ESC HEART FAILURE ORIGINAL ARTICLE ESC Heart Failure 2023; 10: 568–577 Published online 11 November 2022 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.14132 Time course, factors related to, and prognostic impact of venoarterial extracorporeal membrane flow in cardiogenic shock Santiago Montero1,2 , Mercedes Rivas-Lasarte3, Florent Huang2, Juliette Chommeloux2, Pierre Demondion4,5, Nicolas Bréchot2,5, Guillaume Hékimian2,5, Guillaume Franchineau2,5, Romain Persichini6, Charles-Édouard Luyt2,5, Cosme Garcia-Garcia1, Antoni Bayes-Genis1, Guillaume Lebreton4,5, Juan Cinca7, Pascal Leprince4,5, Alain Combes2,5, Jesus Alvarez-Garcia8 and Matthieu Schmidt2,5* 1 Acute Cardiovascular Care Unit, Cardiology, Hospital Germans Trias i Pujol, Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain; 2Medical Intensive Care Unit, Assistance Publique–Hôpitaux de Paris, Pitié–Salpêtrière Hospital, Paris Cedex 13, France; 3Advanced Heart Failure and Heart Transplant Unit, Cardiology Department, Hospital Universitario Puerta de Hierro Majadahonda, CIBERCV, Madrid, Spain; 4Thoracic and Cardiovascular Department, Assistance Publique– Hôpitaux de Paris, Pitié–Salpêtrière Hospital, Paris Cedex 13, France; 5Institute of Cardiometabolism and Nutrition, Sorbonne Université, INSERM UMRS_1166-iCAN, 75651, Paris Cedex 13, France; 6Medical–Surgical Intensive Care Unit, CHU de La Réunion, Felix-Guyon Hospital, Saint Denis, La Réunion, France; 7Cardiology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; and 8Cardiology Department, Hospital Ramón y Cajal, Centro de Investigación en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain Abstract Aims Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is currently one of the most used devices in refractory cardiogenic shock. However, there is a lack of evidence on how to set the ‘optimal’ flow. We aimed to describe the evolution of VA-ECMO flows in a cardiogenic shock population and determine the risk factors of ‘high-ECMO flow’. Methods and results A 7 year database of patients supported with VA-ECMO was used. Based on the median flow during the first 48 h of the VA-ECMO run, patients were classified as ‘high-flow’ or ‘low-flow’, respectively, when median ECMO flow was ≥3.6 or <3.6 L/min. Outcomes included rates of ventilator-associated pneumonia, ECMO-related complications, days on ECMO, days on mechanical ventilation, intensive care unit and hospitalization lengths of stay, and in-hospital and 60 day mor- tality. Risk factors of high-ECMO flow were assessed using univariate and multivariate cox regression. The study population included 209 patients on VA-ECMO, median age was 51 (40–59) years, and 78% were males. The most frequent aetiology lead- ing to cardiogenic shock was end-stage dilated cardiomyopathy (57%), followed by acute myocardial infarction (23%) and fulminant myocarditis (17%). Among the 209 patients, 105 (50%) were classified as ‘high-flow’. This group had a higher rate of ischaemic aetiology (16% vs. 30%, P = 0.023) and was sicker at admission, in terms of worse Simplified Acute Physiology Score II score [40 (26–58) vs. 56 (42–74), P < 0.001], higher lactate [3.6 (2.2–5.8) mmol/L vs. 5.2 (3–9.7) mmol/L, P < 0.001], and higher aspartate aminotransferase [97 (41–375) U/L vs. 309 (85–939) U/L, P < 0.001], among others. The ‘low-flow’ group had less ventilator-associated pneumonia (40% vs. 59%, P = 0.007) and less days on mechanical ventilation [4 (1.5–7.5) vs. 6 (3–12) days, P = 0.009]. No differences were found in lengths of stay or survival according to the ECMO flow. The multivariate analysis showed that risk factors independently associated with ‘high-flow’ were mechanical ventilation at cannulation [odds ratio (OR) 3.9, 95% confidence interval (CI) 2.1–7.1] and pre-ECMO lactate (OR 1.1, 95% CI 1.0–1.2). Conclusions In patients with refractory cardiogenic shock supported with VA-ECMO, sicker patients had higher support since early phases, presenting thereafter higher rates of ventilator-associated pneumonia but similar survival compared with patients with lower flows. Keywords Cardiogenic shock; Extracorporeal membrane oxygenation; ECMO flow; Mechanical ventilation; Outcome Received: 31 March 2022; Revised: 6 August 2022; Accepted: 18 August 2022 *Correspondence to: Matthieu Schmidt, MD, PhD, Médecine Intensive Réanimation, iCAN, Institute of Cardiometabolism and Nutrition, Hôpital de la Pitié–Salpêtrière, 47, bd de l’Hôpital, 75651 Paris Cedex 13, France. Tel: +33 (0)142162937; Fax: +33 (0)1 42163817. Email: matthieu.schmidt@aphp.fr Dr Jesus Alvarez-Garcia and Dr Matthieu Schmidt contributed equally to this study. © 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Time course of ECMO flow in cardiogenic shock 569 Introduction CS was defined as sustained systolic blood pressure < 90 mmHg or requiring vasoactive drugs to main- Refractory cardiogenic shock (CS) represents the worst clini- tain it ≥90 mmHg, with concomitant evidence of tissue cal scenario of acute heart failure, consisting of profound sys- hypoperfusion.12,13 CS was considered refractory when temic hypoperfusion due to a primary cardiac dysfunction.1,2 acute cardiovascular failure developed despite high-dose In such cases, venoarterial extracorporeal membrane oxygen- catecholamine infusion (epinephrine ≥ 1 μg/kg/min or ation (VA-ECMO) has arisen as one of the most used devices dobutamine ≥ 15 μg/kg/min or norepinephrine ≥ 1 μg/kg/ for mechanical circulatory support (MCS), given its ease of min). Exclusion criteria were patients aged <18 or deployment and widespread availability.3,4 >75 years old, cannulated during cardiopulmonary resuscita- Management of VA-ECMO requires a high level of exper- tion, post-cardiotomy, or patients with atypical CS aetiol- tise and appropriate assessment of multiple elements, ogies. In addition, we excluded patients in cardiac arrest that including ventilator parameters, sedation, anticoagulation, required intubation before starting ECMO, those with ECMO pharmacokinetics, and optimal VA-ECMO performance to for ≤24 h, and patients who were transferred late to our cen- avoid complications. In VA-ECMO-supported patients, the tre without information about mechanical ventilation (MV) blood flow goes in a non-physiological, retrograde direction details of the early part of the ECMO run. Moreover, patients that increases left ventricular (LV) afterload and LV with no data regarding ECMO flow on Days 1 (D1) and 2 (D2) end-diastolic pressure, thus favouring the development of were also excluded (see Supporting Information, Table S1 for pulmonary oedema. The drawbacks of this ‘reverse’ flow additional information regarding basal characteristics of the have been consistently reported,5,6 and several strategies to latter). ‘unload’ the left ventricle have been proposed.7,8 Pharmaco- The study complies with the Declaration of Helsinki and is logical unloading with inotropic drugs and reduction of the in accordance with the ethical standards of our hospital’s in- VA-ECMO flow are commonly the first steps.9 Nevertheless, stitutional review board and French law. Informed consent these measures are often insufficient, and additional was not necessary due to the retrospective and observational unloading with devices such as intra-aortic balloon pump design of this study. The National Commission for Informatics (IABP) or Impella is frequently needed. The choice of the and Liberties approved this study (No. 1950673). unloading strategy usually depends on the clinician’s experi- ence, centre availability, and CS aetiology. Moreover, refractory CS is a dynamic clinical condition that demands Extracorporeal membrane oxygenation continuous assessment of the VA-ECMO performance. management However, there is a lack of evidence on what the ‘optimal’ ECMO flow is, and how it can be assessed. Because a reason- VA-ECMO cannulas were inserted by trained cardiovascular able strategy would consist of assuring ‘the minimum flow to surgeons with femoral–femoral 23F to 29F–15F to 18F cannu- maintain organ perfusion’,10 a sustained high flow beyond las as previously described.14 An additional 7F catheter was the early phases of CS could turn out to be deleterious. systematically inserted into the femoral artery to prevent In the present work, we sought to describe the evolution leg ischaemia. For highly unstable patients, our mobile ECMO of VA-ECMO flow in a CS population according to the degree team travelled to primary-care hospitals to implant the de- of support (‘low-flow’ vs. ‘high-flow’) during the first 48 h. vice at the bedside and to transport the patient to our centre. Secondly, we analysed the unloading strategy, the factors as- The management of VA-ECMO, including ECMO flow, sociated with ‘high-flow’, and the impact on short-term depended on the physician in charge. As is usual practice in outcomes. our centre, most patients were initially managed with an unloading strategy that usually began with implantation of an IABP combined with ECMO in the contralateral femoral access, at the same time as VA-ECMO implantation. If despite routine unloading measures, the patient develops progres- Methods sive pulmonary oedema or the aortic valve opens only sporadically, we would consider upgrading to Impella. Study population and design This is a retrospective, single-centre study including patients Data collection in refractory CS supported with peripheral VA-ECMO admitted at La Pitié-Salpêtrière University Hospital in Paris between 1 At intensive care unit (ICU) admission, we collected demo- January 2010 and 31 December 2016. The database for this graphic information, cardiovascular risk factors, main comor- study has previously been used to analyse the impact of an bidities, and Simplified Acute Physiology Score (SAPS) II. awake VA-ECMO strategy published elsewhere.11 During the pre-ECMO period, the Sequential Organ Failure ESC Heart Failure 2023; 10: 568–577 DOI: 10.1002/ehf2.14132 570 S. Montero et al. Assessment (SOFA) score, the Survival after Veno-Arterial Results ECMO (SAVE) score,15 the inotrope score, the Interagency Registry for Mechanically Assisted Circulatory Support Clinical characteristics and time course of (INTERMACS) classification, the Society for Cardiovascular extracorporeal membrane oxygenation flow in Angiography and Interventions (SCAI) classification of CS,16 the study population cannulation by the mobile ECMO team, haemodynamic pa- rameters, blood–gas analysis, renal and liver functions, left Two hundred and nine patients were included in the analysis ventricular ejection fraction (LVEF), and intubation status (Figure 1). Overall, the median age was 51 (40–59), where were noted. Because all patients had digitized medical charts, 78% were males, and the median SAPS II was 51 (32–66) (Ta- ECMO flow, intubation and MV status, and need of renal re- ble 1). The most frequent aetiology leading to CS was placement therapy (RRT) were recorded daily for a maximum end-stage dilated cardiomyopathy (DCM) (57%), followed by of 14 days on ECMO. According to the time on MV during the acute myocardial infarction (AMI) (23%) and fulminant myo- ECMO run, patients were categorized as ‘awake’ or ‘non- carditis (17%). awake’ ECMO when time on invasive MV was ≤50% or One hundred and four (50%) patients were classified as >50% of the total time on VA-ECMO run, respectively, as de- ‘low-flow’ and 105 (50%) as ‘high-flow’. In general, the me- scribed previously.11 dian ECMO flow showed a tendency to decrease, from the Based on the median flow through the first 48 h of initial 3.7 (3.0–4.2) L/min on Day 1 to 3.2 (2.7–3.8) L/min VA-ECMO run of the whole cohort, patients were classified on Day 6. Median flows between both groups were as ‘high-flow’ or ‘low-flow’ if ECMO flow was ≥3.6 or continuously lower in ‘low-flow’ patients at any time point, <3.6 L/min, respectively. with the ‘low-flow’ group maintaining VA-ECMO flows around 3.0–3.1 L/min. Figure 2A shows the evolution of the VA-ECMO support during the first 14 days for these groups. Compared with the ‘low-flow’ patients, those with ‘high-flow’ Outcomes had similar demographic and cardiovascular risk profiles, but ischaemic aetiology was more frequent. Moreover, they had Complications during ECMO support included rates of greater ICU severity scores and a lower SAVE score. In ventilator-associated pneumonia (VAP), stroke, leg ischaemia, addition, MV at cannulation and cannulation by the mobile bacteraemia, cannula site infection, vena cava thrombosis, ECMO unit was more frequent in the ‘high-flow’ group and conversion to central ECMO. We also reported days on (Table 1). ECMO, days on MV, and ICU and hospitalization length of stay. Lastly, bridge to heart transplant (HTx), time from ECMO to HTx, and in-hospital and 60 day mortality were noted. Factors related to high extracorporeal membrane Details about ECMO-related complications are reported in oxygenation flows the supporting information. In the multivariate analysis, MV at implantation and pre-ECMO lactate were independently associated with high ECMO-flows {with respective odds ratio [OR] 3.9 [95% confi- Statistical analysis dence interval (CI) 2.1–7.1], P < 0.001 and 1.1 [95% CI 1.0– 1.2], P < 0.001}. Continuous variables were expressed as median [interquartile range (IQR)] and compared with Wilcoxon rank-sum tests. Categorical variables were expressed as numbers (percent- Extracorporeal membrane oxygenation age) and compared with χ 2 tests. management To identify the factors related to ‘high-flow’ support, a multivariate stepwise logistic regression model was con- More than 40% of all patients were managed with an structed including the baseline variables found to be associ- awake strategy, with a higher rate in the ‘low-flow’ group ated in the univariate analysis with a P value < 0.10. (52% vs. 30%, P < 0.001). Additionally, 54% required RRT, Kaplan–Meier curves were used to evaluate the associa- with higher needs in the ‘high-flow’ group (41% vs. 66%, tion between the VA-ECMO flow classification with 60 day P < 0.001). mortality. Almost 70% of the study population was managed with All statistical tests were two-sided, with a P value ≤ 0.05 LV unloading with no differences between the two groups considered significant. Statistical analysis was computed with (Table 1). Regarding the type of LV unloading, IABP was the STATA software, Version 13.1 (Stata Corp, College Station, most employed device (94%). Baseline characteristics were Texas). similar among the non-unloaded and unloaded subgroups, ESC Heart Failure 2023; 10: 568–577 DOI: 10.1002/ehf2.14132 Time course of ECMO flow in cardiogenic shock 571 Figure 1 Flow chart of the study population. CS, cardiogenic shock; D1, Day 1; D2, Day 2; eCPR, ECMO-rescued cardiopulmonary resuscitation; MV, mechanical ventilation; VA-ECMO, venoarterial extracorporeal membrane oxygenation. except for the predominance of males (83% vs. 67%, found in the ICU length of stay or the days of hospitaliza- P = 0.011) and non-myocarditis aetiology in the unloaded tion. The ‘low-flow’ group was more frequently bridged to subgroup (Supporting Information, Table S2). Unloaded transplant during the index admission (33% vs. 18%, patients were managed with higher flows (Figure 2B) and P = 0.015), with no differences in rates of bridging to left higher doses of inotropic drugs from Day 3 to Day 5, and they ventricular assist device (LVAD) (24% vs. 20%, P = 0.481) were also more frequently managed with an awake ECMO (Table 2). strategy (47% vs. 29%, P = 0.012) (Supporting Information, On the other hand, non-unloaded patients were less fre- Table S3). quently bridged to HTx (21% vs. 41%), and the waiting time from ECMO implantation to HTx was significantly shorter [5 (1–15) days vs. 13 (5–165) days, P = 0.031]. Outcomes accord- Outcomes ing to mechanical LV unloading are reported in Supporting In- formation, Table S3. Half of the study population presented with at least one VAP Comparison among in-hospital survivors did not show sig- during admission, followed by cannula site infection (42%) nificant differences in either MV or VA-ECMO duration nor and bacteraemia (30%). Patients with ‘high-flow’ had more in ICU or hospitalization length of stay. In-hospital survivors VAP and leg ischaemia episodes than ‘low-flow’ patients, did not present significant differences in rates of transplant but fewer bacteraemia and cannula site infections. or LVAD (Supporting Information, Table S4). The median length of VA-ECMO support was 9 (5–15) Finally, in-hospital mortality of the study population was days, with no differences between groups. The median 46%, with a non-significant lower mortality rate in the ‘low- length of time on MV was 4 (2–10) days, with a signifi- flow’ group (41% vs. 51%, respectively, P = 0.144). Mortality cantly shorter time in the ‘low-flow’ group [4 (1.5–7.5) vs. at 60 days was comparable in the two groups (log-rank 6 (3–12) days, P = 0.009, respectively]. No differences were P = 0.222) (Figure 3). ESC Heart Failure 2023; 10: 568–577 DOI: 10.1002/ehf2.14132 572 S. Montero et al. Table 1 Baseline characteristics and outcomes of the study population according to the median VA-ECMO flow in the first 48 h Variable Study population (n = 209) Low-flow (n = 104; 50%) High-flow (n = 105; 50%) P value Age, years 51 (40–59) 51 (37–58) 52 (42–61) 0.194 Male sex 162 (78) 80 (77) 82 (78) 0.839 Body mass index 25.2 (23.1–27.8) 25.2 (22.2–27.6) 25.3 (23.4 29.4) 0.216 Diabetes mellitus 48 (23) 24 (23) 24 (23) 0.970 Dyslipidaemia 38 (18) 15 (14) 23 (22) 0.161 Pre-ECMO data Aetiology 0.023 Dilated cardiomyopathy 119 (57) 69 (66) 50 (48) Acute myocardial infarction 48 (23) 17 (16) 31 (30) Fulminant myocarditis 36 (17) 14 (13) 22 (21) Other 6 (3) 4 (4) 2 (2) SAPS II 51 (32–66) 40 (26–58) 56 (42–74) <0.001 APACHE II 23 (12–32) 15 (9–28) 29 (17–35) <0.001 SOFA pre-implantation 10 (6–13) 8 (5–12) 12 (8–14) <0.001 SAVE score 3 ( 8 to 1) 1 ( 5 to 1) 6 ( 10 to 0) <0.001 INTERMACS category 0.047 I 115 (55) 49 (48) 66 (63) II 79 (38) 44 (43) 35 (33) SCAI classification <0.000 Stage D 59 (28) 44 (42) 15 (14) Stage E 150 (72) 60 (58) 90 (86) MV at implantation 114 (55) 38 (37) 76 (73) <0.001 Inotrope score, μg/kg/min 37 (11–102) 18 (11–72) 57 (15–128) 0.029 pH 7.41 (7.26–7.46) 7.43 (7.36–7.49) 7.35 (7.20–7.44) <0.001 Lactate pre-ECMO, mmol/L 4.5 (2.5–7) 3.6 (2.2–5.8) 5.2 (3–9.7) <0.001 LVEF, % 15 (10–20) 15 (10–15) 15 (10–20) 0.144 Creatinine, mmol/L 135 (100–185) 125 (98–175) 147 (105–196) 0.078 AST, U/L 158 (52–720) 97 (41–375) 309 (85–939) <0.001 Bilirubin, mmol/L 25 (14–39) 22 (13–36) 26 (15–41) 0.249 Mobile ECMO unit 62 (30) 22 (21) 40 (38) 0.007 Management ECMO flow D3, L/min 3.5 (2.9–4.2) 3.1 (2.6–3.5) 4.2 (3.6–4.7) <0.001 ECMO flow D5, L/min 3.3 (2.8–4) 3.1 (2.6–3.4) 3.7 (3.2–4.3) <0.001 ECMO flow D7, L/min 3.3 (2.7–3.9) 3.1 (2.7–3.5) 3.7 (2.9–4.3) 0.001 ECMO flow D14, L/min 3.5 (2.8–4) 3.2 (2.7–3.8) 3.7 (2.9–4.2) 0.13 LV unloading 139 (67) 72 (69) 67 (64) 0.406 a Awake status <0.001 Awake 85 (41) 54 (52) 31 (30) Non-awake 124 (59) 50 (48) 74 (70) RRT 112 (54) 43 (41) 69 (66) <0.001 Note: Values are expressed as median (interquartile range) or n (%). Abbreviations: APACHE II, Acute Physiology And Chronic Health Eval- uation II; AST, aspartate aminotransferase; D1, Day 1; D2, Day 2; D3, Day 3; D4, Day 4; D5, Day 5; D6, Day 6; D7, Day 7; D14, Day 14; ECMO, extracorporeal membrane oxygenation; INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; LV, left ventricular; LVEF, left ventricular ejection fraction; MV, mechanical ventilation; RRT, renal replacement therapy; SAPS II, Simplified Acute Physiology Score II; SAVE, Survival after Veno-Arterial ECMO; SOFA, Sequential Organ Failure Assessment. Definition: ≤50% of the time of ECMO support without MV or >50% of the time of ECMO support with MV. a Discussion the high-flow group. The independently associated factors with higher ECMO support in the first 48 h were MV at im- Main findings plantation and pre-ECMO lactate. Finally, the decision of adding LV unloading was influenced by the aetiology of CS To the best of our knowledge, this is the largest study to re- but did not affect survival in our cohort. port the time course, factors related to, and prognostic im- Nowadays, there is a lack of solid recommendations re- pact of ECMO flow on patients with VA-ECMO-supported re- garding the proper VA-ECMO flow throughout the different fractory CS. In our population, sicker patients at ECMO phases of CS. There is a variety of clinical practice recommen- cannulation were managed with higher flows from early dations ranging from 60–80 mL/kg17 to 50–70 mL/kg,18 or stages and the divergence of ECMO flows was kept from ini- even 5 L/min during the first 24 h.19 However, reported data tial assessments during the first week of support. Whereas on VA-ECMO flows in MCS literature are scarce and the so-called ‘high-flow’ group had higher rates of VAP, the heterogeneous.19–21 Theoretically, the amount of flow ‘low-flow’ had higher rates of ‘awake ECMO’ management needed may vary widely throughout VA-ECMO support de- and fewer days of MV but eventually did not have signifi- pending on the CS phase and the clinical profile of patients. cantly different short-term survival when compared with Thus, patients with a more profound CS at admission are sup- ESC Heart Failure 2023; 10: 568–577 DOI: 10.1002/ehf2.14132 Time course of ECMO flow in cardiogenic shock 573 Figure 2 VA-ECMO support during the first 14 days showing the VA-ECMO flow in the ‘low flow’ vs. ‘high flow’ and unloaded vs. non-unloaded groups. (Panel A) Differences in VA-ECMO flow are overt during the first 3 days, reaching differences of 1 L/min between groups. Thereafter, differences began to shorten, mainly from D5. (Panel B) The VA-ECMO flows are not different in the early phases according to the unloading, but, thereafter, they tended to be lower in the ‘non-unloaded’ group. The predominance of myocarditis, the lesser bridge to transplant in the index admission, and the lesser ino- tropic support in early phases in the latter might suggest a perception of a lower severity by the treating physicians or a presumed prompt ECMO explantation because of a nearly expected heart transplant or in self-limited aetiologies like myocarditis. ECMO, extracorporeal membrane oxygenation. posed to require a higher degree of VA-ECMO support, at the classical marker of tissular hypoperfusion. As such, the least in the early phase. Similarly to our results, Truby et al. higher levels of lactate at cannulation in sicker patients may reported a median flow of 3.61 ± 0.84 L/min in the first 2 h be logically associated with a higher degree of support in in a study evaluating LV distension.21 the early phases. Patients mechanically ventilated at Not surprisingly, the independent factors related to early VA-ECMO implantation are usually sicker, so again higher ‘high-flow’ were both related to clinical severity. Lactate is flows appear logical. Furthermore, MV at cannulation ap- ESC Heart Failure 2023; 10: 568–577 DOI: 10.1002/ehf2.14132 574 S. Montero et al. Table 2 Complications and outcomes of the study population most constant around 3.0–3.1 L/min in the ‘low-flow’ group. according to the median VA-ECMO flow in the first 48 h From D4 to D5, the differences began to decrease but re- Study Low-flow High-flow mained constant until the end of the first week. Interestingly, population (n = 104; (n = 105; P despite having achieved practical normalization of levels of (n = 209) 50%) 50%) value lactate, the ‘high-flow’ group kept a higher degree of VA- Complications VAP 104 (50) 42 (40) 62 (59) 0.007 ECMO support after the acute phase was over, likely because Stroke 35 (17) 18 (17) 17 (16) 0.829 of an increased perception of severity by the physicians in Leg ischaemia 33 (16) 11 (11) 22 (21) 0.04 charge. Nevertheless, whether the worse prognosis was re- Bacteraemia 63 (30) 39 (37) 24 (23) 0.021 Cannula site 87 (42) 52 (50) 35 (33) 0.015 lated to the initial greater severity or rather to the pulmonary infection effects of higher afterload remains uncertain and warrants Conversion to 17 (8) 7 (7) 10 (10) 0.460 future research. central ECMO Vena cava 32 (15) 15 (14) 17 (16) 0.723 In some circumstances, the severity of CS might drive to thrombosis look for increasing VA-ECMO flows due to the refractoriness Outcome measures of multiorgan failure. However, disproportionately high Days on ECMO 9 (5–15) 9.5 (5.5–17) 9 (5–15) 0.747 Days on MV, total 4 (2–10) 4 (1.5–7.5) 6 (3–12) 0.009 VA-ECMO flows are not useful for improving microcirculation. Days in ICU 22 (12–37) 22 (13–35) 21 (10–37) 0.515 This relates to the well-known lack of relationship between Days of 37 (24–66) 41 (24–70) 36 (21–62) 0.302 macrocirculation and microcirculation22–24 and also corrobo- hospitalization Bridge to 53 (22) 34 (33) 19 (18) 0.015 rates the need of keeping VA-ECMO flow as low as possible transplant on to maintain the aortic valve opened, the mean arterial ECMO admission pressure > 65 mmHg, and normal lactate levels. Bridge to LVAD 46 (22) 25 (24) 21 (20) 0.481 In-hospital 97 (46) 43 (41) 54 (51) 0.144 When comparing unloaded and non-unloaded patients, mortality our findings showed a clear predominance of non-unloading Dead 60-D 70 (34) 31 (30) 39 (38) 0.239 in myocarditis compared with AMI or DCM. Indeed, reduced Note: Values are expressed as median (interquartile range) or n (%). VA-ECMO flow in non-unloaded patients from D2 to D7 is ac- Abbreviations: 60-D, 60 days; ECMO, extracorporeal membrane companied by less pharmacological unloading with dobuta- oxygenation; ICU, intensive care unit; LVAD, left ventricular assist device; MV, mechanical ventilation; VAP, ventilator-associated mine. Likely, that might be explained by a perception of a pneumonia. lower severity by the treating physicians or a presumed prompt ECMO weaning because of an expected HTx or Figure 3 Kaplan–Meier survival curves at 60 days according to the self-limited aetiologies like myocarditis. VA-ECMO support in the first 48 h. Kaplan–Meier survival estimates for The increase in afterload of VA-ECMO has potentially harm- patients with ‘low-flow’ (blue line) and ‘high-flow’ (red line) showed ful consequences at the pulmonary level. Alveolar oedema lower mortality in the ‘low-flow’ group, although not reaching statistical produces local hypoxia, reduces the production of alveolar significance. ECMO, extracorporeal membrane oxygenation. surfactant, produces local vasoconstriction, and, eventually, induces self-perpetuation of the systemic inflammatory re- sponse syndrome (SIRS).25–28 These pulmonary effects may imply ventilator-induced lung injury and prolonged MV.21 In our study, patients within the ‘low-flow’ group had a median of two fewer days of MV than the ‘high-flow’ patients. Al- though there may be clinical confounders, the previous path- ophysiological effects could have contributed to prolonged MV. We believe our study is hypothesis-generating and this fact should be studied in specifically designed studies. Clinical research on LV unloading has developed enor- mously in recent years. However, data on VA-ECMO flow in these studies are generally lacking and, in our opinion, are critical to understand the best time for implantation and to decide the best type of unloading device. In our experience, IABP is generally enough in most patients to unload the LV, especially if care is taken with disproportionate flows and peared independently associated with reduced odds of LV distension.21 In our study, 94% of unloaded patients were ‘awake ECMO’ management,11 and that might also have unloaded with IABP, whereas only 12 patients (9%) needed prognostic importance. Impella. The usefulness of the IABP in reducing afterload Median VA-ECMO flows were more than 1 L higher in the and intraventricular pressures has been known for years, as ‘high-flow’ group during the first 72 h of support, keeping al- well as its effect in reducing pulmonary oedema or days of ESC Heart Failure 2023; 10: 568–577 DOI: 10.1002/ehf2.14132 Time course of ECMO flow in cardiogenic shock 575 MV.29 However, there exists up to seven different methods of were not significantly different compared with patients with unloading,6,8,30 from which the combination of VA-ECMO and lower flows. Independently related factors with a higher de- Impella (i.e. ECMELLA/ECPELLA) has recently gained strong gree of VA-ECMO support were MV at cannulation and attention.30–34 In most of these studies, the mortality risk pre-ECMO lactate. Future research is now warranted to ad- was reduced when unloading was added, yet the high rates dress the specific and direct impact of higher flows in lung in- of complications make its routine applicability dubious. At jury or length of MV, as well as the best timing and type of present, there is still a lack of a randomized controlled trial unloading strategy for these patients. (RCT) comparing these strategies to define the time of im- plantation and the ideal clinical scenario. In our study, the worse condition of the ‘high-flow’ group Acknowledgements may have led to a greater number of complications. It is known that the probability of infection while on ECMO in- We thank our medical colleagues from the referral centres in creases with the severity of illness before initiation of the Ile-de-France region, French Caribbean, and Reunion MCS,35,36 so higher rates of VAP might have been likely con- islands for reporting thorough and detailed information. We ditioned by that. Yet, the potential impact of the pathophys- thank Theodore Chalkley for his grammatical revisions. iological mechanisms explained above cannot be disregarded, and therefore, our study aims to be suggestive rather than conclusive in terms of respiratory outcomes. Specifically de- signed RCTs evaluating different flow strategies in CS and mo- Conflict of interest dalities of LV unloading are now warranted to test if early CEL reports personal fees from Carmat, Merck, Biomérieux, high flows while on VA-ECMO do impact the length of MV, Thermofischer Brahms, Bayer Healthcare, and Faron; AC re- rates of VAP, or mortality. ports personal fees from Getinge and Baxter; MS received lecture fees from Getinge, Xenios, and Dräger. The other au- Limitations thors declare that they have no competing interests. First, the present study has the inherent limitations of a ret- rospective design. However, we present the largest series of Funding patients supported by VA-ECMO, reporting the VA-ECMO flow data throughout the first 14 days of support. Secondly, S. Montero was funded by a 2016 Clinical Training Grant unavoidable confounding factors prevent the conclusion of awarded by the European Society of Cardiology. The other any definitive association between flows and outcomes. How- authors have no disclosures to declare. ever, even though sicker patients are managed with higher flows, it is plausible that an increased afterload may have an impact on prolonged MV duration or rates of VAP because Supporting information of greater lung injury. Thirdly, VA-ECMO flows are dependent on preload, afterload, impeller revolutions, and static vari- Additional supporting information may be found online in the ables like diameter and cannula length, and we lack this infor- Supporting Information section at the end of the article. mation. Lastly, data on pulmonary congestion (x-ray, B-lines on pulmonary echo, or pulmonary artery catheter Table S1. Baseline characteristics of the excluded population information)37–39 would have enabled the comparison of flow compared to the study population. impact and afterload on pulmonary pathophysiology but Table S2. Baseline characteristics according to the presence were not available for this study. of mechanical left ventricular unloading during VA-ECMO support. Table S3. Management and outcomes according to the pres- Conclusions ence of mechanical left ventricular unloading during VA-ECMO support. In patients with refractory CS supported with VA-ECMO, Table S4. Outcomes of the in-hospital survivors according to sicker patients were managed with higher support from early the early ECMO flow. phases. Patients with high flows had higher rates of VAP and Figure S1. 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