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Strategies of left ventricular unloading during VA-ECMO support: a network meta-analysis
Journal Pre-proof Strategies of left ventricular unloading during VA-ECMO support: A network META-analysis
Luca Baldetti, Mario Gramegna, Alessandro Beneduce, Francesco Melillo, Francesco Moroni, Francesco Calvo, Giulio Melisurgo, Silvia Ajello, Evgeny Fominskiy, Federico Pappalardo, Anna Mara Scandroglio PII:
S0167-5273(19)35668-2
DOI:
https://doi.org/10.1016/j.ijcard.2020.02.004
Reference:
IJCA 28334
To appear in:
International Journal of Cardiology
Received date:
13 November 2019
Revised date:
12 January 2020
Accepted date:
2 February 2020
Please cite this article as: L. Baldetti, M. Gramegna, A. Beneduce, et al., Strategies of left ventricular unloading during VA-ECMO support: A network META-analysis, International Journal of Cardiology(2018), https://doi.org/10.1016/j.ijcard.2020.02.004
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2018 Published by Elsevier.
Journal Pre-proof Short Communication
STRATEGIES OF LEFT VENTRICULAR UNLOADING DURING VA-ECMO SUPPORT
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A NETWORK META-ANALYSIS
Luca Baldetti, MD1; Mario Gramegna, MD2; Alessandro Beneduce, MD3; Francesco Melillo, MD4; Francesco Moroni, MD3; Francesco Calvo, MD1; Giulio Melisurgo, MD1; Silvia Ajello,
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MD1; Evgeny Fominskiy, MD1; Federico Pappalardo, MD1; Anna Mara Scandroglio, MD1
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Cardiac Surgery Intensive Care Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy Coronary Intensive Care Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy 3 Unit of Cardiovascular Interventions, IRCCS San Raffaele Scientific Institute, Milan, Italy Unit 4 Unit of Echocardiography, IRCCS San Raffaele Scientific Institute, Milan, Italy
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The Authors takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
Disclosures: None of the Authors has relevant conflicts of interest to disclose.
Corresponding Author Dr. Luca Baldetti Cardiac Intensive Care Unit, “San Raffaele Hospital”, Milan, Italy Via Olgettina, 60 – 20132 Milan, Italy Email: [email protected] Phone: +39 0226437338 Fax: +39 0226437339
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Total word count: 1500 words
Journal Pre-proof Funding statement: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Note: the first 20 references appear in the manuscript, the rest is available in the Supplementary
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Appendix.
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Abstract
Background: Left ventricle (LV) unloading during VenoArterial ExtraCorporeal Membrane Oxygenation (VA-ECMO) reduces the risk of LV distention, stagnation and pulmonary congestion resulting from the increased afterload. Lacking direct comparisons between unloading strategies we used network meta-analysis to indirectly compare different unloading approaches.
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Methods: A literature research was performed to include all studies on VA-ECMO reporting data on mechanical LV unloading. The pre-specified outcome was in-hospital death. Results: Literature search identified 389 studies: 16 were included in the analysis (3930
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patients). Two strategies of mechanical LV unloading were compared: afterload reduction (IABP)
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and preload reduction (Impella pump, right upper pulmonary/trans-septal catheters, LV surgical
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vents). Any LV unloading strategy was associated with mortality reduction with overall OR=0.54; 95%CI 0.42-0.70; p<0.001. Targeting afterload was associated with reduced mortality (OR=0.61
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95%CI 0.46-0.81; p<0.001; I2=61%), as targeting preload (OR=0.34 95%CI 0.21-0.55; p<0.001;
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I2=0%). Significant between group difference was observed (p=0.04): to further explore this we performed a network meta-analysis. Indirect comparisons between afterload and preload reduction
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were estimated. Any unloading technique was confirmed better than none but preload targeting resulted better than afterload targeting. Conclusion: Any unloading strategy in VA-ECMO patients was associated with lower mortality as compared to no-unloading. Preload reduction strategies resulted superior to afterload reduction.
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Background VenoArterial ExtraCorporeal Membrane Oxygenation (VA-ECMO) therapy guarantees blood oxygenation and end-organ perfusion in patients with cardiogenic shock (CS), thereby offering a precious time window to allow for cardiac recovery (bridge to recovery) or implementation of definitive treatments (bridge to transplant/ventricular assist device [VAD]). While VA-ECMO does not per se positively affect myocardial recovery, it may on the other side worsen left ventricle (LV) hemodynamics, damage the lungs and negatively affect myocardial
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recovery1–3. This detrimental effect is largely attributed to the increase in afterload generated by VA-ECMO flow2–6, an unfavorable side-effect of VA-ECMO support that may be lessened by
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strategies of LV unloading.
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To this end, a number of drugs, techniques and devices has been employed, ranging from
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those reducing the LV afterload (vasodilators, intra-aortic balloon pump [IABP]) to those reducing LV preload (Impella pump, surgically implanted LV vent, catheter venting of the left atrium from
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the right upper pulmonary vein or via trans-septal catheters/septostomy)2,5,7,8. While these strategies of LV unloading have recently been demonstrated to be associated with lower mortality during VA-
Aims
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ECMO support9,10, uncertainty persist whether one approach is superior to other5.
Lacking direct randomized trials or studies comparing one strategy over another we used network meta-analysis techniques to perform indirect comparisons between mechanical approaches targeting either LV preload or afterload and calculate the probability of each mechanical LV unloading strategy being the best over the others.
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Methods This network meta-analysis was reported in accordance with the “PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions”11. Quality assessment of non-randomized observational studies included in this report was done with the Newcastle-Ottawa Scale (NOS) tool12,13.
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Search strategy Two authors (L.B., M.G.) independently searched PubMed, Embase, BioMedCentral, Google Scholar, and the Cochrane Central Register of Controlled Trials, from inception to 18th
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September 2019 using the following combination of search keywords: “VA-ECMO”, “venoarterial
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extracoroporeal membrane oxygenation”, “left ventricle”, “LV”, “unloading”, “decompression”,
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“venting”, “IABP”, “intra-aortic balloon pump”, and “Impella”. Backward snowballing (review of
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references from identified articles and pertinent reviews) was also performed.
Study selection and data extraction
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All published clinical studies investigating VA-ECMO circulatory support and reporting
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data on mechanical LV unloading strategies were evaluated for inclusion in this meta-analysis. We considered for inclusion retrospective or prospective cohort studies comparing different approaches of LV unloading during VA-ECMO. Studies not clearly reporting death rates for unloading vs no unloading cohorts were excluded. Studies with <20 patients per arm were also excluded. Any type of cardiogenic shock etiology requiring VA-ECMO support was considered for this analysis. All authors independently assessed identified studies for possible inclusion. Two investigators (L.B., M.G.) independently extracted data on study designs, measurements, patient characteristics, and outcomes using a standardized data extraction form. Data collection included authors, year of publication, inclusion and exclusion criteria, sample size, type of unloading and study outcome.
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Study outcome The pre-specified efficacy outcome was the occurrence of in-hospital all-cause death.
Statistical analyses Cumulative event rates for mortality endpoint were obtained and reported. When pairwise comparisons were available from relevant literature a random-effects model meta-analysis was
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performed with the Mantel-Haenszel method to calculate the pooled estimate rates and 95% confidence intervals (CI) of study outcomes. Statistical significance was set at p-value <0.05 (two-
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sided) and with a 95% CI not crossing 1.00. To assess heterogeneity across studies, we used
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Cochrane Q statistic to compute I2 values: <25%, 25-50%, or >50% indicated low, moderate, or high heterogeneity, respectively14.
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Network meta-analysis was conducted based on a frequentist approach to compare
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treatments without direct pairwise comparisons15. We also checked evidence of consistency for each analysis (no discrepancy between direct and indirect effect size for a treatment comparison)16.
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The Surface Under the Cumulative Ranking (SUCRA) values were calculated to
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hierarchically rank each treatment based on the probability of being the best for a given outcome: treatments were ranked from best to worse based on progressively lower SUCRA values17. Statistical analyses were conducted with STATA 14.0 (StataCorp LP, College Station, Texas, USA) using the package “mvmeta” and with Review Manager (RevMan 5.3, The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark).
Results Literature search identified 389 studies: a total of 365 were excluded during screening based on title and abstract. Of the remaining 24 eligible studies, 16 studies passed a second verification phase and were eventually included in this analysis, for a total population of 3930 patients18–33.
Journal Pre-proof Exclusion reasons during the second verification phase included: small sample size (n=4)34–37, no control group (n=3)5,28,38,39, no investigation of the study outcome (n=1)40. Consort diagram is available at eFigure 1-A. Summary of included studies is available at eTable 1. All studies were observational by design. Risk of bias assessment is reported in Supplementary Appendix. Study years range from 2004 to 2019; studies sample sizes range from 33 to 1647 patients. In-hospital mortality ranged between 16-76%. A significantly lower mortality in recent years was documented (general univariate linear model p=0.033), this trend was largely accounted for by
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studies published in year 2019 (Supplementary Figure 1). Two strategies of mechanical LV unloading were compared: afterload reduction (IABP) and preload reduction (Impella pump,
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surgically implanted LV vent, catheter venting of the left atrium from the right upper pulmonary
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vein or via trans-septal catheters, atrial septostomy).
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Left ventricle unloading and death outcome meta-analysis
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Any LV unloading strategy was associated with mortality reduction with an overall OR=0.54; 95%CI 0.42-0.70; p<0.001. Approaches targeting afterload (IABP) were associated with
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reduced mortality OR=0.61 95%CI 0.46-0.81; p<0.001, as were those targeting preload (Impella
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pump and venting catheters) OR=0.34 95%CI 0.21-0.55; p<0.001. Heterogeneity was high for studies in the afterload subgroup, but low in preload subgroup studies (I2=61% and 0%, respectively). A significant between group difference was observed (p=0.04) (Figure 2). To further explore this issue we performed a network meta-analysis.
Left ventricle unloading and death outcome network meta-analysis Network map is available at eFigure 1-B. Direct comparisons included afterload reduction vs no unloading and preload reduction vs no unloading. Indirect comparisons between afterload and preload reduction were estimated. Contribution plot is reported in Supplementary Figure 2. Any
Journal Pre-proof unloading technique was confirmed better than none. Notably, preload targeting techniques resulted better than afterload reduction to reduce mortality (Table 2). Probability rank analysis was in line with these findings. Based on the SUCRA values treatments targeting preload had the highest probability of being the best treatment in reducing death outcome (98.9%), while afterload-reducing strategies ranked second (51.0%). These results
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are summarized in Table 2 and Supplementary Figure 3.
Discussion
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In this network meta-analysis comparing different LV unloading strategies during VA-
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ECMO support, preload- and afterload-reducing techniques resulted better than no unloading in
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reducing all-cause death.
During VA-ECMO support effective arterial elastance (Ea) increases (as a consequence of
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increased afterload to the LV due to arterial cannula retrograde flow in aorta): in conditions of severely impaired and unchangeable myocardial contractility the end-systolic pressure-volume
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relationship (ESPVR) cannot vary and the ultimate consequence of this unfavorable ventricular-
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arterial coupling is LV dilatation according to the Frank-Starling mechanism. In acutely failing ventricles, this translates in lower LV stroke volume, and higher LV end-diastolic volume (LVEDV) causing a rapid increase in end-diastolic pressures (LVEDP) with resulting pulmonary congestion, higher myocardial oxygen consumption and LV blood stagnation2–4 (eFigure 3). Left ventricle distension during VA-ECMO may occur in up 30-70% of patients41. To avoid this vicious cycle, supportive measures to prevent LV distension may target either afterload (e.g. IABP) or preload (e.g. Impella trans-aortic axial-flow pump or left atrial/ventricular catheter venting). Indeed, the synchronized systolic deflation of IABP creates a “suction” phenomenon in the descending aorta, thereby reducing LV afterload (Ea) and enhancing its emptying into the ascending aorta. Moreover IABP diastolic inflation backwardly improves
Journal Pre-proof coronary perfusion possibly strengthening myocardial contraction (i.e. increasing the ESPVR slope). Impella trans-aortic axial-flow pump and surgical/percutaneous venting catheters continuously draw blood out of the LV sections into either ascending aorta or VA-ECMO circuit respectively, directly reducing LVEDV and LVEDP. Despite some differences on morphology of pressure-volume loops with each LV and left atrial venting technique, we decided to group all these under the “preload reduction” label as pivotal effect of such treatments is reduction in LVEDP. This is opposed to afterload-reducing techniques where primary effect is arterial elastance (Ea) reduction,
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with secondary and milder effect on LVEDP (Supplementary Figure 6)2,3,42. To avoid detrimental VA-ECMO related LV overload, Impella device may be used in
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isolation for hemodynamic support in CS, especially in cases of myocardial ischemia43–45 (this
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approach is further discussed in Supplementary Appendix).
Our analysis suggests that specific differences in unloading technique may account for
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different effect on mortality during VA-ECMO. Findings of this meta-analysis support the notion
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that preload reduction with either trans-aortic axial flow pumps or direct LV/left atrium venting is associated with lower mortality.
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Different hemodynamic effects of IABP, primarily affecting arterial blood pressure, and LV
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venting techniques, chiefly affecting cardiac cycle volumes, may account for the observed differences in efficacy. However, the extent to which this effect is related to the specific approach employed (i.e. targeting afterload vs preload) or to the degree of unloading attained is unknown. Indeed, afterload group included studies reporting on IABP as the only adjunct device to VAECMO, while in the preload group a variety of devices was employed, most of these being highly effective pumps. While IABP modestly reduces pulmonary artery wedge pressure (PAWP) at most by 4-5 mmHg27, Impella pump may reduce PAPWP by 7-10 mmHg2,39 and left atrial venting by 417 mmHg47: this “gradient” of expected LV decompression is coherent with the results of the network meta-analysis.
Journal Pre-proof Our findings reinforce the notion that any unloading strategy resulted superior to no unloading in VA-ECMO patients with regard to mortality, but LV unloading by means of preload reduction resulted better than afterload reduction.
Limitations Inherent limitations of network meta-analysis are those of included studies: as no
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randomized trial is ongoing or is planned to our knowledge, cohort studies represent the best available evidence on this clinical scenario to date. Nevertheless, many studies include a limited number of patients: to limit the small-study effect we excluded those with <20 patients per group.
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Moreover, venting techniques
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Conclusions
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In conclusion, any unloading strategy in VA-ECMO patients was associated with lower mortality as compared to no unloading. A strategy of LV unloading based on preload reduction
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resulted superior to afterload reduction in this network meta-analysis. Based on the results of this
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analysis a combined strategy embodying LV unloading in VA-ECMO recipients is strongly warranted, possibly preferring preload targeting devices.
Journal Pre-proof Figure 1 – Consort diagram for study selection (Panel A). Network map for meta-analytic treatments comparison (Panel B): solid lines represent direct comparisons, dashed lines indirect comparisons.
Figure 2 – Forrest plot of death endpoint meta-analysis.
Figure 3 – Pressure-volume loops (PVL) changes with VA-ECMO. Panel A: green loop represents
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baseline conditions; VA-ECMO flow increases LV afterload and end-systolic point (ESP). As contractile reserve is almost absent in failing left ventricle (LV), the ESPVR slope cannot change.
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In consequence, the effective arterial elastance (Ea) that always intersects the ESPVR at the ESP
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level, shifts right towards higher LVEDV (red arrow). This causes the entire LV PVL to move rightward and upward (yellow loop) towards higher EDV and EDP via the Frank-Starling
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mechanism (Panel B). EDP – end-diastolic pressure; EDPVR – end-diastolic pressure volume
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ESV – end-systolic volume.
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relationship; EDV – end-diastolic volume; ESPVR – end-systolic pressure volume relationship;
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Journal Pre-proof AUTHOR STATEMENT
Luca Baldetti: Conceptualization; Luca Baldetti, Mario Gramegna, Alessandro Beneduce, Francesco Moroni: Data curation; Luca Baldetti, Francesco Moroni: Formal analysis;
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Luca Baldetti, Mario Gramegna: Investigation; Luca Baldetti, Francesco Melillo: Methodology;
Anna Mara Scandroglio, Evgeny Fominskiy, Giulio Melisurgo: Supervision;
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Federico Pappalardo: Validation;
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Luca Baldetti, Evgeny Fominskiy: Roles/Writing - original draft;
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Luca Baldetti, Francesco Calvo, Anna Mara Scandroglio, Silvia Ajello: Writing - review & editing.
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Study
Indications
Patients Total
ECMO
ECMO + Unloading
Venting approach
In-Hospital Mortality
Complications
Routine n.a. Routine/Bail-out Routine Routine/Bail-out n.a. Routine/Bail-out n.a. Bail-out Bail-out Routine n.a. n.a. Bail-out
24 (63) 1038 (63) 29 (17) 137 (53) 79 (52) 167 (76)* 34 (57) 254 (48)† 67 (63) 51 (53) 45 66 (67) 41 (68) 44 (51)
Bail-out n.a. Routine/Bail-out
131 (58) 114 (73) 46 (70)
92 (41) 49 (31) 33 (50)
Bail-out n.a. Routine/Bail-out
45 (23) 50 (71) 30 (62)*
4 (6)
Bleeding
RRT
34 (89)
15 (25)
14 (37) 406 (25) 28 (17) 182 (70) 68 (45) 122 (56) 24 (40)
34 (35) 180 (71)
26 (10)
IABP Aoyama et al Aso et al Barge-Caballero et al Bréchot et al Chen et al Doll et al Kai Chen et al Lin et al Overtchouk et al Park et al Ro et al Sakamoto et al Tepper et al Wang et al Akanni et al Pappalardo et al Patel et al Alghanem et al Ok et al Shmack et al
ACS ACS, AHF, Others ACS, PCS ACS, AHF, Others PCS PCS PCS PCS, AHF, ACS, Other ACS ACS PCS, AHF, ACS, Other ACS PCS, others PCS PCS, ACS, Others ACS ACS Pediatric ACS, PCS, Others AHF, Others
38 1650 169 259 152 219 60 529 106 96 253 98 60 87 225 157 66
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n r u
o J 194 70 48
3 (8) 1046 (63) 96 (57) 155 (60) 75 (49) 75 (34) 0 227 (43) 42 (40) 55 (57) 193 (76) 4 (4) 30 (50) 46 (53) 196 (87) 123 (78) 36 (55)
35 (92) 604 (37) 73 (43) 104 (40) 77 (51) 144 (66) 60 (100) 302 (57) 64 (60) 41 (43) 60 (24) 94 (96) 30 (50) 41 (47)
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e
r P
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57 (34) 24 (16)
19 (32) 22 (25)
Impella 29 (13) 34 (22) 30 (45)
57 (25) 39 (25) 7 (11)
LA Decompression 173 (89) 45 (64) 28 (58)
21 (11) 25 (36) 20 (42)
Table 1 – Summary of selected studies. Legend: ACS – acute coronary syndrome; AHF – acute heart failure; ECMO – ExtraCorporeal Membrane Oxygenation; IABP – intra-aortic balloon pump; LA – left † atrium; O – others; PCS – postcardiotomy shock; RRT – renal replacement therapy; RUPV – right upper pulmonary vein. *30-day mortality; 2-weeks mortality.
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Table 2 – League table with respect of death outcome (upper part). Green colour indicates favourable and red unfavourable odds ratios (OR) with respective 95% confidence intervals. In the lower part, probability ranks with respect of death outcome are reported. The Surface Under the Cumulative Ranking (SUCRA) values represent the cumulative probability from each treatment being the best with regard to death outcome (the closer to 100% the value is, the higher the
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likelihood that a therapy is in the top rank). Mean rank represents the likely ranking of each treatment.
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Death outcome odds ratio according to type of unloading No unloading 0.66 (0.51, 0.85) 0.35 (0.20, 0.60) 1.52 (1.17, 1.97) Afterload reduction 0.53 (0.29, 0.98) 2.85 (1.66, 4.91) 1.88 (1.03, 3.43) Preload reduction Best treatment probability rankings Treatment SUCRA (%) Mean Rank No unloading 0.1 3.0 Afterload reduction 51.0 2.0 Preload reduction 1.0 98.9
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Highlights
VA-ECMO increases LV afterload, leading to LV distention and pulmonary congestion. Mechanical unloading (either reducing afterload or preload) reduces this risk. No comparison between afterload-reducing vs preload-reducing techniques is available. In this meta-analysis any mechanical LV unloading was confirmed better than none.
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In this network meta-analysis preload reduction was superior to afterload reduction.
Figure 1
Figure 2
Figure 3
Luca Baldetti, Mario Gramegna, Alessandro Beneduce, Francesco Melillo, Francesco Moroni, Francesco Calvo, Giulio Melisurgo, Silvia Ajello, Evgeny Fominskiy, Federico Pappalardo, Anna Mara Scandroglio PII:
S0167-5273(19)35668-2
DOI:
https://doi.org/10.1016/j.ijcard.2020.02.004
Reference:
IJCA 28334
To appear in:
International Journal of Cardiology
Received date:
13 November 2019
Revised date:
12 January 2020
Accepted date:
2 February 2020
Please cite this article as: L. Baldetti, M. Gramegna, A. Beneduce, et al., Strategies of left ventricular unloading during VA-ECMO support: A network META-analysis, International Journal of Cardiology(2018), https://doi.org/10.1016/j.ijcard.2020.02.004
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2018 Published by Elsevier.
Journal Pre-proof Short Communication
STRATEGIES OF LEFT VENTRICULAR UNLOADING DURING VA-ECMO SUPPORT
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A NETWORK META-ANALYSIS
Luca Baldetti, MD1; Mario Gramegna, MD2; Alessandro Beneduce, MD3; Francesco Melillo, MD4; Francesco Moroni, MD3; Francesco Calvo, MD1; Giulio Melisurgo, MD1; Silvia Ajello,
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MD1; Evgeny Fominskiy, MD1; Federico Pappalardo, MD1; Anna Mara Scandroglio, MD1
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Cardiac Surgery Intensive Care Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy Coronary Intensive Care Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy 3 Unit of Cardiovascular Interventions, IRCCS San Raffaele Scientific Institute, Milan, Italy Unit 4 Unit of Echocardiography, IRCCS San Raffaele Scientific Institute, Milan, Italy
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The Authors takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
Disclosures: None of the Authors has relevant conflicts of interest to disclose.
Corresponding Author Dr. Luca Baldetti Cardiac Intensive Care Unit, “San Raffaele Hospital”, Milan, Italy Via Olgettina, 60 – 20132 Milan, Italy Email: [email protected] Phone: +39 0226437338 Fax: +39 0226437339
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Total word count: 1500 words
Journal Pre-proof Funding statement: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Note: the first 20 references appear in the manuscript, the rest is available in the Supplementary
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Appendix.
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Abstract
Background: Left ventricle (LV) unloading during VenoArterial ExtraCorporeal Membrane Oxygenation (VA-ECMO) reduces the risk of LV distention, stagnation and pulmonary congestion resulting from the increased afterload. Lacking direct comparisons between unloading strategies we used network meta-analysis to indirectly compare different unloading approaches.
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Methods: A literature research was performed to include all studies on VA-ECMO reporting data on mechanical LV unloading. The pre-specified outcome was in-hospital death. Results: Literature search identified 389 studies: 16 were included in the analysis (3930
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patients). Two strategies of mechanical LV unloading were compared: afterload reduction (IABP)
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and preload reduction (Impella pump, right upper pulmonary/trans-septal catheters, LV surgical
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vents). Any LV unloading strategy was associated with mortality reduction with overall OR=0.54; 95%CI 0.42-0.70; p<0.001. Targeting afterload was associated with reduced mortality (OR=0.61
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95%CI 0.46-0.81; p<0.001; I2=61%), as targeting preload (OR=0.34 95%CI 0.21-0.55; p<0.001;
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I2=0%). Significant between group difference was observed (p=0.04): to further explore this we performed a network meta-analysis. Indirect comparisons between afterload and preload reduction
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were estimated. Any unloading technique was confirmed better than none but preload targeting resulted better than afterload targeting. Conclusion: Any unloading strategy in VA-ECMO patients was associated with lower mortality as compared to no-unloading. Preload reduction strategies resulted superior to afterload reduction.
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Background VenoArterial ExtraCorporeal Membrane Oxygenation (VA-ECMO) therapy guarantees blood oxygenation and end-organ perfusion in patients with cardiogenic shock (CS), thereby offering a precious time window to allow for cardiac recovery (bridge to recovery) or implementation of definitive treatments (bridge to transplant/ventricular assist device [VAD]). While VA-ECMO does not per se positively affect myocardial recovery, it may on the other side worsen left ventricle (LV) hemodynamics, damage the lungs and negatively affect myocardial
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recovery1–3. This detrimental effect is largely attributed to the increase in afterload generated by VA-ECMO flow2–6, an unfavorable side-effect of VA-ECMO support that may be lessened by
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strategies of LV unloading.
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To this end, a number of drugs, techniques and devices has been employed, ranging from
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those reducing the LV afterload (vasodilators, intra-aortic balloon pump [IABP]) to those reducing LV preload (Impella pump, surgically implanted LV vent, catheter venting of the left atrium from
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the right upper pulmonary vein or via trans-septal catheters/septostomy)2,5,7,8. While these strategies of LV unloading have recently been demonstrated to be associated with lower mortality during VA-
Aims
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ECMO support9,10, uncertainty persist whether one approach is superior to other5.
Lacking direct randomized trials or studies comparing one strategy over another we used network meta-analysis techniques to perform indirect comparisons between mechanical approaches targeting either LV preload or afterload and calculate the probability of each mechanical LV unloading strategy being the best over the others.
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Methods This network meta-analysis was reported in accordance with the “PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions”11. Quality assessment of non-randomized observational studies included in this report was done with the Newcastle-Ottawa Scale (NOS) tool12,13.
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Search strategy Two authors (L.B., M.G.) independently searched PubMed, Embase, BioMedCentral, Google Scholar, and the Cochrane Central Register of Controlled Trials, from inception to 18th
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September 2019 using the following combination of search keywords: “VA-ECMO”, “venoarterial
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extracoroporeal membrane oxygenation”, “left ventricle”, “LV”, “unloading”, “decompression”,
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“venting”, “IABP”, “intra-aortic balloon pump”, and “Impella”. Backward snowballing (review of
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references from identified articles and pertinent reviews) was also performed.
Study selection and data extraction
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All published clinical studies investigating VA-ECMO circulatory support and reporting
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data on mechanical LV unloading strategies were evaluated for inclusion in this meta-analysis. We considered for inclusion retrospective or prospective cohort studies comparing different approaches of LV unloading during VA-ECMO. Studies not clearly reporting death rates for unloading vs no unloading cohorts were excluded. Studies with <20 patients per arm were also excluded. Any type of cardiogenic shock etiology requiring VA-ECMO support was considered for this analysis. All authors independently assessed identified studies for possible inclusion. Two investigators (L.B., M.G.) independently extracted data on study designs, measurements, patient characteristics, and outcomes using a standardized data extraction form. Data collection included authors, year of publication, inclusion and exclusion criteria, sample size, type of unloading and study outcome.
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Study outcome The pre-specified efficacy outcome was the occurrence of in-hospital all-cause death.
Statistical analyses Cumulative event rates for mortality endpoint were obtained and reported. When pairwise comparisons were available from relevant literature a random-effects model meta-analysis was
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performed with the Mantel-Haenszel method to calculate the pooled estimate rates and 95% confidence intervals (CI) of study outcomes. Statistical significance was set at p-value <0.05 (two-
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sided) and with a 95% CI not crossing 1.00. To assess heterogeneity across studies, we used
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Cochrane Q statistic to compute I2 values: <25%, 25-50%, or >50% indicated low, moderate, or high heterogeneity, respectively14.
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Network meta-analysis was conducted based on a frequentist approach to compare
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treatments without direct pairwise comparisons15. We also checked evidence of consistency for each analysis (no discrepancy between direct and indirect effect size for a treatment comparison)16.
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The Surface Under the Cumulative Ranking (SUCRA) values were calculated to
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hierarchically rank each treatment based on the probability of being the best for a given outcome: treatments were ranked from best to worse based on progressively lower SUCRA values17. Statistical analyses were conducted with STATA 14.0 (StataCorp LP, College Station, Texas, USA) using the package “mvmeta” and with Review Manager (RevMan 5.3, The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark).
Results Literature search identified 389 studies: a total of 365 were excluded during screening based on title and abstract. Of the remaining 24 eligible studies, 16 studies passed a second verification phase and were eventually included in this analysis, for a total population of 3930 patients18–33.
Journal Pre-proof Exclusion reasons during the second verification phase included: small sample size (n=4)34–37, no control group (n=3)5,28,38,39, no investigation of the study outcome (n=1)40. Consort diagram is available at eFigure 1-A. Summary of included studies is available at eTable 1. All studies were observational by design. Risk of bias assessment is reported in Supplementary Appendix. Study years range from 2004 to 2019; studies sample sizes range from 33 to 1647 patients. In-hospital mortality ranged between 16-76%. A significantly lower mortality in recent years was documented (general univariate linear model p=0.033), this trend was largely accounted for by
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studies published in year 2019 (Supplementary Figure 1). Two strategies of mechanical LV unloading were compared: afterload reduction (IABP) and preload reduction (Impella pump,
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surgically implanted LV vent, catheter venting of the left atrium from the right upper pulmonary
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vein or via trans-septal catheters, atrial septostomy).
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Left ventricle unloading and death outcome meta-analysis
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Any LV unloading strategy was associated with mortality reduction with an overall OR=0.54; 95%CI 0.42-0.70; p<0.001. Approaches targeting afterload (IABP) were associated with
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reduced mortality OR=0.61 95%CI 0.46-0.81; p<0.001, as were those targeting preload (Impella
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pump and venting catheters) OR=0.34 95%CI 0.21-0.55; p<0.001. Heterogeneity was high for studies in the afterload subgroup, but low in preload subgroup studies (I2=61% and 0%, respectively). A significant between group difference was observed (p=0.04) (Figure 2). To further explore this issue we performed a network meta-analysis.
Left ventricle unloading and death outcome network meta-analysis Network map is available at eFigure 1-B. Direct comparisons included afterload reduction vs no unloading and preload reduction vs no unloading. Indirect comparisons between afterload and preload reduction were estimated. Contribution plot is reported in Supplementary Figure 2. Any
Journal Pre-proof unloading technique was confirmed better than none. Notably, preload targeting techniques resulted better than afterload reduction to reduce mortality (Table 2). Probability rank analysis was in line with these findings. Based on the SUCRA values treatments targeting preload had the highest probability of being the best treatment in reducing death outcome (98.9%), while afterload-reducing strategies ranked second (51.0%). These results
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are summarized in Table 2 and Supplementary Figure 3.
Discussion
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In this network meta-analysis comparing different LV unloading strategies during VA-
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ECMO support, preload- and afterload-reducing techniques resulted better than no unloading in
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reducing all-cause death.
During VA-ECMO support effective arterial elastance (Ea) increases (as a consequence of
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increased afterload to the LV due to arterial cannula retrograde flow in aorta): in conditions of severely impaired and unchangeable myocardial contractility the end-systolic pressure-volume
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relationship (ESPVR) cannot vary and the ultimate consequence of this unfavorable ventricular-
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arterial coupling is LV dilatation according to the Frank-Starling mechanism. In acutely failing ventricles, this translates in lower LV stroke volume, and higher LV end-diastolic volume (LVEDV) causing a rapid increase in end-diastolic pressures (LVEDP) with resulting pulmonary congestion, higher myocardial oxygen consumption and LV blood stagnation2–4 (eFigure 3). Left ventricle distension during VA-ECMO may occur in up 30-70% of patients41. To avoid this vicious cycle, supportive measures to prevent LV distension may target either afterload (e.g. IABP) or preload (e.g. Impella trans-aortic axial-flow pump or left atrial/ventricular catheter venting). Indeed, the synchronized systolic deflation of IABP creates a “suction” phenomenon in the descending aorta, thereby reducing LV afterload (Ea) and enhancing its emptying into the ascending aorta. Moreover IABP diastolic inflation backwardly improves
Journal Pre-proof coronary perfusion possibly strengthening myocardial contraction (i.e. increasing the ESPVR slope). Impella trans-aortic axial-flow pump and surgical/percutaneous venting catheters continuously draw blood out of the LV sections into either ascending aorta or VA-ECMO circuit respectively, directly reducing LVEDV and LVEDP. Despite some differences on morphology of pressure-volume loops with each LV and left atrial venting technique, we decided to group all these under the “preload reduction” label as pivotal effect of such treatments is reduction in LVEDP. This is opposed to afterload-reducing techniques where primary effect is arterial elastance (Ea) reduction,
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with secondary and milder effect on LVEDP (Supplementary Figure 6)2,3,42. To avoid detrimental VA-ECMO related LV overload, Impella device may be used in
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isolation for hemodynamic support in CS, especially in cases of myocardial ischemia43–45 (this
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approach is further discussed in Supplementary Appendix).
Our analysis suggests that specific differences in unloading technique may account for
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different effect on mortality during VA-ECMO. Findings of this meta-analysis support the notion
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that preload reduction with either trans-aortic axial flow pumps or direct LV/left atrium venting is associated with lower mortality.
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Different hemodynamic effects of IABP, primarily affecting arterial blood pressure, and LV
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venting techniques, chiefly affecting cardiac cycle volumes, may account for the observed differences in efficacy. However, the extent to which this effect is related to the specific approach employed (i.e. targeting afterload vs preload) or to the degree of unloading attained is unknown. Indeed, afterload group included studies reporting on IABP as the only adjunct device to VAECMO, while in the preload group a variety of devices was employed, most of these being highly effective pumps. While IABP modestly reduces pulmonary artery wedge pressure (PAWP) at most by 4-5 mmHg27, Impella pump may reduce PAPWP by 7-10 mmHg2,39 and left atrial venting by 417 mmHg47: this “gradient” of expected LV decompression is coherent with the results of the network meta-analysis.
Journal Pre-proof Our findings reinforce the notion that any unloading strategy resulted superior to no unloading in VA-ECMO patients with regard to mortality, but LV unloading by means of preload reduction resulted better than afterload reduction.
Limitations Inherent limitations of network meta-analysis are those of included studies: as no
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randomized trial is ongoing or is planned to our knowledge, cohort studies represent the best available evidence on this clinical scenario to date. Nevertheless, many studies include a limited number of patients: to limit the small-study effect we excluded those with <20 patients per group.
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Moreover, venting techniques
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Conclusions
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In conclusion, any unloading strategy in VA-ECMO patients was associated with lower mortality as compared to no unloading. A strategy of LV unloading based on preload reduction
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resulted superior to afterload reduction in this network meta-analysis. Based on the results of this
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analysis a combined strategy embodying LV unloading in VA-ECMO recipients is strongly warranted, possibly preferring preload targeting devices.
Journal Pre-proof Figure 1 – Consort diagram for study selection (Panel A). Network map for meta-analytic treatments comparison (Panel B): solid lines represent direct comparisons, dashed lines indirect comparisons.
Figure 2 – Forrest plot of death endpoint meta-analysis.
Figure 3 – Pressure-volume loops (PVL) changes with VA-ECMO. Panel A: green loop represents
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baseline conditions; VA-ECMO flow increases LV afterload and end-systolic point (ESP). As contractile reserve is almost absent in failing left ventricle (LV), the ESPVR slope cannot change.
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In consequence, the effective arterial elastance (Ea) that always intersects the ESPVR at the ESP
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level, shifts right towards higher LVEDV (red arrow). This causes the entire LV PVL to move rightward and upward (yellow loop) towards higher EDV and EDP via the Frank-Starling
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mechanism (Panel B). EDP – end-diastolic pressure; EDPVR – end-diastolic pressure volume
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ESV – end-systolic volume.
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relationship; EDV – end-diastolic volume; ESPVR – end-systolic pressure volume relationship;
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Luca Baldetti: Conceptualization; Luca Baldetti, Mario Gramegna, Alessandro Beneduce, Francesco Moroni: Data curation; Luca Baldetti, Francesco Moroni: Formal analysis;
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Luca Baldetti, Mario Gramegna: Investigation; Luca Baldetti, Francesco Melillo: Methodology;
Anna Mara Scandroglio, Evgeny Fominskiy, Giulio Melisurgo: Supervision;
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Federico Pappalardo: Validation;
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Luca Baldetti, Evgeny Fominskiy: Roles/Writing - original draft;
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Luca Baldetti, Francesco Calvo, Anna Mara Scandroglio, Silvia Ajello: Writing - review & editing.
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Study
Indications
Patients Total
ECMO
ECMO + Unloading
Venting approach
In-Hospital Mortality
Complications
Routine n.a. Routine/Bail-out Routine Routine/Bail-out n.a. Routine/Bail-out n.a. Bail-out Bail-out Routine n.a. n.a. Bail-out
24 (63) 1038 (63) 29 (17) 137 (53) 79 (52) 167 (76)* 34 (57) 254 (48)† 67 (63) 51 (53) 45 66 (67) 41 (68) 44 (51)
Bail-out n.a. Routine/Bail-out
131 (58) 114 (73) 46 (70)
92 (41) 49 (31) 33 (50)
Bail-out n.a. Routine/Bail-out
45 (23) 50 (71) 30 (62)*
4 (6)
Bleeding
RRT
34 (89)
15 (25)
14 (37) 406 (25) 28 (17) 182 (70) 68 (45) 122 (56) 24 (40)
34 (35) 180 (71)
26 (10)
IABP Aoyama et al Aso et al Barge-Caballero et al Bréchot et al Chen et al Doll et al Kai Chen et al Lin et al Overtchouk et al Park et al Ro et al Sakamoto et al Tepper et al Wang et al Akanni et al Pappalardo et al Patel et al Alghanem et al Ok et al Shmack et al
ACS ACS, AHF, Others ACS, PCS ACS, AHF, Others PCS PCS PCS PCS, AHF, ACS, Other ACS ACS PCS, AHF, ACS, Other ACS PCS, others PCS PCS, ACS, Others ACS ACS Pediatric ACS, PCS, Others AHF, Others
38 1650 169 259 152 219 60 529 106 96 253 98 60 87 225 157 66
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o J 194 70 48
3 (8) 1046 (63) 96 (57) 155 (60) 75 (49) 75 (34) 0 227 (43) 42 (40) 55 (57) 193 (76) 4 (4) 30 (50) 46 (53) 196 (87) 123 (78) 36 (55)
35 (92) 604 (37) 73 (43) 104 (40) 77 (51) 144 (66) 60 (100) 302 (57) 64 (60) 41 (43) 60 (24) 94 (96) 30 (50) 41 (47)
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e
r P
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57 (34) 24 (16)
19 (32) 22 (25)
Impella 29 (13) 34 (22) 30 (45)
57 (25) 39 (25) 7 (11)
LA Decompression 173 (89) 45 (64) 28 (58)
21 (11) 25 (36) 20 (42)
Table 1 – Summary of selected studies. Legend: ACS – acute coronary syndrome; AHF – acute heart failure; ECMO – ExtraCorporeal Membrane Oxygenation; IABP – intra-aortic balloon pump; LA – left † atrium; O – others; PCS – postcardiotomy shock; RRT – renal replacement therapy; RUPV – right upper pulmonary vein. *30-day mortality; 2-weeks mortality.
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Table 2 – League table with respect of death outcome (upper part). Green colour indicates favourable and red unfavourable odds ratios (OR) with respective 95% confidence intervals. In the lower part, probability ranks with respect of death outcome are reported. The Surface Under the Cumulative Ranking (SUCRA) values represent the cumulative probability from each treatment being the best with regard to death outcome (the closer to 100% the value is, the higher the
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likelihood that a therapy is in the top rank). Mean rank represents the likely ranking of each treatment.
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Death outcome odds ratio according to type of unloading No unloading 0.66 (0.51, 0.85) 0.35 (0.20, 0.60) 1.52 (1.17, 1.97) Afterload reduction 0.53 (0.29, 0.98) 2.85 (1.66, 4.91) 1.88 (1.03, 3.43) Preload reduction Best treatment probability rankings Treatment SUCRA (%) Mean Rank No unloading 0.1 3.0 Afterload reduction 51.0 2.0 Preload reduction 1.0 98.9
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Highlights
VA-ECMO increases LV afterload, leading to LV distention and pulmonary congestion. Mechanical unloading (either reducing afterload or preload) reduces this risk. No comparison between afterload-reducing vs preload-reducing techniques is available. In this meta-analysis any mechanical LV unloading was confirmed better than none.
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In this network meta-analysis preload reduction was superior to afterload reduction.
Figure 1
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Figure 3