#16 Pulmonary Embolism Part 2

in Part II  of our discussion of PE, Nick & Cyrus discuss the Pillars of PE Management! We review the literature behind lytics in non-massive PEs, talk about airway management, hemodynamics and more! Make sure you listen to Part I if you missed it as it sets the stage for this fantastic, treatment focused discussion.

Quick Take Home Points:

1. Treatment of PE is complex and requires carefully balancing individualized risks and benefits. A structured multidisciplinary approach (e.g. PERT) is beneficial.

2. Correcting hypoxemia with supplemental oxygen both improves tissue perfusion & potentially reduces pulmonary artery pressures by relaxing hypoxic pulmonary vasoconstriction (HPV).

3. Stabilizing hemodynamics requires careful assessment of volume status as too much volume resuscitation can exacerbate RV failure. Choice of vasopressors is also important to minimize increase in PA pressures & RV afterload.

4. Anticoagulation with low molecular weight heparin (LMWH) is generally superior to unfractionated heparin (UFH).

5. Risk prognostication scores (PESI, Bova) is useful to determine which patients are candidates for additional therapies.

6. Several advanced therapies are available including systemic thrombolysis, catheter directed thrombolysis, catheter mediated clot removal, and surgical embolectomy. None is clearly superior in head to head trials, but specific patient circumstances (e.g. clot in transit) may dictate the specific approach.

Infographic:

ICU OnePager Infographic about approach to diagnosis, prognostication, and treatment of PE

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Pulmonary Embolism is a complex and challenging clinical problem that varies from incidental to immediately life threatening. This OnePager summarizes Nick’s approach to PE including diagnosis, prognostication, and how he manages anticoagulation, hemodynamics, and thrombolysis or other therapies.

Show Notes:

First steps in PE management:

1. As a reminder, the first step of PE management - after immediate life saving interventions / necessary stabilization - is risk stratification. We like the system outline in the acute PE guideline published by the European Society of Cardiology 2019. 

1. For our purposes, we are primarily focused on intermediate-high risk PEs. Lower risk PE patients are almost exclusively managed through anticoagulation and inpatient monitoring (if indicated) while high-risk PE patients get systemic thrombolysis. 

2. Specifically, those patients with PEs in the intermediate-high risk category have elevated cardiac biomarkers (specifically troponin as other biomarkers may be helpful but are not included in their risk stratification) and objective evidence of right-heart strain via echocardiography or CT.

Pulmonary Embolism Scoring Systems:

1. There are numerous other tools that can be used for PE risk stratification. These include scoring systems like the Bova score and the PESI (or sPESI). Institutions will vary based upon which they use and how they are used to determine what interventions a PE may warrant.

1. The Bova score looks at BP, HR, presence of RV dysfunction and presence of troponin to risk stratify in low, intermediate and high risk which suggests increasing likelihoods of PE-related complications and mortality.

1. A 2018 prospective validation supports this stratification as related to complications, however, all-cause mortality was actually similar between the different groups - suggesting that PE patients may need repeated risk-stratification estimates as they can cross over into high risk strata with little-to-no warning.

2. The PESI score (2005) uses 11 clinical markers to estimate 30 day mortality in patients with PE. It places patients into 5 different risk-classes that correlate with estimated mortality.

1. In 2008 a multicenter, prospective validation supported it is principally effective in identifying candidates for outpatient therapy versus those that should be considered for admission, for whom further scrutiny is warranted outside of the PESI score.

2. The sPESI is a faster alternative to the PESI that was demonstrated to perform similarly to the PESI in the 2010 study in which it was proposed.
   

The Pillars of PE Management:

1. PE management in the critically ill patient can be primarily divided into four pillars of management which include

1. Correcting hypoxemia

2. Addressing hemodynamics

3. Anticoagulation

4. Thrombolysis

2. PE management is complex and patients often benefit from a multidisciplinary approach to decision making. 

1. PERT (PE Response Teams) can help with risk stratification, management of the pillars as above and navigating treatment algorithms.

2. Overall, data supports that most PERT teams favor greater-versus-fewer interventions, which in turn shortens hospital stays and benefits hemodynamics acutely, and may even convey a mortality benefit (Wright et al, Chaudhury et al).

Correcting Hypoxemia:

1. In our initial discussion of PE, we stress that it is not hypoxemia, but hemodynamic collapse (due to a combination of obstructive & consequent cardiogenic shock - i.e. pump failure) that contributes to significant morbidity and mortality in PE.

2. Hypoxemia, however, is a major issue - especially in large PEs.

1. Why does hypoxemia occur in PE? The mechanism is surprisingly complicated!

2. Reminder: Under normal circumstances, alveoli that are not filled with oxygen-rich air, trigger hypoxic vasoconstriction. This physiology is important! We don’t “want” to supply blood to alveoli that are not able to participate in gas exchange.In fact, we use this property of the alveolar-capillary interface to our advantage when doing thoracic surgery and using single-lung ventilation.

3. In the setting of PE, there are potentially several contributors to hypoxemia which include V/Q mismatch, low mixed-venous oxygen saturation, shunting, and an increase in alveolar dead space.

1. V/Q mismatch occurs due to the clot burden (and associated neurohormonal vasoconstriction) that precludes distal blood flow, thus the result is regions of lung that are able to function “normally” but gas exchange cannot be achieved because of the absence of blood flow to these regions of lung.

2. A combination of limited gas exchanged due to V/Q mismatch and developing heart failure can contribute to low mixed-venous oxygen saturation - which can contribute to low arterial oxygen saturation (if the venous sat is very low and the lungs are compromised, the resultant arterial saturation “post-gas-exchange” may be less than normal.

3. Shunting may occur if there are other disease processes at play (such as pneumonia which should trigger hypoxic vasoconstriction) or in the presence of pulmonary AVMs or an ASD (PFO or otherwise). This may not occur in all patients, but should be considered in refractory hypoxemia in the PE patient! 

4. An increase in alveolar dead space - i.e. alveoli that are not performing gas exchange irrespective of issues with pulmonary vasculature in acute PE - can be seen due to atelectasis (especially if alveolar hemorrhage occurs and surfactant is compromised) or the pendelluft phenomenon.

1. This is usually discussed in the context of mechanical ventilation, however, gas exchange at-large can occur within regions of the lung outside of the context of breathing that can the result in “regional hypocarbia related to regional hypoperfusion (which) induces bronchoconstriction” and thus adds to alveolar dead space. 

2. Pendelluft may be seen in non-mechanically ventilated patients especially when there is significant atelectasis (i.e. unrecruited lung).

3. What do we do?

1. Supplemental oxygen! Aside from shunt, this should help mitigate hypoxemia from the other contributing factors.

2. Mechanical Ventilation (MV): in extreme cases this may be necessary as a patient shows evidence of impending respiratory collapse / fulminant respiratory failure.

1. Recall from our previous discussion of the “physiologically difficult airway” that these are very challenging intubations primarily due to their hemodynamics and pre-load dependency - all of which is perturbed during the induction process. 

2. Be very careful with these intubations, ensure all resuscitative efforts have been initiated prior to induction, consider ketamine (or etomidate) as they are hemodynamically neutral versus propofol or benzodiazepines.

3. Pulmonary vasodilators can help with oxygenation and with hemodynamics by reducing right-heart strain. This can also be an option for therapy prior to or after intubation (i.e. patients do NOT need to be on MV). This may be part of your “resuscitation”- perhaps PREsuscitation - in respiratory failure / hemodynamic compromise in acute PE.
   

Addressing Hemodynamics:

1. As we discussed, the pathophysiology of PE is complex but the major contributor to morbidity and mortality is shock. That shock is primarily obstructive in nature due to the sudden rise in PVR, however, consequent cardiogenic shock can occur as well, prior to cardiac arrest.

2. Judicious fluid resuscitation is recommended based upon POCUS findings, other objective testing, and the patient response. Yes, these patients are often dependent on preload to overcome high PVR, but if they are euvolemic - or in some cases hypervolemic - additional fluid resuscitation can tax an already handicapped RV.

3. Vasopressors and inotropes can be helpful - consider agents such as norepinephrine, epinephrine, dobutamine and milrinone. 

4. Vasopressin can be particularly useful - so consider early use - as it does not cause pulmonary arterial vasoconstriction, but in fact causes vasodilation of these vessels.

5. As discussed earlier, pulmonary vasodilators - epoprostenol, nitric oxide - can be helpful adjuncts to resuscitative efforts.

6. V-A ECMO can be an option also in patients that are rapidly deteriorating due to the effects of an acute pulmonary embolism. This will buy your team time to intervene definitively and may also be a viable “presuscitation” strategy in certain cases (i.e. proactive/preemptive ECMO).
   
   

Anticoagulation:

1. For patients with intermediate risk PE for whom intervention is not warranted, anticoagulation and monitoring (based on risk factors, scoring systems, etc.) is the standard of care (2020 ASH Guidelines, 2019 ESC Guidelines, 2016 CHEST Guidelines).

1. The ESC guidelines specifically state: “LMWH and fondaparinux are preferred over UFH for initial anticoagulation in PE, as they carry a lower risk of inducing major bleeding and heparin-induced thrombocytopenia.”

2. The preference for LMWH is one that resonates with us at Critical Care Time as well - there is no need to routinely monitor these patients and they get a therapeutic dose right up front.

3. UFH is a reasonable option if intervention is being considered, as most feel more comfortable with thrombolysis in the setting of continuous UFH that can be stopped, reversed with protamine if needed.

4. UFH is the preferred option in cases of serious renal impairment.

Thrombolysis:

1. The use of thrombolysis in PE management is a hotly debated topic when it comes to their use in intermediate-high risk PE. The aforementioned guidelines do not address this head on, other than to suggest low/poor quality evidence suggests considering systemic thrombolysis or catheter-directed thrombolysis in certain intermediate-high risk patients.

2. What data is out there? This is not an exhaustive list of every single study, but some worthy of note…  

1. 2002 MAPPET-III: 

1. 256 patients, with RV dysfunction or PH based on echo findings and/or RHC data. 118 got heparin plus alteplase and 138 received heparin plus placebo.

2. Primary Outcome: In-hospital death or clinical deterioration requiring escalation of treatment (need for catecholamines, rescue thrombolysis, intubation, CPR or emergency surgical embolectomy or thrombus fragmentation)

3. 11% in treatment group vs 24.6% in control - NNT 7.5

4. This is a COMPOSITE ENDPOINT 

5. Mortality was not significantly different between the groups - both relatively low at 3.4% and 2.2% (treatment vs placebo)

6. No fatal bleeding or cerebral bleeding occurred in patients who received alteplase(???). Alteplase dose was full dose TPA - 100mg over 2 hours. 32 of the 138 control patients required rescue thrombolysis. Also, interestingly, they cite 1 major bleeding in the heparin plus alteplase group and 5 in the placebo group.

2.  2013 MOPETT:

1. “Among patients with submassive PE, does low-dose tPA reduce the incidence of pulmonary hypertension or recurrent PE when compared to anticoagulation alone?” 

2. Low-dose tPA plus anticoagulation reduced the incidence of pulmonary hypertension and of the composite outcome of pulmonary hypertension or recurrent PE compared to anticoagulation alone.

3. Used a very unusual definition for PE: Moderate PE = 70% involvement of thrombus in >/= 2 lobar or either the left or right main pulmonary arteries OR high probability VQ scan + 2 or more PE symptoms (things like chest pain, tachypnea, dyspnea, etc.) 

4. Single-center, 121 patients, randomized to half dose TPA or 0.5 mg/kg MAX of 50mg via bolus of 10mg and 40mg / 2 hours, all received heparin and warfarin and had pre/post echo - half-dose regimen

5. PH and PH + Recurrent PE outcomes favored tPA with NNT of 2

6. No significant bleeding complications…?

1.  Not consistent with most data on the use of heparin and TPA that would suggest some bleeding risk.

7. Mortality benefit not significant, sample size small. 

3. 2014 PEITHO:

1. “Among patients with submassive PE being treated with unfractionated heparin, does administration of tenecteplase reduce all-cause mortality or hemodynamic decompensation at 7 days when compared to placebo?”

2. Multicenter, RCT, double blinded with 1005 patients

3. 506 got tenecteplase (30-50mg IV x1 push dose) + UFH versus 499 that got UFH alone

4. Inclusion criteria: confirmed PE, RV dysfunction on echo and/or CT, elevated cTnI or cTnT

5. All cause mortality or hemodynamic decompensation at 7 days occurred statistically more frequently in those that did not get tenecteplase (NNT 33)

6. All cause mortality itself: not significant at 7 or 30 days

7. HD decompensation at 7 days, very significant (p = 0.002)

8. Major/minor bleeding: statistically more in those given tenecteplase, risk of hemorrhagic stroke increased as well 

3. 2014 Chatterjee Meta-Analysis:

1. 16 study meta-analysis in JAMA. This included 8 studies including patients who were hemodynamically stable with RV dysfunction. They received separate statistical analysis.

1. Lower mortality: 1.39% vs 2.92%

2. Increased bleeding risk 7.74% vs 2.25%

4. 2021 Yilmaz/Uzun: 

1. Small, single-center study (<80 patients total) suggested ½ dose systemic TPA and LMWH vs LMWH demonstrated significant improvement in 7 day and 30 day death and/or HD compromise with a negligible impact on bleeding.

5. 2023 Mathew Meta-Analysis:

1. “...meta-analysis of randomized controlled trials of systemic thrombolysis with newer thrombolytic agents vs anticoagulation in intermediate risk PE.”

2. Did not include studies where urokinase or streptokinase were used

3. Only cases with RV dysfunction were used

4. Only looked at studies where standard, systemic thrombolytics were used

5. No significant difference regarding mortality or MAJOR bleeding

6. Thrombolytics → significant increase in ICH but low risk of needing vasopressor therapy or salvage intervention(s). 

6. PEITHO-III: pending study, currently recruiting

1. Will enroll a goal of approximately 600 patients, half will receive A/C and weight based alteplase versus half that will receive A/C and placebo.”

2. “Primary efficacy outcome is the composite of all-cause death, hemodynamic decompensation, or PE recurrence within 30 days of randomization.”

3. Secondary endpoints will include assessments at 12 and 24 months to include echocardiography.

7. What about CDT?

1. CDT (catheter-directed thrombolysis) and mechanical thrombectomy pose interesting alternatives to just using A/C versus using systemic thrombolysis

2. Currently, the two emerging and most popular options are ultrasound-guided thrombolysis using TPA (EKOS system from Boston Scientific) and mechanical/suction thrombectomy (Inari FlowTriever).

3. Most data we reviewed (ULTIMA, SEATTLE-II, OPTALYSE-PE - summarized briefly HERE) suggest swift reduction in RV:LV ratio, improvement in hemodynamics (specifically right-sided pressures) and in some cases, reduced time in-hospital & reduced vasopressor requirement with a modest increase in bleeding risk (if any), but there is no long term data to guide decision making. Many of your true “high-risk” intermediates will “cross-over” into the frankly high-risk category and get systemic TPA, so the results of these studies are difficult to interpret. 

4. Recent studies like FLARE and REAL-PE present compelling yet confusing results - specifically, we see increased bleeding complications - to include ICH - with MT vs CDT despite the absence of TPA. These studies also lean on early, composite endpoint outcomes. 

8. Our take:

1. The evidence is complicated and confusing! 

2. Patients with high-risk PE without shock (intermediate-high or submissive) should be admitted and receive anticoagulation.

3. Ideally, based upon a multidisciplinary PERT discussion, options such has half-dose versus low-dose versus CDT vs MT should be considered but we recognize the level of evidence for all these interventions is fairly weak.

4. The literature refers to intermediate-high-risk patients with “risk factors” for further decompensation as being good candidates for proactive intervention which seems logical, although, there is no consensus definition for who these patients are.

5. CDT or MT seems to be a reasonable option for those with strong contraindications to systemic TPA, however, if using low-dose TPA and considering the short half-life of TPA, it possible that even patients with classic contraindications would have a good outcome - it’s just not really testable in a practical way and the theoretical risks are so high that most would opt for an alternative - rightfully so.

6. If it pans out, PEITHO-III may be the best answer to the question… we’ll wait and see!

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• References

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  Management of PE. American College of Cardiology. 2020.

  Tu T, Toma C, Tapson VF, et al. A prospective, single-arm, multicenter trial of catheter-directed mechanical thrombectomy for intermediate-risk acute pulmonary embolism. JACC: Cardiovascular Interventions. 2019;12(9):859-869.

  Monteleone P, Ahern R, Banerjee S, et al. Modern treatment of pulmonary embolism (Uscdt vs mt): results from a real-world, big data analysis(Real-pe). Journal of the Society for Cardiovascular Angiography & Interventions. 2024;3(1):101192.

• RCTs Discussed

  PEITHO

  PEITHO-III

  MAPPET-III

  MOPETT

  ULTIMA

  SEATTLE-II

  OPTALYSE-PE

  FLARE

  REAL-PE

• See Also