Venous thromboembolism (VTE) has a mortality rate of 10–30% within the first month of diagnosis (1). The number of annual VTE cases in the United States and Western Europe is approximately 900,000 and 700,000, respectively (2,3). The spectrum of pulmonary embolism (PE) severity ranges from low-risk to submassive to massive PE, each with an escalating expected mortality (4,5). A massive PE is defined by the American College of Chest Physicians (ACCP) as acute PE with sustained hypotension (systolic blood pressure < 90 mm Hg or systolic pressure drop > 40 mm Hg for at least 15 minutes, or requiring vasopressor or inotropic support) (6–9). Although only 8–10% of PEs are massive, they account for most of the PE-related mortality (4,6,10). Within massive PE, the hemodynamic instability can be further delineated by refractory hypotension, obstructive shock, or cardiac arrest (8). Massive PE leading to cardiac arrest has a mortality as high as 90–95% (11,12).
Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is an emerging therapeutic option in the management of cardiogenic shock, with or without cardiac arrest, either as a bridge-to-therapy or bridge-to-recovery (13–16). VA-ECMO in massive PE-related cardiac arrest can unload the right ventricle and prevent subsequent cardiac arrest by rapidly establishing critical organ reperfusion and tissue oxygenation.
Guidelines from the ACCP (Grade 2B), American Heart Association (AHA) (class IIA, level of evidence B), and European society of cardiology (ESC) [class I, level of evidence B], all recommend the use of a systemic thrombolytic infusion for massive PE (8,9,17). Recently updated ESC 2019 guidelines suggest considering VA-ECMO for massive PE patients (class IIb, level of evidence C), in the appropriate clinical setting, even though randomized control trials are lacking (8). Massive PE-related cardiac arrest management is controversial with AHA guidelines recommending push-dose systemic thrombolysis in confirmed massive PE-related cardiac arrest (Class IIa, level of evidence C) (9,12). Push-dose thrombolytic brings an increased risk of bleeding particularly in the setting of ongoing cardiopulmonary resuscitation (CPR). Furthermore, traumatic or prolonged (≥ 10 min) CPR is a relative contraindication to the use of systemic thrombolysis (17,18). Whether VA-ECMO has any role in massive PE-related cardiac arrest remains unknown, particularly with the potential background thrombolysis. Previously published systematic reviews investigated outcomes of VA-ECMO in massive PE, not massive PE-related cardiac arrest (6,14). In this systematic review, we explored the role of VA-ECMO in massive PE-related cardiac arrest and performed multivariate analysis for predictors of death.
MATERIALS AND METHODS
To identify studies to include or consider for this systematic review, the reviewers worked with a medical librarian with systematic review expertise to develop the search. We created and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis checklist protocol (Appendix 1, http://links.lww.com/CCM/G116). The search was developed for PubMed and translated for Embase, Cochrane Central, Cinahl, and Web of Science using a combination of subject headings and free-text terms. A gray literature search included a trial registry: clinicaltrials.gov and a Preprint search engine: bioPreprint. The search included no major limits or date restrictions. We began developing the search February 16, 2020, and last literature search was completed on March 16, 2020.
The search (complete details of the PubMed [National Library of Medicine] provided in Appendix 2, http://links.lww.com/CCM/G117) initially resulted in the 1,374 studies with the following studies from each database: PubMed 357 results, Embase (Elsevier) 568 results, Web of Science (Clarivate Analytics) 339 results, Cinahl (Ebscohost) 81 results, and Cochrane CENTRAL (Wiley) 16 results. There were 259 duplicate references found and omitted using Refworks, leaving 1,115 references (13 additional from gray literature sources) for screening (Fig. 1).
Studies were screened by title and abstract by two blinded and independent reviewers using the Rayyan online software (https://rayyan.qcri.org). If a tiebreaker was needed, a third reviewer was also called in. This process was repeated for full-text article screening and selection.
Articles and abstracts were considered eligible for inclusion if they: 1) described very specific clinical scenario of massive PE with cardiac arrest managed with VA-ECMO and 2) reported whether patient(s) survived to discharge. All dates of publication prior to our search date were included. Articles were excluded if not published in English. About 77 studies were included in this review (Fig. 1) and were assessed for bias using Joanna Briggs Institute Critical Appraisal Checklist for Systematic Reviews and Research Syntheses (19–95). Our review considered articles to have a low risk of bias if all checklist criteria were met, moderate risk if greater than or equal to 75% of criteria were met, and high risk if less than 75% of criteria were met. Risk of bias assessment found 34 articles to be low risk, 37 moderate risk, and six high risk (Supplemental Table 1, http://links.lww.com/CCM/G118). Data were extracted independently by four physician participants. The primary outcome was survival to discharge. Secondary outcomes included the impact of age, systemic thrombolysis before extracorporeal membrane oxygenation (ECMO), ECMO cannulation during CPR or after return of spontaneous circulation (ROSC), PE as primary reason for admission, and hospital location of ECMO cannulation on mortality. We also recorded the occurrence rate of major bleeding (Appendix 3, http://links.lww.com/CCM/G117, for complete definitions ) and neurologic outcome per the cerebral performance category (CPC) score.
Differences between the groups were assessed using unpaired t tests for continuous variables and chi-square tests for categorical variables. Univariate analyses on the secondary outcomes listed above were examined with t test or chi-square test as well. Univariate and multivariable logistic regression models were performed to derive the unadjusted or adjusted odds ratios (ORs) of mortality. ORs and 95% CIs (95% CI) were calculated and based on the selected published studies. A p value of less than 0.05 was considered statistically significant. All the data were analyzed using Stata 14.0 (Stata Corp., College Station, TX).
About 301 patients met inclusion criteria and were used for analysis. The mean age was 48 years old (n = 113) and 63% (n = 71) were females. About 183 out of 301 patients (61%) survived to discharge. There was a three-fold increase in risk of death for patients greater than 65 years old (OR, 3.56; 95% CI, 1.29–9.87; p = 0.02). Patients who were cannulated during CPR (survival 65%; n = 64 of 99) (Fig. 2) had a seven-fold increase in risk of death (OR, 6.84; 95% CI, 1.53–30.58; p = 0.01) compared with those cannulated after ROSC (survival 93%; n = 25 of 27).
We identified a cohort of 51 patients who received systemic thrombolysis prior to VA-ECMO cannulation. Survival to discharge in this cohort was 67% (n = 34). There was no increased risk of death in patients receiving systemic thrombolysis prior to VA-ECMO cannulations versus those who did not (OR, 0.78; 95% CI, 0.39–1.54; p = 0.48) (Table 1). Six patients who received thrombolysis prior to cannulation had a reported major bleeding event; all of them survived.
There was no difference in survival when PE was the primary reason for admission (76%, n = 68 of 90) or not (83%, n = 30 of 36) (OR, 1.62; 95% CI, 0.60–4.40; p = 0.35]. Non-PE-related admissions were for surgery (n = 15), trauma (n = 11), cesarean section (n = 3), myocardial infarction (n = 3), deep venous thrombosis (n = 1), and diabetic ketoacidosis (n = 1). We did not find a difference in risk of death based on where in the hospital VA-ECMO cannulation was performed (emergency department [ED] vs all other sites; OR, 2.52; 95% CI, 0.69–9.26; p = 0.16). Locations for cannulation were the ED (n = 35) with 77% survival, cardiac catheterization laboratory (n = 15; 80% survival), ICU (n = 10; 90% survival), operating room (n = 10; 100% survival), and medical/surgical floors (n = 3; 100% survival). About 21 patients had reported major bleeding with 76% survival (n = 16), whereas 30 patients had no major bleeding with 80% survival (n = 24). Seven patients experienced critical site bleed with six surviving. About 88% of patients were neurologically intact (CPC of 1) at discharge or follow-up (n = 53 of 60).
Multivariate analysis demonstrated statistically significant risk of death for two secondary outcomes: age greater than 65 and cannulation during CPR. There was still a three-fold increase in the adjusted risk of death for patients greater than 65 years old (adjusted OR, 3.08; 95% CI, 1.09–8.67; p = 0.03). Patients who were cannulated during CPR had a six-fold increase in the adjusted risk of death (adjusted OR, 5.67; 95% CI, 1.23–26.20; p = 0.03) compared with those cannulated after ROSC.
In our large cohort of 301 patients presenting with massive PE-related cardiac arrest that was managed with post-arrest VA-ECMO, we found survival to discharge to be 61%. We identified age greater than 65 and cannulation during CPR to be independent markers of mortality (adjusted OR, 3.08; p = 0.03 and adjusted OR, 5.67; p = 0.03, respectively) in our multivariate analysis.
Massive PE-related cardiac arrest has mortality as high as 90% (11,12). We specifically assessed whether thrombolysis before ECMO cannulation lowered the chance of survival. Prior literature, particularly Al-Bawardy et al (19) in a small case series, showed a survival rate of 62% (eight of 13) when thrombolysis and ECMO were used concomitantly in setting of massive PE. We identified 51 cases (17% of total 301 patients) in our review who had systemic thrombolysis prior to VA-ECMO; survival to hospital discharge was 67% (34 of 51). The odds of death for patients receiving pre-ECMO thrombolytics versus not (OR, 0.78; 95% CI, 0.39–1.54; p = 0.48) (Table 1) were not different. There were only six patients with reports of major bleed in this cohort (all survived). These findings are suggestive that preceding thrombolysis did not confer an additional risk of death leading us to feel it should not be considered a contraindication to subsequent ECMO. This finding is particularly germane given the high likelihood that patients with massive PE-related cardiac arrest have been considered for or have received preceding thrombolytics (8,9,17). Once thrombolytics are used but unsuccessful at restoring hemodynamic stability, the use of other reperfusion modalities (e.g., pulmonary embolectomy, catheter-directed thrombolysis, and VA-ECMO) is often not considered in the immediate postthrombolytic setting due to the increased risk of bleeding.
TABLE 1. -
Odds Ratios for Secondary Outcomes With the Number of Patients That These Values Were Reported on
||Number of Patients With Variable Known
||OR (Risk of Death) (95% CI)
|Age > 65 vs age ≤ 65
|Male vs female
|Pulmonary embolism primary reason for admission vs not primary reason for admission
|Systemic thrombolysis prior to ECMO cannulation vs no systemic thrombolysis prior to ECMO cannulation
|Cannulation during cardiopulmonary resuscitation vs after return-of-spontaneous-circulation
|Cannulated in emergency department vs all other sites combined
ECMO = extracorporeal membrane oxygenation, OR = odds ratio.
There were 21 (7% of all patients in our review, n = 301) reports of major bleeding reported in our study and the survival among that cohort was 76% (n = 16). For comparison, Al-Bawardy et al (19) reported 54% major bleeding events in their case series and a large meta-analysis involving 1,866 patients looking at ECMO complications in patients with cardiogenic shock reported close to 40% major bleeding events (97). Based on these prior reports, we suspect our reported rate of bleeding rates may be subject to reporting bias and the true occurrence rate is likely higher. We found no significant difference in survival when PE was the primary reason for admission versus not (76% and 83%, respectively). This likely reflects that ECMO centers were prepared for emergent cannulation irrespective of the primary reason for hospitalization. There was also no difference in risk of death if cannulation occurred in the ED versus other sites in the hospital (OR, 2.52; p = 0.16), again likely reflecting ECMO centers’ preparedness.
In addition to survival, neurologic recovery remains the other main important outcome for massive PE-related cardiac arrest. Stub et al (98), in a single-center prospective study showed that nearly half of the patients (54%) had acceptable neurologic outcomes (CPC of 1) at the time of hospital discharge in the setting of ECMO use in cardiac arrest. Our study had 60 patients with reported neurologic outcomes, 88% (n = 53) of whom had an excellent neurologic recovery (CPC of 1). Although encouraging, this finding is limited by the absence of a neurologic status at discharge being reported for the majority of our included patients.
There are several limitations of this review, reporting bias being the most notable. Our study can only report a survival to discharge without significant comment on short- or long-term survival. Literature in abstract form was used but often did not often provide additional detail beyond our primary outcome. Furthermore, there was heterogeneous reporting of important clinical variables (neurologic status at discharge, presence or absence of significant bleed, cannulation during or after CPR, and duration of CPR) among the majority of literature found that made it difficult to comment confidently on all of these variables’ impact on survival. We also did not have sufficient detail to comment on comorbid conditions and other important secondary outcomes: long-term need for dialysis, chronic ventilator dependency, discharge to nursing facilities versus home, need for percutaneous endoscopic gastrostomy and artificial feeding, readmissions, and long-term PE-related complications like chronic thromboembolic pulmonary hypertension.
This review reflects the continued emergence of VA-ECMO as a treatment modality for patients with obstructive shock due to massive PE (6,54,99). A strength of this study is that we sought to identify the cohort with the highest risk of death by selecting patients who not only had massive PE but also presented with or acutely developed cardiac arrest. To our knowledge, this is the first systematic review focused on evaluating outcomes of VA-ECMO in massive PE-related cardiac arrest or attempted to identify predictors of mortality with multivariate analysis (6,14,100). We were able to find the largest number of patients to include in our systemic review, which allowed us to perform a multivariate analysis that led to significant findings of age greater than 65 years old and cannulation during CPR being associated with a notable increased risk of death. We feel our findings are helpful for clinical decision-making in rapidly accessing candidacy for VA-ECMO and providing assurance that systemic thrombolysis is not a contraindication for ECMO use.
The use of VA-ECMO in management of massive PE-related cardiac arrest has a survival rate of 61%. Systemic thrombolysis prior to VA-ECMO did not confer increased odds of death and this review suggests that both modalities can be complimentary to each other with a focus on achieving ROSC. In our study, age greater than 65 and ECMO cannulation during CPR had increased mortality (three- and six-fold risks of death, respectively) and may aid in the decision-making process of deploying VA-ECMO for massive PE-related cardiac arrest.
Drs. Scott and Rali involved with article selection, data extraction, and article preparation. Drs. Gordon, Desai, Marchetti, Mamary, Panaro, Cohen, Bashir, Lakhter, Toyoda, Criner, and Moores contributed to article review and preparation. Dr. Vender helped in article selection (third party for disagreements) and data extraction. Drs. Pettigrew and Kim involved in data extraction and article assessment for risk-of-bias. Mr. Roth provided complete literature search and software to include or exclude articles in addition to guidance on systematic review methods. Dr. Zhao helped in statistical analysis.
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