG is probably telling you that there is an abnormal echocardiogram. It would be a mistake to add those two variables together to increase your risk, when they are probably saying the exact same thing. 

Some sources suggest management based on the PESI or simplified PESI. I think these scores are subject to the many problems that plague all of our decision tools, and so I would be cautious in using them. That being said, decision tools probably provide more value as prognostic tools than as dichotomous diagnostic rules, and so I am less skeptical of their use here. On the other hand, these scores really just incorporate everything discussed above, and so probably mirror your clinical judgment, but there is no evidence that decisions made using these scores are any better than clinical judgment. (One sign that a score is not ideal is the need to modify it over time. Another sign of inadequate decision tools is the existence of many other options without a clear gold standard. For PE risk stratification, you will also see the BOVA score, the FAST score, the PREP score, and the PROTECT index also suggested as possible risk stratification tools, which makes me concerned about the value of any specific tool.) (Pastre 2022)

A specific concern about these PE prognostic scores is that they often include variables that don’t help you make treatment decisions. I am trying to find patients at high risk of short term mortality who might be helped by thrombolysis. While it is true that cancer increases mortality, it doesn’t increase the patient’s chance of being helped by thrombolysis. In fact, it probably pushes me in the opposite direction. The prognostic tools all seem to lump these variables together, and therefore seem useless to me for making decisions about advanced therapy.

Of course, although the discussion is often focused on a single point in time, pulmonary embolism is a dynamic process. As emergency physicians, we generally want to just make a decision and move on, but the most important prognostic factor in these patients might be their clinical course over the course of 6-12 hours. Repeat clinical assessments, laboratory studies, and echocardiograms are probably essential when making decisions about the many borderline patients you will see. This is especially true, considering that most of the benefit seen in the submissive patients is “prevention of hemodynamic decompensation”, but that really just means you are giving everyone thrombolytics up front, instead of only giving them to a select few patients later. Considering the proven harms of thrombolytics, it makes sense to wait and reevaluate.

On paper, the wait and reevaluate approach makes sense. However, in many hospital settings, it makes me nervous. In many community settings, even if the patient is admitted to the ICU, the intensivist isn’t in house. The physicians covering ICU overnight are usually incredibly busy with other patients. The subtle hypotensive episodes that might be critical to decision making in these patients are common and less important in other patients, and so easily overlooked. Once these patients leave the emergency department, the level of attention can vary dramatically. The best approach will be highly dependent on your individual system. 

After reviewing all this evidence, I don’t think I can improve much on the PulmCrit/IBCC risk stratification, so I will just copy and paste his schema here:

His scheme (and this article) isn’t really focused on the low risk patients, and there are numerous other factors that you will consider if you are thinking about sending a patient home (bleeding risk, current anticoagulation, renal function, liver disease, social issues, etc), but that is a topic for another time. 

The key to this schema is that the management of submassive PE is nuanced. In the high risk submassive patients, there will be a consideration of advanced therapies, but based on the uncertainty in the current literature, this is usually not a decision I will make on my own in the emergency department. I like Farkas’ algorithm because it reminds us of the importance of re-evaluation in the lower-risk submassive patients, and the value of ICU admission and consultation in the higher risk patients.

One key point that doesn’t make it into this graphic: although we rarely use unfractionated heparin anymore, these submissive PE patients should all start on unfractionated heparin, because if they deteriorate or require thrombolytic therapy, that is much safer when unfractionated heparin has been used. (Although listen to the EMCases podcast on the topic, where Lauren Westafer presents very strong opinions to the contrary.)

Guidelines

The 2011 AHA guidelines (Jaff 2011) suggest thrombolysis in patients with RV strain and either evidence of shock or respiratory failure (any hypotension, shock index >1, respiratory distress (SaO2 <95% with Borg score>8, or altered mental status, or appearance of suffering), or evidence of moderate of severe RV strain based on echo or significantly elevated troponin or NBP.

The 2016 ACCP guidelines recommend systemic thrombolysis for patients with hypotension, but suggest against thrombolysis in most patients without hypotension. (Kearon 2016) “In selected patients with acute PE who deteriorate after starting anticoagulant therapy but have yet to develop hypotension and who have a low bleeding risk, we suggest systemically administered thrombolytic therapy over no such therapy.” Things they suggest watching for include a progressive increase in heart rate, a drop in blood pressure (but which still remains above 90 systolic), an increasing JVP, worse gas exchange, clinical signs of shock, progressive right heart dysfunction on echo, or an increase in cardiac biomarkers. The key seems to be that the decision is made over time.

The 2019 ESC guidelines state that “rescue thrombolytic therapy is recommended for patients with haemodynamic deterioration on anticoagulation treatment.” (Konstantinides 2020)

The 2023 Thrombosis Canada guidelines are a little more anti-thrombolysis, stating “Harm with thrombolysis outweighs the benefit in most patients with PE, except in those who present with high risk (massive) PE… Thrombolysis is NOT routinely indicated in intermediate risk (also called sub-massive) PE (normotensive with right ventricular dysfunction on imaging or with elevated cardiac biomarkers), as it increases major bleeding and hemorrhagic stroke. For select patients with intermediate risk PE who are not at high risk of bleeding AND who have severe persistent symptoms with signs of right heart failure or cardiopulmonary deterioration, thrombolysis may be considered after discussion with a thrombosis expert.” (Thrombosis Canada 2023) 

Contraindications

Of course, the standard contraindications of thrombolysis still apply. That being said, most contraindications are relative rather than absolute. If a patient is peri-arrest, the benefits of thrombolysis are probably going to outweigh the harms. On the other hand, with no clear evidence of benefit in the submassive group of patients, any contra-indication needs to be taken seriously. The exact list of conta-indications and whether they are “absolute” or “relative” varies between guidelines. Below is an amalgamation that does not perfectly match any individual guideline:

Contraindications (Jaff 2011; Kearon 2016; Konstantinides 2020)

I find the terminology of “absolute” and “relative” to be clinically useless, as there is really no such thing as an absolute contraindication, and relative is only helpful if accompanied by some estimate of risk of hemorrhage. Ideally, each of these risk factors would be listed with their individual risk of harm. Barring that, I like the breakdown that Scott Weingart uses, instead breaking patients into high, moderate, and low risk for bleeding, and proceeding accordingly. 

If giving thrombolytics, what is the dose?

The dosing of thrombolytics in PE seems to be based on the doses used in MI and stroke. Given the larger datasets available in those conditions, it is understandable why that happened, but PE is unlike stroke and MI in a very important way. The pulmonary arteries receive 100% of the circulating blood volume, as compared to the much smaller percentage that travels through the coronary or cerebral circulation. Therefore, theoretically, it makes sense to use much lower doses when treating PE. 

To start with some basic definitions, “full dose” in the context of PE is usually considered to be tPa (alteplase) 100 mg IV given over 2 hours. “Half dose” as defined by the MOPETT trial was 0.5 mg/kg to a maximum of 50mg, with the first 10 mg given as a push and the remainder over 2 hours. 

The MOPPET trial is a small single center trial with 121 adult patients with moderate PE, comparing a ‘half dose’ of tPA (0.5 mg/kg, max 50 mg. 10 mg bolus with the rest over 2 hours) plus anticoagulation to anticoagulation alone. (Sharifi 2013) Most of the anticoagulation was full dose enoxaparin. The primary outcome was pulmonary hypertension, which was better with thrombolytics. The trial wasn’t powered for clinical outcomes, but mortality and recurrent PE also both look better with treatment. They record no bleeding at all (which is somewhat unbelievable). Without a comparison to ‘standard dose’ tPa, this trial doesn’t really help determine the best dose. (I guess it fits better above, with PEITHO and the other trials, demonstrating some potential benefit of thrombolytics in moderate risk patients.)

There is a multi-center RCT with 118 patients with acute PE and either hemodynamic instability or a large clot burden on imaging that compared a 50 mg dose of tPa to 100 mg (both over 2 hours). They found less bleeding with the lower dose, but no differences in the (primarily surrogate) efficacy outcomes. It is a very small trial, but essentially all point estimates look better with the 50 mg dose. (Wang 2010) 

There is a meta-analysis that bumps these numbers up to 5 total studies and 440 patients, and the results are the same; no change in efficacy but less bleeding when 50 mg is used instead of 100 mg. (Zhang 2014)

There is a propensity matched retrospective cohort, comparing full dose and half dose alteplase. (Kiser 2018) They didn’t find any difference in bleeding rates, but clinical outcomes also look basically the same. There was more “escalation of care”, but seeing as that was usually just giving the other half of the alteplase dose, I don’t think that is a bad thing. Obviously, this is not randomized data, and people choose to start with a half dose in a much different population. 

There are case reports of successful use of much lower dose thrombolytics (0.5-4mg of tPa), especially in patients with contraindications to thrombolytics. (Boone 2011) Low doses make a lot of theoretic sense, given the percentage of systemic circulation that goes through the pulmonary arteries, and the fact that you can always add more if your first dose didn’t help. However, these case reports do very little for us, because people are highly unlikely to publish the cases in which they deviated significantly from standard care and the patient had a bad outcome. 

Somewhat more convincing, both because it is prospectively collected data, and because it focused on the sicker “massive” PE subset, was an observational trial of 37 patients who received 25 mg of tPa over 6 hours (so a quarter dose given more slowly than usual). (Aykan 2023) All patients had improvement in the clinical indicators of RV dysfunction after treatment. No major bleeding was observed. One patient died while in hospital. This data obviously has very significant limitations, with no control group, and only surrogate disease oriented outcomes. However, it sets the stage for n of 1 trials with patients, because you lose very little by starting low and slow, because you can always increase the dose of alteplase if the patient is not improving (or increase the speed if they are deteriorating). 

Although limited, I think this literature makes it very clear that “half dose” tPa is the highest dose that I would start with. The evidence all seems to support half dose over full dose, and you really lose nothing, because if the patient is not improving, you can always add the second half of the dose. The real question is how much lower we should go. It seems like much lower doses might be reasonable, again with the same logic that you can always add more, but can’t take any away. 

Bottom line: Once again, I tend to agree with Josh Farkas’s (IBCC) interpretation of this literature:

“For a patient who isn’t actively dying, the most sensible approach could be to provide titrated doses of fibrinolytic, while closely monitoring coagulation parameters (especially fibrinogen). There are roughly two ways to do this:

What about catheter directed thrombolysis?

My instinct is that, given that the entire circulating blood volume goes through the lungs (as compared to the small fraction that goes through the cerebral or coronary arteries), there should be no advantage to giving thrombolytics through a specialized catheter as compared to a peripheral IV. Clot retrieval makes more sense, but thus far has shown no benefit. 

The PERFECT trial was a prospective observational trial looking at 100 patients with massive and submassive PE, treated with catheter-directed mechanical or pharmacomechanical thrombectomy and/or catheter-directed thrombolysis through low-dose hourly drug infusion with tissue plasminogen activator (tPA) or urokinase. (Kuo 2015) 97% if the submassive and 86% if the massive PE patients had improved hemodynamics after treatment, but obviously this tells us very little without a control group. The average dose of tPA was 28 mg. 

The SEATTLE II trial is another small prospective observational trial with no control group that included 150 patients with massive or submassive PE and treated with 24 mg of tPa through an “ultrasound facilitated” catheter. (Piazza 2015) Pulmonary artery pressures improved. 10% of patients had moderate bleeding events. 

The ULTIMA study is an industry run trial that provides essentially no clinical information. (Kucher 2013) They took 59 patients with acute PE and RV enlargement, and randomized them to 10mg of tPa through the EkoSonic endovascular system over 15 hours plus heparin or heparin alone. They left out the comparison that would have actually helped: tPa through a peripheral IV. The tPa group had improved markers on an echocardiogram, but no patients in either group had any hemodynamic decompensation, and therefore there was no possibility of demonstrating a clinical benefit in a trial. This is a thinly veiled advertisement, and doesn’t help us clinically (aside from furthering the idea that lower doses of tPa might be effective in PE). 

The OPTALYSE is another trial that doesn’t provide much value, because it doesn’t include a proper control group, just sort of assuming a catheter directed approach is a good idea, and comparing different catheter directed doses. (Tapson 2018) Not surprisingly, this trial was also run by the company trying to sell you these catheters. 101 adult patients with acute intermediate risk PE with RV enlargement were randomized to one of 4 doses of tPA (all given through the sponsor’s ultrasound catheter). Doses ranged from as low as 4 mg to as high as 24 mg. All patients were also on therapeutic unfractionated heparin. Echocardiograms looked better after treatment. There were not enough clinical events (deaths or recurrent PEs) to really comment. Bleeding looks higher with higher doses. Without a proper control group, this trial cannot be used to support a catheter based approach, but there is a little more data to suggest lower doses of thrombolytics are better. 

The PEERLESS study compared catheter directed thrombolysis to mechanical thrombectomy. There is a full post here discussing the details, but the short story is that there doesn’t seem to be any clinical difference between the two techniques. (Jaber 2024)

Bottom line: I don’t think there is any reason to use catheter directed thrombolysis or “ultrasound facilitated thrombolysis” at this time. There is no good evidence, and they don’t make physiologic sense. Using interventional radiology techniques to mechanically retrieve the clot might make more sense, and are discussed below, but also have absolutely no evidence supporting them at this time. 

There are a number of ongoing studies in this area, but unfortunately almost all of them seem to be poorly designed. They are almost all comparing catheter directed thrombolysis to heparin, which is fair, but doesn’t do anything to prove that the catheter adds any value. What you really need to see is a comparison between catheter directed and systemic thrombolysis. Ideally, I would use the exact same dosing regimen. In other words, if the catheter directed approach is to give tPa at 1 mg per hour, that is exactly how I would dose tPA through a peripheral IV. It doesn’t make any sense to comepare 12 mg of tPa through a catheter to 50 mg through an peripheral IV. In order to prove that the catheter provides value, you need to compare the exact same medication at the exact same dose being delivered both with and without the catheter. As far as I can tell, there is not a single study in the works that takes that approach, and therefore it seems very unlikely that anyone is going to effectively settle this issue in the near future.

What is the thrombolytic dose for cardiac arrest?

The recommendations around thrombolytics during cardiac arrest tend to focus on the PEAPETT study, in which 23 patients with confirmed pulmonary embolism and PEA arrest were treated with a 50 mg IV push of tPa, and return of spontaneous circulation was achieved in 22 of the 23 patients. (Sharifi 2016) 21 of the 23 patients survived to hospital discharge and 20 (87%) were still alive at 3 month follow-up, which is an unheard of number for PEA arrest. Obviously, without a control group, the conclusions are limited. 

Therefore, in an arrest, my current approach is to give tPa as a 50 mg IV bolus, and I am willing to repeat that bolus once if unsuccessful.

As mentioned above, the outcomes for PE patients treated with thrombolytics are much better than for almost any other cause of PEA arrest. I think that is the logic that leads to the ESC guideline to recommend “once a thrombolytic drug is administered, cardiopulmonary resuscitation should be continued for at least 60-90 min before terminating resuscitation attempts.” (Konstantinides 2020) That time frame seems unrealistic to me, but you certainly need to run these codes longer than you are used to. 

How do you resuscitate a patient with a massive / submassive PE?

A sick patient with pulmonary embolism is in right ventricular failure, which, as we have covered before, is an incredibly high risk scenario. We need to be incredibly careful about anything that could either increase pulmonary artery pressures or impair RV perfusion, which means meticulously avoiding hypoxia, hypercapnia, positive pressure ventilation, and hypotension.

A general lesson that I took away from this literature is that we should always be prepared for these patients to deteriorate or arrest, but when they do, we should be more aggressive than usual (or at least more willing to run a prolonged code) because outcomes seem to be good. In the PEAPETT study that looked at tPa during PEA arrest, 87% of the patients were still alive at 3 months. (Sharifi 2016) In the MAPPET study, 35% of the patients who received CPR survived to hospital discharge. (Kasper 1997) Those are much higher numbers than we are used to, especially in PEA arrests, so although our goal should be resuscitating in a manner that avoids arrest, we should also be optimistic and aggressive if an arrest does occur. 

Airway

An endotracheal tube is not a solution to massive pulmonary embolism. Plastic between the cords will not solve the issue, even if there is hypoxia. On the other hand, everything we do to intubated patients, from the medications we give them, to the peri-intubation risk of hypoxia and hypercapnia, to the transition to positive pressure ventilation, has the potential to kill these patients. In general, our goal is to avoid intubation. Consider all alternatives, such as high flow nasal oxygen, before intubation.

Massive pulmonary embolism causes acute pulmonary hypertension and acute right heart failure. I have an entire post dedicated to the management of pulmonary hypertension and right heart failure, but the conclusion there is the same: if at all possible, do not intubate. 

If an intubation is absolutely required, it should be an awake intubation (or, realistically for most departments, a ketamine facilitated breathing intubation). The idea of an awake airway is not just to avoid complications such as hypoxia and hypercapnia during tube passage, or to limit the hemodynamic impacts of sedatives. The transition to positive pressure ventilation can be very problematic, as you are adding pressure against which the already strained right ventricle will have to push. The goal is an awake intubation that maintains negative pressure respirations throughout. 

The nuances of airway management in right heart failure or massive PE could be an article in itself. For my purposes here, I think the main take home point is to remember that plastic between the cords is unlikely to solve any of your issues, but might cause a heap more. Avoid intubation if possible. If you want a more in depth conversation about airway management, check out the Internet Book of Critical Care, as well as EMCrit’s Hemodynamically Neutral Intubation.

Fluids

Avoid fluid resuscitation

No one is going to fault you for trying a little fluid resuscitation in a hypotensive patient, but when dealing with a massive PE, they are more likely to harm than help. (Konstantinides 2020) The RV is already overloaded. Further stretch will make things worse by increasing tricuspid regurgitation, pushing the septum in the left ventricle, decreasing LV output, and increasing tension on the RV wall, which impairs perfusion and increases ischemia. 

If the patient is fluid responsive, or if there is a small IVC on ultrasound, you probably aren’t dealing with a hemodynamically consequential PE. If you know it is a hemodynamically consequential PE, avoid IV fluids.

Pressors

Aside from pretty strong data that dopamine is a bad choice in all clinical settings, we really don’t have strong data comparing (or even really supporting) vasopressors. I don’t think you would be wrong for starting with your usual choice of norepinephrine, but some experts suggest epinephrine as the vasopressor of choice in massive PE for theoretical reasons (the beta activity might cause pulmonary vasodilation, these patients almost certainly need inotropy in addition to pure vasoconstriction, and bradycardia is common in the pre-arrest stage). Vasopressin might also have beneficial effects in the setting of pulmonary hypertension, but is harder to titrate, and so is probably relegated to a second line agent. (Condliffe 2017; Joshi 2022)

Plan ahead

A really important part of caring for critically ill patients is being cognizant of next steps, especially if the patient deteriorates. We are usually really good at this, involving specialists or arranging transfers early, even if the patient doesn’t necessarily need their care right now. One thing to keep in mind with the sick PE patient is the chance of thrombolysis in the near future, even if you decide not to prescribe it immediately. Consider the impact of thrombolysis on the procedures you are performing. There is almost never a reason to perform an ABG, but avoiding arterial sticks makes even more sense if you are going to use a thrombolytic. We know peripheral vasopressors are a fine option, so there is no need for an inexperienced proceduralist to perform an immediate central line. If you are placing a central line, put it in a compressible location. 

ECMO

Although a pipe dream for most of us working in the community, VA-ECMO would be a reasonable rescue therapy for patients with massive PE. (Konstantinides 2020) There are patients with a clearly defined therapy (anticoagulation, thrombolysis, surgery, intervention), and ECMO could provide the added time needed in selected patients. Of course, there is no evidence at all and this isn’t even an option where most of us work. 

This is a case report of a pregnant woman who had a perioperative PEA arrest to do presumed PE, was not revived with 2 doses of tenecteplase, and was therefore started on ECMO 85 minutes into the resuscitation. She was ultimately discharged home with no physical or neurologic sequelae. (Fernandes 2014) There are a couple other case series with similarly good outcomes. (Kawahito 2000; Malekan 2012) Amazing outcomes, but of course you don’t publish your bad outcomes. 

Potential reasons to consider ECMO: (Weinberg 2017) Cardiac arrest, severe hemodynamic compromise, contraindications to thrombolysis, failure of thrombolysis, severe hypoxemia

Contraindications to ECMO: (Weinberg 2017) Contraindications to anticoagulation, poor baseline functional status, severe comorbidities, unrecoverable condition. 

Surgical thrombectomy

Despite seeing pictures of this dramatic procedure on the internet, I have never worked in a center where this was possible. I have never really known when I might want to push for surgery. It is often described as an alternative to thrombolysis when there are contraindications to thrombolytics. (Machanahalli Balakrishna 2022) 

In a retrospective look at 2,111 patients who either underwent thrombolysis or surgical embolectomy, there was no difference in 30 day mortality (15% vs 13%). (Lee 2018) Thrombolysis had a higher rate of stroke and reintervention, but surgery had more major bleeding. Only 12% of patients went for surgery, and these would have been selected on criteria not evident in a chart review, so all you can really say is that experienced surgeons seem to be good at selecting candidates for surgery. 

There is another retrospective look at surgical thrombectomy that concludes that the procedure is “is safe and can be performed with acceptable in-hospital outcomes”, but looking through the results, I am less convinced. (Keeling 2016) The trial consisted of a chart review of 214 patients, 82% of which were submassive. They seem to focus on the overall mortality rate of 11%, which might be good in a peri-arrest or massive PE group, but sound pretty bad in a submassive PE group. In patients who had CPR performed before surgery, hospital mortality was 32%. I would take that number in patients who had already died. But in patients who had not had CPR performed, mortality was 8.6%, and overall among submassive patients, mortality was 9.1%. They don’t give enough information in the paper to determine exactly how sick this submissive group was, but this seems to suggest surgery should be reserved only for the sickest patients. 

Bottom line: There is very little evidence, the outcomes don’t seem great, and it is rarely available. However, in a very sick patient with contraindications to thrombolysis, it is worth having a discussion with a vascular surgeon. 

What is the evidence for inhaled pulmonary vasodilators? How do I use them in the emergency department?

Very few of us have mastered the emergency management of severe pulmonary hypertension. A large pulmonary embolism results in acute pulmonary hypertension, not just because of mechanical clogging of the pulmonary arteries, but also through inflammatory and hypoxia mediated pulmonary vasoconstriction. Inhaled pulmonary vasodilators may improve both hemodynamics and oxygenation (hypoxia being caused by VQ mismatch).

Before jumping to medications to address pulmonary vasoconstriction, remember high quality supportive care. The most common causes of vasoconstriction are hypoxia and hypercarbia. High flow oxygen and good ventilation are essential as a baseline of care. 

There are a number of case reports of patients with massive PEs improving rapidly after being given inhaled nitric oxide. (Szold 2006; Summerfield 2012; Kline 2014)

Surprisingly (to me at least) there is actually a multi-center RCT (the iNOPE trial) looking at inhaled nitric oxide (iNO) in pulmonary embolism patients. (Kline 2019) 76 patients were randomized to placebo vs. iNO at a dose of 50 parts per million for 24 hours. Unfortunately, this trial used a strange, composite, and definitely not patient oriented outcome based around echocardiographic parameters and troponin. There were actually big absolute differences between the groups (24% vs 13%), but this difference was not statistically different. There was a statistical improvement in the proportion of patients with a normal RV at 24 hours, but this is a secondary outcome in a negative trial. Perhaps the most important bit of data from this trial was that there were no adverse events. 

Obviously, that is not strong data, and there is no way we should be using pulmonary vasodilators routinely. This is somewhat promising, and definitely warrants large RCTs. For the most part, this sounds like an ICU therapy to me, but for a really sick patient, I might try to get it started while waiting for people to return my calls. 

I have never used inhaled nitric oxide, but my understanding is that it is very expensive and difficult to use. Epoprostenol is an intravenous agent used as an infusion to manage pulmonary hypertension that some people might have available. Oral sildenafil (Viagra) has the same physiologic effects, and is often used to treat chronic pulmonary hypertension, but it will take a few hours to have an effect, which is not ideal in a critically ill patient.

If you don’t have immediate access to epoprostenol or nitric oxide, the general recommendation that I have seen from multiple sources (IBCC, EM:RAP, conferences) is to use nebulized nitroglycerine. Put 5 mg of IV nitroglycerine in your normal nebulizer. Repeat as necessary. I can find reports of this treatment being used in pediatric congenital heart disease, and in animal studies, but I think that is the totality of the evidence. (Nebulization makes sense over IV because the significant pulmonary vasoconstriction we are trying to treat will limit medication delivery to the areas of need if given intravenously.) The primary concern is that the patients you would be considering this in are at high risk of hemodynamic collapse, and so giving a medication that will drop the blood pressure is not without risk. 

What anticoagulant is best for submissive PE?

A semi-irrelevant aside

One of my favourite EBM issues to discuss is the fact that we have no good evidence that anticoagulation actually helps in the routine management of pulmonary embolism as we use it today. It was essentially grandfathered into practice from an era prior to science. If you trace the citation chain back, the primary reason that we give patients heparin is a 1960 publication in Lancet by Barrit and Jordan, in which hospital inpatients diagnosed with PE entirely on clinical grounds (no imaging at all) were given either heparin and nicoumalone (a vitamin K antagonist) or nothing. The trial wasn’t randomized. It was stopped after 35 patients, because there were 5 deaths in the no treatment group and none in the anticoagulant group. They added observational data on another 54 patients who they anticoagulated, and there were no deaths in that cohort. Of course, this is unblinded data, and with only 5 deaths, which could be from chance alone. More importantly, these patients look nothing like our patients. They were diagnosed without imaging. Now, they have autopsy data that demonstrates the 5 deaths were all from PE, but imagine how sick a patient has to be to have excellent accuracy in the diagnosis of PE without imaging. 

And, for the most part, that is what our treatment recommendations are based upon. Not exactly what you are used to. I will acknowledge that the results are dramatic, but even if these results are true, it doesn’t really apply to the average PE patient we diagnose these days. 

There are two small RCTs comparing NSAIDs to anticoagulation, summarized in a 2006 Cochrane review, that concludes “the limited evidence from RCTs of anticoagulants versus NSAIDs or placebo is inconclusive regarding the efficacy and safety of anticoagulants in VTE treatment.” (Cundiff 2006)

One of the 2 trials is in Danish, and I can’t read it, but it seemed to compare heparin followed by warfarin to placebo in patients with lower limb DVT. (Ott 1998) It only included 23 patients, but the outcomes look identical across the board. 

The other trial randomized 90 patients with confirmed DVT to either heparin followed by phenprocoumon (a vitamin k antagonist) targeting an INR between 2.0 and 4.3 or phenylbutazone (an NSAID). (Nielson 1994) Although the study was only of DVT patients, they did lung scans on everyone, and 50% of patients had asymptomatic PEs at the time of enrollment. It was a negative trial, with no significant difference in progression of disease. In terms of clinical outcomes, 3 patients in the anticoagulant group went on to have a symptomatic PE as compared to one patient in the NSAID group. Not a perfect trial by any means, but it is reasonable randomized data showing no benefit from anticoagulation in DVT (and asymptomatic PE).

Considering the harms of anticoagulation, this is a topic that sorely needs more research. Now, I am not a nihilist, and there are other strands of data that suggest benefit with anticoagulation. For example, we do now have some trials that appear to show benefit of anticoagulation even in superficial thrombophlebitis and below knee DVTs. But overall the evidence for anticoagulation is way less robust than you would like. 

Bottom line: There really is not good evidence for anticoagulation in PE, and it probably does require large high quality RCTs, especially starting in the lowest risk patients we diagnose. That being said, it is clearly the current standard, and we are all proceeding with anticoagulation until we see better data. 

OK, enough of the EBM BS. How do I actually anticoagulate?

The key when deciding about anticoagulation is to remember that you are not treating the current clot burden, but trying to prevent more clot from forming. 

Low molecular weight heparin (LMWH) is no more effective than unfractionated heparin, but does consistently demonstrate less bleeding. For the average low risk patient, LMWH is the way to go, if you are starting with heparin. However, this article is focused on high risk patients, and the major advantage of unfractionated heparin is that it can be stopped, titrated, and reversed. If there is any chance that a patient is going to need thrombolysis or a procedure for their PE in the next 24 hours, I would choose unfractionated heparin over LMWH. Most guidelines don’t make this point, but Thrombosis Canada specifically says if “thrombolysis is being considered … intravenous (IV) UFH is preferred in the short-term due to its short half-life in the context of the bleeding risk associated with thrombolysis.” (Thrombosis Canada 2023)

In the PEITHO trial, the mean time between randomization and deterioration in the heparin arm was 1.8 days, with 95% confidence intervals out to 3.4 days. Although it won’t be my decision in the ED, that seems to indicate that 3 days of unfractionated heparin might be the ideal in higher risk submassive PE patients. 

How do you coordinate thrombolytics and heparin?

If a patient is being given a thrombolytic dose, when should you start heparin and at what dose? There isn’t really a strong evidence based answer to this question, which is probably not all that surprising given that there really isn’t any evidence of benefit from heparin at all in PE.

Both the MOPPETT and PEITHO trials combined full dose heparin (enoxaparin and unfractionated heparin respectively) with thrombolytics (half and full dose respectively). Therefore the combination is possible, and somewhat evidence based. However, PEITHO had a high rate of intracranial hemorrhage (Meyer 2014), and most experts agree the combination adds risk without proven benefit. 

I have not done this enough to have an established practice pattern, but the approach that makes the most sense to me is to hold heparin during the administration of thrombolytics, and only restart when the PTT falls below 1.5-2 times normal. 

The timing of heparin might be influenced by the dose of thrombolytics. If you are convinced by the low dose thrombolytic literature, heparin is probably less likely to cause problems and can perhaps be started earlier. That being said, I see no value in rushing, and would just wait for PTT values to guide me. 

When (if ever) are interventional therapies indicated?

As we discussed above, there doesn’t seem to be any value in using catheters to deliver thrombolytics, but what about for the mechanical removal of clots? Unfortunately, there is no science to support this practice as of 2024. 

The FLARE study is an uncontrolled observational dataset / device advertisement, in which 106 hemodynamically stable adult patients with acute PE and increased RV/LV ratio on CT underwent an interventional procedure with the Inari FlowTriever. (Tu 2019) The size of the RV went down after the procedure, but 3.8% (with 95% CI up to 8.6%) of patients had significant adverse events within 48 hours. Without a control group, we obviously have no idea what these numbers mean, and this data cannot at all be used to support the use of this device. The only firm conclusion possible from this data is that this interventional device does cause harm (vascular injury and pulmonary hemorrhage). 

There is another single-center retrospective chart review that is sometimes cited, in which they look at 46 patients in whom this device was used, and conclude that mean pulmonary artery pressure decreases post procedure, but that major procedure-related complications happen in about 4% of cases. (Wible 2019) This surrogate disease oriented outcome is enough to warrant proper RCTs, but obviously we have no idea if there is benefit that outweighs the proven harm of this procedure. 

As always, we are forced to act in a world with imperfect information. At this point, there is proven harm and no proven benefit, so interventional approaches should not be considered routine, and probably should not be used at all outside of a proper randomized trial. That being said, there is a hint of physiologic improvement, and so it might be worth considering in high risk submassive PE patients with contra-indiations to thrombolysis, or in patients in whom thrombolysis has failed. There just isn’t any good evidence to support that approach. 

What is the evidence for / value of PE teams?

Recent years have brought about the concept of PE teams, or PE response teams (PERT). The evidence for these teams is quite scant. One before and after study showed no difference in clinical outcomes, but a change away from systemic thrombolysis to the more expensive catheter directed thrombolysis, to me indicating overall harm or at least added cost from the introduction of a PE response team. (Carroll 2020) Another before and after study claims to show a 10% absolute decrease in mortality with the introduction of a PE team, which would obviously be amazing, but seems pretty unrealistic seeing as none of the interventions they have available to them decrease mortality in RCTs. (Wright 2021) This is more likely to be confounding in unblinded observational data with lots of conflict of interest, but clearly warrants follow-up. Another before and after study, with the same conflicts and risks of bias, also shows an association with decreased mortality, as well as shorter time to therapeutic anticoagulation and lower rates of bleeding complications. (Chaudhury 2019) 

Overall, this is very low quality data at very high risk for bias with lots of conflict of interest, but with some promising outcomes. Obviously, if you have access to one of these teams, and you are making difficult decisions around the management of patients with intermediate risk PEs, you should get them involved. 

Unfortunately, the key gap in the literature for PERT teams has nothing to do with their benefits. It makes sense that a team focused on one specific diagnosis could improve outcomes by improving expertise in complex scenarios. The problem is the cost and opportunity cost. Nothing comes for free, and we cannot afford to have a team of people dedicated to the management of every single diagnosis that presents to the hospital. Why not a CHF team? A sepsis team? A pneumothorax team? The addition of these types of teams often draws attention and resources away from patients with other diagnoses, and so a few studies showing possible benefit cannot address the larger systems question of whether these teams are truly a good idea. 

Another excellent algorithm: The EMCrit approach

I have included an algorithmic approach from Josh Farkas vis the IBCC above. Scott Weingart (EMCrit) also provides a very sensible approach, that is easy to follow, and I think fits well with the literature I have reviewed. This is a link to his PDF version, or you can review a screenshot here:

Other FOAMed

PulmCrit IBCC: Submassive & Massive PE

PulmCrit- Inhaled NO for submassive PE: iNOPE or iYEP?

The Bottom Line: MAPPETT 3

The Bottom Line: TOPCOAT

The Bottom Line: PEITHO

Eight pearls for the crashing patient with massive PE

Pulmonary hypertension and right ventricular failure – The first 10 minutes

REBELEM: The Critical Pulmonary Embolism Patient

EMCrit RACC Pulmonary Embolism Pathway

PEERLESS: Interventional therapies for pulmonary embolism

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