In addition to today’s resource, I link to and embed the flow chart from Emergency Medicine Cases Ep 203 Intermediate Risk Pulmonary Embolism Risk Stratification, Management and Algorithm:*
*Helman, A. Morgenstern, J. Tillmann, B. Westafer, L. Intermediate Risk Pulmonary Embolism Risk Stratification, Management and Algorithm. Emergency Medicine Cases. Month, 2024. https://emergencymedicinecases.com/intermediate-risk-pulmonary-embolism-risk-stratification-management. Accessed May 7, 2025
Today, I review, link to, and excerpt from First10EM‘s Management of intermediate and high risk pulmonary embolism (aka submassive/massive PE).*
*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
Note to myself and my readers: Dr. Morganstern’s post is outstanding and should be read in its entirety. I just excerpted some of his points.
All that follows is from the above resource.
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.
*Helman, A. Morgenstern, J. Tillmann, B. Westafer, L. Intermediate Risk Pulmonary Embolism Risk Stratification, Management and Algorithm. Emergency Medicine Cases. Month, 2024. https://emergencymedicinecases.com/intermediate-risk-pulmonary-embolism-risk-stratification-management. Accessed May 4, 2025
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)
- Systolic BP < 90 mm for 15 minutes.
- Fall in systolic BP by >40 mm for 15 minutes.
- Requirement for vasopressors.
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.
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.
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.)
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.
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.
*The pathway below is bigger and easier t0 read in the above link.
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.
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.
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).
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.
Surgical thrombectomy
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 anticoagulant is best for submissive PE?
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)
Other FOAMed
PulmCrit IBCC: Submassive & Massive PE
PulmCrit- Inhaled NO for submassive PE: iNOPE or iYEP?
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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