Keywords
pulmonary embolism - extracorporeal membrane oxygenation - pulmonary revascularization - multidisciplinary care
Introduction
Pulmonary embolism (PE) ranks high among the causes of cardiovascular mortality.[1]
[2] Most patients who die from PE remain undiagnosed throughout their lives,[3] and many succumb suddenly or within a few hours of the acute event before therapy can be initiated or take effect.[4] Most deaths due to PE within the first 3 months of follow-up occur during the first week after diagnosis.[5]
[6] Mortality from PE as reported in large registries ranges from 5.4 to 10.5% at 3 months, with the majority of deaths occurring early after the index event.[7]
[8]
[9]
[10]
The mortality and morbidity of patients with acute PE vary by clinical presentation, the presence of comorbid disease, and other underlying factors. Estimation of prognosis helps with prioritization of appropriate management strategies.[11]
[12]
[13] Studies have shown that risk stratification and use of a management pathway for hospitalized patients with acute PE reduces the length of hospital stay without compromising safety,[14] and this might be associated with improved short-term survival.[15] Overall, most patients treated with anticoagulant therapy (i.e., low- and intermediate-low-risk PE, according to the European Society of Cardiology [ESC] risk stratification[13]) survive and do not have a recurrent event or a major complication associated with therapy.[16]
[17] However, patients with evidence of right ventricular (RV) dysfunction and myocardial injury (i.e., intermediate-high-risk PE) have a short-term mortality rate of approximately 10%.[18] High-risk PE includes patients with arterial hypotension, cardiogenic shock, and those suffering of a cardiac arrest. This critical condition occurs in fewer than 5% of patients with acute symptomatic PE,[19] but is associated with an overall mortality rate of up to 30%, which increases to 65% in case of a cardiac arrest.[20]
[21]
[22]
[23]
[24]
[25]
[26] Patients with high-risk PE require prompt therapeutic anticoagulation and additional advanced therapies to improve clinical outcomes.[27]
Advanced Therapies for High-Risk PE
Advanced Therapies for High-Risk PE
The armamentarium of treatment options for the management of high-risk PE includes various systemic thrombolytic regimens, surgical embolectomy, lysis and nonlysis catheter-directed therapies (CDT), and mechanical circulatory support ([Fig. 1]).
Fig. 1 Evidence-based international guidelines on risk stratification and management of acute pulmonary embolism.
Systemic Thrombolysis
Only one small randomized controlled trial has compared thrombolytic therapy plus anticoagulation with anticoagulation alone in patients with “life-threatening” PE.[28] In that study, none of the four patients who received systemic streptokinase died, whereas the four patients who received heparin died. In addition to the small sample size, the study was limited by an imbalance between groups, since the four patients allocated to heparin treatment were admitted for an acute episode of unstable PE despite previous therapeutic anticoagulation. A systematic review and meta-analysis identified four randomized controlled trials comparing anticoagulation plus systemic thrombolysis with anticoagulation alone for 130 patients with acute PE (including high-risk PE).[29] Thrombolytic treatment was associated with a significant reduction of PE-related mortality (odds ratio [OR], 0.15; 95% confidence interval [CI], 0.03–0.78, p < 0.001). Although the American College of Chest Physicians (ACCP) guidelines and the American Heart Association Scientific Statement recommend the use of thrombolytic therapy for patients with acute symptomatic PE and hemodynamic instability and in those who do not have major contraindications due to bleeding risk,[12]
[30] the RIETE registry showed that only one-fifth of 1,207 unstable patients with acute PE actually received reperfusion therapies in clinical practice.[19]
Surgical Embolectomy
Nowadays, surgical embolectomy is considered for patients with acute PE after failure of thrombolysis or when thrombolysis is contraindicated.[27]
[31] Approximately 40% of patients have contraindications to systemic thrombolysis, and 8 to 22% have failed thrombolysis.[32]
[33] Postoperative in-hospital mortality ranges from 2.3 to 13.2%, mostly associated with the need for preoperative cardiopulmonary resuscitation (CPR).[34] In addition, failed thrombolysis is associated with compromised postsurgical outcomes.[33]
[35]
Catheter-Directed Therapy
Catheter-directed therapy (CDT) for the treatment of acute PE includes catheter-directed thrombolysis, pharmacomechanical therapy, and mechanical embolectomy. The evidence base for the efficacy and safety of these techniques is largely based on observational studies with surrogate endpoints, and there are no randomized controlled trials with adequate power to evaluate clinical outcomes.[36]
Ultrasound Facilitated Catheter-Directed Thrombolysis
The diffusion of high-frequency ultrasound within the thrombus is thought to enhance the action of the thrombolytic therapy by disaggregating the fibrin fibers.[37] The EKOS Endovascular System (Boston Scientific, Marlborough, MA, United States) is currently the device with the largest body of available evidence. The Prospective, Single-Arm, Multi-Center Trial of EkoSonic Endovascular System and Activase for Treatment of Acute Pulmonary Embolism (SEATTLE) II trial evaluated the safety and efficacy of ultrasound-facilitated, catheter-directed thrombolysis in 150 patients with high-risk (n = 31) or intermediate-risk (n = 119) acute PE.[38] The decrease in the mean RV-to-left ventricle (LV) diameter ratio from baseline to 48 ± 6 hours was similar in high- and intermediate-high-risk PE patients (–0.51 vs. –0.43; p = 0.31). Likewise, the decrease in mean pulmonary artery systolic pressure from baseline to procedure completion (–12.6 vs. –14.3; p = 0.61) and from baseline to 48 ± 6 hours (–14.2 vs. –15.0; p = 0.81) was also similar in high-risk and intermediate-high-risk PE patients. High-risk PE patients were more likely to experience major bleeding than intermediate-high-risk PE patients (23 vs. 7%, p = 0.02). The OPTALYSE-PE study demonstrated the advantages of reducing both the duration and dose of in situ thrombolysis.[39] The results of the OPTALYSE-PE study, with clinical follow-up at 1 year, showed that there was a persistent improvement in RV systolic function, associated with an improvement in functional capacity as assessed by a 6-minute walk test, as well as an improvement in quality of life.[40]
Moreover, two randomized trials tested the ultrasound-facilitated catheter-directed thrombolysis strategy. In the ULTIMA (the Ultrasound Accelerated Thrombolysis of Pulmonary Embolism) trial, 59 patients with PE and RV dysfunction were randomized to receive either heparin alone (n = 29) or heparin plus in situ thrombolysis (10–20 mg tissue plasminogen activator [tPA]) facilitated by ultrasound (n = 30). The primary endpoint, namely, the difference in the RV/LV ratio from baseline to 24 hours, was significantly improved in the endovascular group compared to the heparin alone group (0.30 ± 0.20 vs. 0.03 ± 0.16; p < 0.001). Recently, the CANARY randomized trial included 85 patients who received CDT (54.1%) or anticoagulation therapy alone (45.9%). The study was prematurely stopped due to the COVID-19 pandemic. The median (interquartile range [IQR]) 3-month RV/LV ratio was significantly lower with CDT (0.7 [0.6–0.7]) than with anticoagulation (0.8 [0.7–0.9); p = 0.01). An RV/LV ratio greater than 0.9 at 72 hours after randomization was observed in fewer patients treated with CDT (13 of 48 [27.0%]) than with anticoagulation (24 of 46 [52.1%]; OR, 0.34; 95% CI, 0.14–0.80; p = 0.01). Fewer patients assigned to CDT experienced a 3-month composite of death or RV/LV greater than 0.9 (2 of 48 [4.3%] vs. 8 of 46 [17.3%]; OR, 0.20; 95% CI, 0.04–1.03; p = 0.048).[41]
The potential drawback of ultrasound-facilitated catheter-directed thrombolysis is the time required for the treatment to take effect in unstable patients.
Catheter-Directed Thrombectomy
Some single-arm studies have evaluated the efficacy of mechanical thrombectomy devices to extract clots from the pulmonary arteries, but specific data for the subgroup of high-risk PE patients are lacking.[42]
[43] The single-armed FlowTriever Pulmonary Embolectomy Clinical Study (FLARE) trial evaluated the FlowTriever System in 106 intermediate-risk PE patients, and showed that, among patients with elevated mean pulmonary artery pressure at baseline, there was a drop of 3.2 mm Hg postprocedure (from 34.7 ± 7.1 to 31.5 ± 7.7 mm Hg; p < 0.0001).[42] The FlowTriever All-Comer Registry for Patient Safety and Hemodynamics (FLASH) registry evaluated the FlowTriever in 800 patients, 7.9% of whom had high-risk PE.[43] Mortality for the total cohort was 0.8% at 30 days with no device-related deaths.
The Prospective, Multicenter Trial to Evaluate the Safety and Efficacy of the Indigo Aspiration System in Acute Pulmonary Embolism (EXTRACT-PE) enrolled 119 intermediate-risk PE patients for treatment with the 8-Fr Indigo system. The intervention reduced the primary outcome of the RV/LV ratio from 1.47 ± 0.30 at baseline to 1.04 ± 0.16 at 48 hours postprocedure. There were three major adverse events occurring in two (1.7%) patients, including one death due to distal vessel perforation.[44]
More recently, the FLAME study reported a significant reduction in the primary composite endpoint of all-cause mortality, bailout to alternate thrombus removal strategy, clinical deterioration, or major bleeding in high-risk PE patients (17.0% in the FlowTriever group vs. 63.9% with other therapies).[45]
These results remain to be confirmed in large-scale, randomized trials. Clinical practice guidelines suggest CDT for high-risk PE patients who also have (1) a high bleeding risk, (2) failed systemic thrombolysis, or (3) shock that is likely to cause death before systemic thrombolysis can take effect, if appropriate expertise and resources are available.[12]
Extracorporeal Membrane Oxygenation
Temporary circulatory support (venoarterial extracorporeal membrane oxygenation [VA-ECMO]) may alleviate the failing RV without direct intervention on the clot burden. VA-ECMO offers cardiac support via an inflow cannula from the femoral vein and an outflow cannula via a peripheral artery, and it is a feasible option for salvage therapy in unstable patients.[46] In fact, contemporary data have shown increasing use of ECMO for patients with high-risk PE. Elbadawi et al evaluated 77,809 hospitalizations for high-risk PE and found an upward trend in the utilization of ECMO from 0.07% in 2005 to 1.1% in 2013 (p = 0.015).[47] In-hospital mortality for patients receiving ECMO did not change over the observational period (p = 0.68). Independent predictors of increased mortality in patients with high-risk PE using ECMO include age, female sex, obesity, congestive heart failure, and chronic pulmonary disease.[47]
Unless contraindicated, all patients should be anticoagulated while on ECMO, usually with a heparin drip. Recent systemic thrombolysis is not an absolute contraindication for VA-ECMO.[34]
Potential Value of PERT in Patients Requiring ECMO
Potential Value of PERT in Patients Requiring ECMO
There are minimal high-quality data to guide strategies for patients with high-risk PE given (1) the lack of well-designed randomized trials, (2) the relatively infrequent incidence at individual centers, and (3) the difficulty in enrolling critically ill patients. In addition, ECMO is a complex technique associated with intensive resource consumption. In this regard, pulmonary embolism response teams (PERTs) may help select appropriate management for high-risk patients with acute PE and identify those who may benefit from ECMO implantation.[48]
[49]
[50] A PERT is composed of a multidisciplinary group of specialists to treat patients with life-threatening PE.[51] The aim is to coordinate the diagnosis and treatment of PE with a team of physicians from different specialties (e.g., cardiac surgery, critical care, emergency medicine, hematology, interventional and noninterventional cardiology, interventional radiology, pulmonary medicine, vascular medicine, vascular surgery, and pharmacy). One of the main advantages of a PERT is that this multidisciplinary approach occurs in real time and allows for rapid evaluation of risks, formulation of an individualized treatment plan for each patient, and mobilization of appropriate resources to provide the highest quality of care to patients with PE.[52] For patients with acute PE (including those with hemodynamically unstable PE), the effect of PERTs on survival is not well known. In a recent systematic review and meta-analysis of nine controlled studies, there was no difference in mortality (risk ratio [RR], 0.89; 95% CI, 0.67–1.19) by comparing the pre-PERT with the PERT era.[53] When analyses were restricted to patients with intermediate- or high-risk PE, short-term mortality tended to be lower for patients treated in the PERT era compared to those treated in the pre-PERT era (RR, 0.71; 95% CI, 0.45–1.12). The use of advanced therapies was higher (RR, 2.67; 95% CI, 1.29–5.50), and the in-hospital stay was shorter (mean difference, –1.6 days) in the PERT era compared to the pre-PERT era. Particularly, among the 1,532 patients with intermediate- and high-risk PE who were managed by a PERT, 3% (34/1,018) received ECMO.[53]
Some reports suggest that higher annual ECMO volume (i.e., more experience) and implementation of a multidisciplinary team-based approach to ECMO care might improve survival to hospital discharge.[54]
[55] Although it remains to be clarified whether it is experience itself or a protocolized approach that is needed for improved outcomes, a multidisciplinary team approach to the management of severe PE and ECMO care seems reasonable.
Practical Aspects of ECMO Placement
Practical Aspects of ECMO Placement
The main purpose of VA-ECMO is to provide temporary cardiopulmonary support as a bridge to recovery from acute PE. Indications are not based on prospective randomized clinical trials, and therefore, the placement of circulatory assistance is often driven by subjective consideration of a risk of imminent death from cardiopulmonary failure. In daily clinical practice, this concerns patients with cardiogenic shock or cardiac arrest. Relative contraindications to VA-ECMO include uncontrollable bleeding or other contraindications to systemic anticoagulation. There are few absolute contraindications, but they include unwitnessed asystole and preexisting or acute conditions that are incompatible with recovery.[56] Cannulation for ECMO can be performed via the central or peripheral approach.[57] The peripheral approach has become very common and can be placed percutaneously or through a surgical cut-down. Percutaneous access is often preferred because the patient can be cannulated while undergoing CPR, in any setting.[56] Peripheral VA-ECMO is classically accomplished through the femoral vessels. ECMO should be implanted under local anesthesia with procedural sedation in a spontaneously breathing patient to avoid any additional increase in the RV afterload and risk of hemodynamic compromise related to mechanical ventilation.[58] Moreover, hemorrhagic complications must be anticipated, especially after failed thrombolysis. Indeed, reported major bleeding rates range from 3.2% in nationwide registries[59] to 12.2% in individual studies evaluating the management of high-risk PE with ECMO support.[60]
Puncture is performed under ultrasound guidance with a 25- to 29-Fr venous cannula and a 15- to 19-Fr arterial cannula inserted, respectively, into the femoral vein and artery using Seldinger's technique. The venous cannula should be inserted at the junction of the right atrium and the superior vena cava, and the arterial cannula in the thoracic descending aorta. Placement of the venous cannula is performed with echocardiographic guidance and, if possible, with the use of fluoroscopy. A 6-Fr distal perfusion catheter is placed in the ipsilateral superficial femoral artery to prevent lower limb ischemia. Anticoagulant therapy with unfractionated heparin is mandatory unless contraindicated, with a target activated clotting time of 180 to 220 seconds.[61]
Reperfusion Strategies for Patients on ECMO
Reperfusion Strategies for Patients on ECMO
The therapeutic management of high-risk PE requiring ECMO support remains controversial due to limited evidence, from small observational studies, and a lack of randomized controlled trials. Three different situations involving circulatory assistance in PE patients can be distinguished. First, ECMO may be implanted as a destination therapy while waiting for the action of physiological fibrinolysis to take effect. Second, it may be considered as a bridge to reperfusion therapy, such as surgical embolectomy or catheter-based clot extraction. Third, VA-ECMO may be considered as an adjunctive hemodynamic support after failed thrombolysis or surgical embolectomy.
Four reperfusion therapy options can be considered, namely, ECMO with associated anticoagulation as a stand-alone treatment; or ECMO plus one of three advanced pulmonary reperfusion strategies, that is, ECMO+ systemic thrombolysis, ECMO+ CDT, or ECMO+ surgical embolectomy.[62]
[63] Overall, the primary strategy used in combination with ECMO was anticoagulation alone for 34.3%, systemic thrombolysis for 27.3%, CDT for 5.5%, and surgical or catheter-based embolectomy for 33.3% ([Table 1]).[63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
[79]
[80]
[81]
[82]
Table 1
Key features of individual patient studies describing different reperfusion strategies in high-risk pulmonary embolism patients with extracorporeal membrane oxygenation (n = 19 studies)
|
Study
|
Study period
|
N
|
Age (y)
|
Cardiac arrest (%)
|
Primary reperfusion strategy (%)
|
Mortality rate (% per method)
|
|
|
|
|
|
|
Surgery[a]
|
CDT
|
Systemic thrombolysis
|
ECMO alone
|
Surgery[a]
|
CDT
|
Systemic thrombolysis
|
ECMO alone
|
|
Al-Bawardy et al[64]
|
2012–2018
|
13
|
49 ± 19
|
13 (100.0)
|
4 (30.8)
|
2 (15.4)
|
6 (46.1)
|
1 (7.7)
|
2 (50.0)
|
1 (50.0)
|
3 (50.0)
|
0 (0)
|
|
Corsi et al[63]
|
2006–2015
|
17
|
51 ± 15.9
|
2 (11.8)
|
4 (23.5)
|
0 (0)
|
8 (47.0)
|
5 (29.4)
|
1 (25.0)
|
0 (0)
|
2 (25.0)
|
3 (60.0)
|
|
Dolmatova et al[65]
|
2011–2015
|
5
|
52 ± 11.5
|
4 (80.0)
|
1 (20.0)
|
0 (0)
|
3 (60.0)
|
1 (20.0)
|
0 (0)
|
0 (0)
|
1 (100.0)
|
0 (0)
|
|
George et al[66]
|
2012–2015
|
32
|
56 [Q1–Q3: 46–66]
|
15 (46.0)
|
6 (18.7)
|
16 (50.0)
|
5 (15.6)
|
5 (15.6)
|
2 (33.3)
|
4 (66.6)
|
5 (100.0)
|
0 (0)
|
|
Ghoreishi et al[67]
|
2015–2018
|
41
|
51 ± 15
|
12 (29.2)
|
11 (26.8)
|
0 (0)
|
9 (21.9)
|
21 (51.2)
|
0 (0)
|
0 (0)
|
0 (0)
|
1 (4.8)
|
|
Ius et al[69]
|
2012–2018
|
36
|
56 (range: 18–79)
|
15 (41.7)
|
20 (55.5)
|
0 (0)
|
9 (25.0)
|
7 (19.4)
|
1 (0.5)
|
0 (0)
|
8 (88.9)
|
3 (42.8)
|
|
Kjaergaard et al[70]
|
2004–2017
|
36
|
55 ± 16.7
|
6 (28.6)
|
4 (11.1)
|
0 (0)
|
22 (61.1)
|
10 (27.8)
|
1 (25.0)
|
0 (0)
|
5 (23.8)
|
5 (50.0)
|
|
Luna-López et al[72]
|
2013–2018
|
11
|
60 ± 8.5
|
9 (81.8)
|
5 (45.4)
|
0 (0)
|
3 (27.2)
|
3 (27.2)
|
1 (20.0)
|
0 (0)
|
2 (66.6)
|
1 (33.3)
|
|
Maj et al[74]
|
–
|
6
|
–
|
6 (100.0)
|
1 (16.6)
|
2 (33.3)
|
2 (33.3)
|
1 (16.6)
|
1 (50.0)
|
1 (100.0)
|
2 (100.0)
|
0 (0)
|
|
Malekan et al[75]
|
2005–2011
|
4
|
46.8 ± 20
|
0 (0)
|
1 (25.0)
|
0 (0)
|
0 (0)
|
3 (75.0)
|
0 (0)
|
0 (0)
|
0 (0)
|
0 (0)
|
|
Meneveau et al[76]
|
2014–2015
|
52
|
47.6 ± 15
|
39 (75.0)
|
17 (32.7)
|
0 (0)
|
17 (32.7)
|
18 (34.6)
|
4 (23.5)
|
0 (0)
|
13 (76.5)
|
14 (77.8)
|
|
Miyazaki et al[77]
|
2014–2017
|
9
|
50 ± 16.1
|
9 (100.0)
|
1 (11.1)
|
0 (0)
|
4 (44.4)
|
4 (44.4)
|
0 (0)
|
0 (0)
|
0 (0)
|
1 (25.0)
|
|
Moon et al[78]
|
2010–2017
|
14
|
53.6 ± 17.7
|
11 (78.6)
|
1 (7.1)
|
0 (0)
|
1 (7.1)
|
12 (85.7)
|
0 (0)
|
0 (0)
|
0 (0)
|
9 (75.0)
|
|
Munakata et al[79]
|
1992–2008
|
10
|
61 ± 10.3
|
9 (90.0)
|
8 (80.0)
|
0 (0)
|
2
|
0 (0)
|
2 (20.0)
|
(0)
|
1 (50.0)
|
0 (0)
|
|
Oh et al[80]
|
2014–2018
|
16
|
51 [Q1–Q3: 38–70]
|
12 (75.0)
|
9 (56.2)
|
0 (0)
|
4 (25.0)
|
3 (18.7)
|
4 (44.4)
|
0 (0)
|
2 (50.0)
|
1 (33.3)
|
|
Pasrija et al[81]
|
2014–2016
|
20
|
47 [Q1–Q3: 32–59]
|
5 (25.0)
|
11 (55.0)
|
1 (5.0)
|
0 (0)
|
8 (40.0)
|
0 (0)
|
0 (0)
|
0 (0)
|
1 (12.5)
|
|
Swol et al[82]
|
2008–2014
|
5
|
45 ± 6.3
|
5 (100.0)
|
2 (40.0)
|
0 (0)
|
3 (60.0)
|
0
|
1 (50.0)
|
0 (0)
|
2 (66.6)
|
0 (0)
|
|
Giraud et al[68]
|
2010–2019
|
36
|
51 [IQR: 23]
|
22 (61.1)
|
17 (47.2)
|
0 (0)
|
0 (0)
|
19 (52.8)
|
11 (64.7)
|
0 (0)
|
0 (0)
|
2 (10.5)
|
|
Ltaief et al[71]
|
2008–2020
|
18
|
57 [Q1–Q3: 47–66]
|
16 (88.9)
|
5 (27.7)
|
0 (0)
|
6 (33.3)
|
7 (38.9)
|
2 (50.0)
|
0 (0)
|
4 (66.6)
|
7 (100.0)
|
Abbreviations: CDT, catheter-directed therapy; ECMO, extracorporeal membrane oxygenation.
a Surgical embolectomy or catheter-directed embolectomy.
ECMO as Stand-Alone Therapy
Some authors have suggested using ECMO and anticoagulation as stand-alone therapy to improve the patient's hemodynamic status while waiting for heparin-induced or spontaneous endogenous thrombolysis to occur. Maggio et al reported outcomes of 21 PE patients managed with ECMO between 1992 and 2005 in a U.S. tertiary care facility. The mortality rate was 38%, and 76% of the patients who lived did not require any additional pulmonary reperfusion therapy. RV function recovery potentially related to clot dissolution enabled weaning from ECMO at 4.7 days among survivors.[73] Corsi et al reported their experience of 17 PE cases managed with ECMO support, of whom 41% were cannulated during CPR. The overall 90-day survival rate was 47%, and among survivors, 61% were managed with ECMO as a stand-alone approach.[63] Finally, a recently published study observed a favorable prognosis in 36 acute PE patients treated with ECMO only (58.3% with a contraindication to thrombolysis), with a 30-day mortality rate of 10.2%. However, a recent meta-analysis evaluating management strategies in high-risk PE patients requiring ECMO life support found that ECMO as a stand-alone approach was associated with worse outcome, with a mortality rate of 77.8% at 30 days, compared to 76.5% for ECMO plus systemic thrombolysis and 14.4% for ECMO plus surgical embolectomy ([Table 1]).[76] Based on the average ECMO weaning duration identified in observational studies, some authors have advocated waiting 5 days with ECMO and anticoagulation, and subsequently referring the patient to surgery if persistent RV dysfunction exists after this time period.[83]
ECMO and Systemic Thrombolysis
Population-based studies provide support for a survival benefit from thrombolysis in high-risk PE patients. Data from nationwide registries are conflicting regarding the value of systemic thrombolysis in combination with ECMO.[59]
[86] In individual patient studies, the crude mortality rate observed in PE patients treated with thrombolysis and ECMO ranged from 50.0 to 100.0% ([Table 1]).[63]
[64]
[65]
[66]
[67]
[69]
[70]
[71]
[72]
[74]
[76]
[77]
[78]
[80]
[82] In a meta-analysis of 188 PE cases requiring ECMO, we observed a higher mortality among patients managed with systemic thrombolysis compared to those treated with surgical embolectomy (43.6 vs. 23.8%; pooled OR, 0.36; 95% CI, 0.18–0.73).[60]
ECMO and Surgical Embolectomy
Small modern series of surgical embolectomy for the management of acute PE reported a dramatic improvement in postoperative in-hospital mortality, ranging from 2.3 to 13.2%, with mortality associated largely with preoperative CPR.[87]
[88]
[89]
[90] We performed a systematic review and meta-analysis of 17 studies including a total of 327 PE patients managed with ECMO life support.[60] This study found that mechanical pulmonary reperfusion (including surgical [86%] and catheter-based embolectomy) seemed to be more effective than other strategies (i.e., systemic thrombolysis, catheter-directed thrombolysis, and stand-alone approach), for mitigating the mortality rate (OR, 0.44; 95% CI, 0.24–0.82), and demonstrated a similar risk of bleeding (OR, 1.27; 95% CI, 0.54–2.96). The timing of ECMO implantation, before or after pulmonary reperfusion, the use of more than one reperfusion strategy, and the clinical presentation of PE (i.e., cardiac arrest or refractory cardiogenic shock) did not affect the observed benefit of mechanical therapies.[60] The favorable effect of surgical embolectomy on mortality compared to other strategies was mainly driven by two studies published in the last 5 years. First, we published the largest (n = 52 patients) and only multicenter (n = 11 centers) individual cohort study to date on this topic. Our results showed an overall mortality rate of 41.2% with the surgical embolectomy approach (23.5% when surgical embolectomy was the only reperfusion strategy used) versus 76.5% with systemic thrombolysis and 77.8% with ECMO as stand-alone therapy.[76] Second, Ius et al reported a mortality rate of 5.0% in patients who underwent surgery (including 50% who received prior thrombolysis) and 69.0% in those who did not undergo surgery (9 patients [56.2%] treated with systemic thrombolysis in this group), among 36 patients with high-risk PE managed with ECMO ([Table 1]).[69]
ECMO and Catheter-Directed Therapy
Data regarding the use of CDT associated with ECMO in PE patients are sparse, with only four published studies, totaling 51 patients.[64]
[66]
[74]
[91] The mortality rate was 25% among 16 patients treated with ultrasound-facilitated CDT versus 100% among 5 patients who received systemic thrombolysis in a retrospective analysis of an institution's ECMO database ([Table 1]).[66] Other authors recently showed preliminary evidence of the feasibility of percutaneous large-bore aspiration embolectomy in combination with ECMO support in a retrospective study of 15 patients included between April 2021 and August 2022. There was one periprocedural death in a patient who did not receive ECMO support following a periprocedural cardiac arrest. ECMO weaning was successful in the remaining patients (n = 14/15, 93.3%) after a mean of 5.4 days.[91]
Indications for ECMO and Integration into the Management of High-Risk PE
Indications for ECMO and Integration into the Management of High-Risk PE
ECMO support appears suitable to reverse the hemodynamic impairment related to acute PE and bridge patients to further reperfusion therapies. Pulmonary surgical embolectomy seems to be associated with a higher rate of survival rate than other strategies. The 2019 ESC guidelines recommend considering ECMO support in patients with high-risk PE and cardiac arrest or refractory shock. Refractory shock is defined by: (1) sustained systolic blood pressure less than 90 mm Hg; (2) evidence of end-organ hypoperfusion, (3) high-dose vasoactive drug infusion of at least two inotropes or vasopressors,[68]
[92] (4) adequate volume loading.[93]
[94]
The ESC guidelines propose referring patients to surgical or catheter-based embolectomy if ECMO is already initiated, while systemic thrombolysis should be used if ECMO is not initiated.[94] Nevertheless, it is not clear from evidence-based clinical practice guidelines whether ECMO is recommended in patients who remain unstable after thrombolysis.
A recent systematic review and meta-analysis assessed whether VA-ECMO improved survival of patients with acute PE.[62] Investigators identified a total of 29 observational studies (n = 1,947 patients; VA-ECMO, n = 1,138; control, n = 809), and did not find a significant difference between treated and control patients (RR, 0.91; 95% CI, 0.71–1.16). For ECMO patients, age older than 60 years (RR, 0.72; 95% CI, 0.52–0.99) and pre-ECMO cardiac arrest (RR, 0.88; 95% CI, 0.77–1.01) were associated with decreased survival, while surgical embolectomy was associated with increased survival (RR, 1.96; 95% CI, 1.39–2.76)[62]
In light of existing evidence regarding the utility of ECMO in the management of high-risk PE patients, a number of possible indications for ECMO utilization have been suggested in the literature:
-
Resuscitation: In patients with resuscitated cardiac arrest, refractory cardiac arrest, or refractory shock, including cases of failed thrombolysis, VA-ECMO should be considered.[60]
[95]
-
As a bridge to decision and possible intervention: VA-ECMO is also useful to stabilize PE patients with cardiogenic shock and affords clinicians the possibility to decide on further interventions such as systemic thrombolysis, percutaneous thrombectomy, or surgical embolectomy.[60]
[68]
-
As a bridge to recovery after surgical embolectomy: Complications after surgical embolectomy include right heart failure, pulmonary edema, and hemoptysis.[60] VA-ECMO is usually the best option to manage these difficulties. In two recent series, the need for postoperative ECMO after embolectomy was rare, and strongly associated with preoperative CPR.[96]
[97]
Age, obesity, comorbidities, life expectancy of less than 1 year, previous cardiac arrest with an unknown no-flow duration, and high lactate at implantation should be taken into consideration before indicating ECMO implantation.[47]
[66]
We recently proposed an updated algorithm for the management of acute high-risk PE, which takes account of the activation of a PERT,[98] international guidelines for the management of acute PE,[12]
[94] ELSO guidelines for the appropriate use of ECMO (www.elso.org), the JACC Scientific Expert Panel,[92] the European Resuscitation Council, and 2021 European Society of Intensive Care Medicine guidelines,[99] as well as recent data from individual studies.[60] We suggest that acute PE patients requiring ECMO for refractory cardiogenic shock or cardiac arrest should be referred to surgical embolectomy (or percutaneous aspiration embolectomy), as a key reperfusion management, regardless of whether thrombolysis has been administered or not, regardless of the timing of ECMO implantation in the reperfusion timeline, and regardless of the clinical presentation at the time of ECMO implantation (i.e., shock or cardiac arrest). Although this algorithm has not been validated in clinical trials, it represents a synthesis of evidence-based approaches to the management of high-risk PE, which may help in guiding clinicians until further evidence becomes available. We updated this algorithm in [Fig. 2] by dichotomizing the management of cardiogenic shock and cardiac arrest. The role of ECMO as a stand-alone therapy will probably be downgraded in light of encouraging recent data from prospective studies of percutaneous thrombo-aspiration.[45] Nevertheless, additional data from cohort studies or randomized controlled trials are warranted to better define the optimal management of PE requiring ECMO, although previous randomized trials in such a severe patient category have been prematurely discontinued as a result of low inclusion rates.[100]
Fig. 2 Proposed algorithm for the management of acute high-risk pulmonary embolism. ACS, acute coronary syndrome; CTPA, computed tomography pulmonary angiography; ECG, electrocardiogram; PE, pulmonary embolism; RV, right ventricular; PERT, pulmonary embolism response team. aHypotension with systolic blood pressure (SBP) less than 90 mm Hg for at least 15 minutes or requiring inotropic support, or shock with signs of tissue hypoxia (e.g., altered mental status, cold clammy skin, oliguria, elevated blood lactates).[12]
[94]
bRefractory shock defined as (1) sustained SBP < 90 mm Hg, (2) evidence of end-organ hypoperfusion (e.g., altered mental status, cold, clammy skin, serum lactate ≥2.3 mmol/L), and (3) high-dose vasoactive drug infusion of at least two inotropes or vasopressors.[92]
cExtracorporeal membrane oxygenation (ECMO) if age less than 75 years, no end-stage renal or liver disease, no extend malignancy, or if cardiac arrest within the first 60 minutes, according to the Extracorporeal Life Support Organization (www.elso.org). dECMO should be used as a stand-alone therapy if there is absolute contraindication to surgical embolectomy, including recent neurosurgery, recent intracranial hemorrhage, and other high bleeding risk conditions. eAccording to the European Resuscitation Council and European Society of Intensive Care Medicine guidelines 2021[99]; e preferred therapeutic option if thrombus is crossing the interatrial septum through a patent foramen ovale or is in transit passing through the right atrium and ventricle.[12]
[94] This algorithm has not been validated in clinical trials, but represents a synthesis of evidence-based approaches to the management of high-risk PE. (Reproduced with permission of Chopard et al.[60])
Conclusion
The use of ECMO in PE should be reserved for the most severe patients among those at high risk including cardiac arrest and refractory shock. The complex management of these individuals requires an urgent yet coordinated multidisciplinary care including PERT and ECMO teams. The challenge consists of identifying the therapeutic strategy behind the use of ECMO. In light of existing evidence regarding the utility of ECMO in the management of high-risk PE patients, a number of possible indications for ECMO utilization have been suggested in the literature. Specifically, in patients with refractory cardiac arrest, resuscitated cardiac arrest, or refractory shock, including in cases of failed thrombolysis, VA-ECMO should be considered, either as a bridge to percutaneous or surgical embolectomy or as a bridge to recovery after surgical embolectomy. There remains a compelling need for large-scale prospective cohorts or randomized trials to clearly define the value and place of ECMO in the management strategy of high-risk PE.
