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HOME > Acute Crit Care > Volume 39(4); 2024 > Article
Review Article
Cardiology
Left ventricle unloading during veno-arterial extracorporeal membrane oxygenation: review with updated evidence
Yongwhan Lim1orcid, Min Chul Kim1orcid, In-Seok Jeong2orcid
Acute and Critical Care 2024;39(4):473-487.
DOI: https://doi.org/10.4266/acc.2024.00801
Published online: November 18, 2024

1Division of Cardiology, Department of Internal Medicine, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea

2Department of Thoracic and Cardiovascular Surgery, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea

Corresponding author: Min Chul Kim Division of Cardiology, Department of Internal Medicine, Chonnam National University Hospital, Chonnam National University Medical School, 42 Jebong-ro, Dong-gu, Gwangju 61469, Korea Tel: +82-62-220-6578 Fax: +82-62-223-3105 E-mail: kmc3242@hanmail.net
• Received: July 6, 2024   • Revised: August 25, 2024   • Accepted: September 4, 2024

© 2024 The Korean Society of Critical Care Medicine

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is widely used to treat medically refractory cardiogenic shock and cardiac arrest, and its usage has increased exponentially over time. Although VA-ECMO has many advantages over other mechanical circulatory supports, it has the unavoidable disadvantage of increasing retrograde arterial flow in the afterload, which causes left ventricular (LV) overload and can lead to undesirable consequences during VA-ECMO treatment. Weak or no antegrade flow without sufficient opening of the aortic valve increases the LV end-diastolic pressure, and that can cause refractory pulmonary edema, blood stagnation, thrombosis, and refractory ventricular arrhythmia. This hemodynamic change is also related to an increase in myocardial energy consumption and poor recovery, making LV unloading an essential management issue during VA-ECMO treatment. The principal factors in effective LV unloading are its timing, indications, and modalities. In this article, we review why LV unloading is required, when it is indicated, and how it can be achieved.
Despite advances in medicine, cardiogenic shock (CS) is still a devastating condition with poor prognosis [1]. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a mechanical circulatory support device that is widely used to treat medically refractory CS and cardiac arrest. The use of VA-ECMO has recently increased exponentially in many countries [2], including South Korea [3]. The circulatory support provided by VA-ECMO has both advantages and disadvantages inherent in its structure. It drains blood from the right atrium using a centrifugal pump and perfuses blood into the arterial system after oxygenating it with a membrane oxygenator. With this circuit structure, VA-ECMO supports both the right and left ventricles (LVs) [2] and both the heart and lungs. In addition, because cannulation for VA-ECMO treatment can be performed using femoral vasculature at the bedside, VA-ECMO can be used emergently for extracorporeal cardiopulmonary resuscitation [4].
Peripherally inserted VA-ECMO, however, perfuses the arterial system with retrograde flow toward the LV, which creates an inherent hemodynamic limitation by increasing the afterload and causing LV overload [2,5]. LV overload can have undesirable consequences; therefore, LV unloading is an essential management issue during VA-ECMO treatment. In this article, we review why LV unloading is required, when it is indicated and how it can be achieved.
LV hemodynamics change from normal conditions to CS to VA-ECMO during CS, and LV overload is caused by the interaction of the disease (CS) and the intervention used to treat it (VA-ECMO). A pressure-volume (PV) analysis or PV loop is a classic, but still very useful, tool to describe many aspects of LV hemodynamics in these conditions.
Figure 1 shows PV loops obtained by simulating (https://harvi.online) each condition. By plotting the PV at each LV cycle in the same plane, this analysis provides information about the parameters that determine the stroke volume (preload, contractility and afterload) (Figure 1A) and energetics related to ventricular hemodynamics (Figure 1B) [6,7]. Figure 1C describes transition of LV hemodynamics from normal LV function to the severely impaired LV function seen in CS. The decreased myocardial contractility caused by an acute insult (CS) is reflected by the decreasing slope of end-systolic elastance (Ees) [8] (depicted as red arrow a), which results in a smaller stroke volume (b to b’) despite higher left ventricular end-diastolic volume and pressure (LVEDV and LVEDP, respectively, depicted as black arrow c), a situation explained by the non-linear end-diastolic pressure-volume relationship (EDPVR) [9].
Figure 1D shows the principal changes in LV hemodynamics caused by the application of VA-ECMO for CS. The retrograde flow provided by VA-ECMO increases the afterload, which in turn increases LVEDV and LVEDP, as shown by the right and upward movement of the PV loops. As higher flow is provided by VA-ECMO, more pronounced changes are observed in the PV loops (blue arrow). During this transition, stroke volume and pulse pressure decrease. This constellation of changes in LV hemodynamics is associated with the undesirable clinical consequences of LV overload during VA-ECMO treatment, such as refractory pulmonary edema, absent or weak aortic valve opening with lower pulse pressure, LV distension, blood stagnation, and intracardiac thrombi [10]. In the aspect of energetics, LV overload during VA-ECMO also increases LV energy consumption, as shown by the PV area (PVA) (Figure 1B). PVA reflects both potential energy (PE) and stroke work (SW), so it correlates with myocardial oxygen consumption (MVO2) [6]. VA-ECMO treatment for CS increases PE and decreases SW, which increases PVA overall, reflecting higher MVO2, especially as the VA-ECMO flow and afterload status increase (Figure 1D). An LV distended by increased afterload is associated with both higher O2 consumption and higher wall stress [11]. In addition, higher LV diastolic pressure during VA-ECMO can affect myocardial perfusion [11], which might already be impaired by coronary artery pathology in cases of ischemic cardiomyopathy. The LV overload caused by VA-ECMO can affect not only LV hemodynamics, leading to the clinical consequences mentioned above, but also LV energetics that can theoretically be related to poor recovery of LV function.
A PV loop simulating LV venting during VA-ECMO (Figure 2) provides some insights about the general goals of LV unloading. Although the efficacy of LV unloading might vary according to measures of different hemodynamic mechanisms [12,13], one of the goals of LV unloading is to ameliorate the clinical features of LV overload by lowering LVEDV, LVEDP, and the pulmonary capillary wedge pressure (PCWP). The left and downward movement of a PV loop reflects those changes, with lower LVEDV and LVEDP induced by LV unloading from the more right and upward location of the loop in the VA-ECMO only status. Another goal of LV unloading is to reduce MVO2, which can be measured as a smaller PVA. Currently, limited data from human and animal experimental models suggest that most LV unloading modalities can reduce PVA and thereby MVO2, but the modes of action might differ by modality. Some modalities reduce both PE and SW, whereas others reduce only PE. The variable effects of each LV unloading modality are reviewed below and summarized in Table 1. Some in vivo studies using animal models [15,17] have reported that LV unloading benefits LV energetics, but no direct clinical evidence in humans indicates that LV unloading can improve myocardial recovery.
Data obtained using invasive and non-invasive measures in patients being treated with VA-ECMO suggest that the hemodynamics of LV overload are complex and dynamic and might be affected by many factors, such as volume status, degree of dysfunction in the right or left ventricle, and the course of disease. For example, Jain et al. [18] reported an increase in PVA 15 minutes after VA-ECMO activation, despite a lower LVEDP than at the beginning of VA-ECMO activation, in a patient with dilated cardiomyopathy who presented with refractory CS. They suggested that LV unloading be understood as an intervention to decrease MVO2, not as an intervention to decrease LVEDP (i.e., LV venting). Ezad et al. [13] also advocated for this concept, and this differentiation has useful implications for further exploration. However, it might be conceptual because most measures for LV venting provide LV unloading at the same time [12]. Nonetheless, direct and indirect in vivo hemodynamic data should be used to classify the various modalities as LV unloading or venting without unloading.
The optimal timing for LV unloading during VA-ECMO treatment is still an open question. LV unloading can be performed when any sign of LV overload refractory to medical treatment appears (therapeutic) or prophylactically to prevent LV overload. Mechanical LV unloading can also be performed before medical treatment begins (early) if LV overload signs are present. The optimal timing for LV unloading was studied in two recently published randomized controlled trials (RCTs) [19,20], and it has been thoroughly explored in observational studies and experimental studies using animal models. For example, Solholm et al. [21] showed that porcine models unloaded with LV venting at the beginning of VA-ECMO showed higher LV stroke volume and better mechanical efficiency (defined as the ratio between PVA and myocardial perfusion) 120 minutes after VA-ECMO weaning than pigs treated with VA-ECMO without LV venting. Everett et al. [22] reported interesting data from porcine VA-ECMO models treated with different timings of LV unloading using Impella. In their experiment, lower SW with smaller infarct size was observed only when LV unloading was performed with Impella 30 minutes before VA-ECMO activation; no such effect was seen in the group treated with LV unloading 30 minutes after VA-ECMO activation.
Schrage et al. [23] showed lower 30-day mortality in patients treated with VA-ECMO and LV unloading using Impella, with significantly lower 30-day mortality in the subgroup treated with Impella within 2 hours of VA-ECMO initiation than in the subgroup treated with Impella more than 2 hours after VA-ECMO initiation. The same group reported similar data in 2023: unloading with Impella within 2 hours was associated with lower 30-day all-cause mortality and a higher rate of successful VA-ECMO weaning [24]. Not only did they show an affect with a binary classification (unloading within or after 2 hours), they also showed a continuous increase in the risk of 30-day all-cause mortality as the interval between VA-ECMO initiation and unloading became longer than 2 hours. Another observational study compared prophylactic and therapeutic LV unloading with percutaneous (transseptal LA cannulation) or surgical measures and found lower 30-day mortality (34.4% vs. 5.6%, P=0.036) as the rate of cardiac replacement therapy (such as heart transplantation or a ventricular assist device) increased in the prophylactically unloaded group [25]. In a previous available meta-analysis [26], early LV unloading (within 12 hours) was associated with a lower risk of 30-day mortality, although the unloading measures in the data were heterogeneous, with the largest proportion treated with an intra-aortic balloon pump (IABP).
The hypothetical benefit of prophylactic or early unloading was tested in two recently published RCTs. The EVOLVE-ECMO (Early left atrial venting versus conventional treatment for left ventricular decompression during veno-arterial extracorporeal membrane oxygenation support) trial [20] is the first RCT to compare early and therapeutic LV unloading strategies using transseptal left atrial (LA) cannulation. Patients who already had LV overload signs at the time of VA-ECMO activation were enrolled, and then LV unloading at the time of VA-ECMO activation (early, n=30) was compared with conventional treatment (n=30), in which unloading was performed only for of refractory pulmonary edema despite medical treatment using inotropes, diuretics, or renal replacement therapy. In the EVOLVE-ECMO trial, none of the predefined endpoints, including VA-ECMO weaning as the primary endpoint (70.0% vs. 76.7%; relative risk, 0.91; 95% CI, 0.67–1.25; P=0.386) and survival to discharge (53.3% vs. 50.0%, P=0.796) differed statistically between groups. The only difference between the groups was a better pulmonary congestion score index 48 hours after LV unloading in the early unloading group. The time from VA-ECMO activation to LV unloading was a median of 2.4 hours vs. 48.4 hours in the early and conventional LV unloading groups, respectively. LV unloading was performed in 76.7% of the conventional group. However, the EVOLVE-ECMO trial was a pilot study that enrolled an insufficient number of patients to test the study hypothesis. In addition, because the EVOLVE-ECMO trial enrolled patients with clinically established LV overload signs (significant pulmonary edema on chest radiography; plentiful, frothy, and blood-tinged secretions; or insufficient aortic valve opening) at the time of enrollment, it did not examine the effect of prophylactic LV unloading, i.e., LV unloading before the onset of LV overload caused by VA-ECMO.
The EARLY-UNLOAD trial (early left ventricular unloading or conventional approach after veno-arterial extracorporeal membrane oxygenation), another RCT on this topic, compared an early LV unloading strategy, i.e., performed within 12 hours of VA-ECMO activation (n=58), with the conventional approach (n=58) of performing LV unloading only when LV overload signs appeared [19]. The EARLY-UNLOAD trial enrolled patients with CS who were treated with VA-ECMO regardless of the presence of LV overload signs and aimed to verify the impact of prophylactic unloading before the onset of clinical LV overload signs. In that trial, early routine LV unloading with transseptal LA cannulation performed within 12 hours of VA-ECMO activation (median, 1.1 hours) did not reduce 30-day mortality (46.6% vs. 44.8%; hazard ratio, 1.02; 95% CI, 0.59–1.74; P=0.942), which was the predefined primary endpoint. Rescue LV unloading was performed in 50% of the conventional approach group 21.8 hours (median) after VA-ECMO activation. The secondary endpoints, including the weaning rate from VA-ECMO and mechanical ventilation, did not differ significantly either.
Despite its theoretical benefits and numerous observations in retrospective and experimental studies suggesting that early or prophylactic LV unloading during VA-ECMO treatment would have beneficial effects, the two recently published RCTs failed to show a mortality benefit from early unloading. The optimal timing for LV unloading during VA-ECMO treatment is, therefore, still uncertain, even after the publication of two RCTs. In addition to sample sizes sufficient to prevent underpowering, many other issues need to be addressed in future research to establish a definitive answer to this question. The transseptal LA cannulation used in both RCTs for LV unloading, for example, is not well validated for its efficacy, and this measure does not provide afterload reduction. Although no research has performed a prospective head-to-head comparison of different LV unloading measures, more data have accumulated about LV unloading using measures with afterload reduction, such as Impella or IABP. Refining the target population might be necessary to prove the benefit of early LV unloading. For example, Bak et al. [27] recently showed the benefit of early (<24 hours) LV unloading in fulminant myocarditis. The specific etiology of CS might have a unique hemodynamic profile with a varying time course for recovery that might require different treatment strategies at different times. For example, a population that requires longer maintenance of VA-ECMO treatment without the expectation of LV function recovery (e.g., waiting for cardiac replacement therapy) might benefit from early LV unloading. In addition, neither RCT adopted invasive hemodynamic monitoring to monitor either LV overload or the effect of LV unloading. Discussions about the optimal indications for rescue or therapeutic LV unloading are also needed because the currently suggested indications are based mainly on non-invasive clinical signs. Invasive hemodynamic monitoring might provide better information for determining the time at which therapeutic LV unloading will offer the best prognosis in this population. Despite the many issues mentioned for future research on the timing of LV unloading, the available evidence is currently insufficient to uniformly recommend early or prophylactic LV unloading in CS patients treated with VA-ECMO.
The true incidence of overt LV overload or therapeutic LV unloading during VA-ECMO is uncertain, and the currently recommended indications for LV unloading seem to largely be based on expert consensus without the validation of prospective studies. Russo et al. [28], for example, reported that 42.0% of patients in a meta-analysis of 17 observational studies were treated with LV unloading during VA-ECMO treatment, but information about the indication for LV unloading (pre-emptive or bail-out) was available for only 23% of those patients. Among them, only 15% of patients received LV unloading for therapeutic purposes. In the two recently published RCTs, therapeutic LV unloading was performed in 50% (EARLY-UNLOAD) and 76.8% (EVOLVE-ECMO) of patients. Because LV overload reflects an interaction between a disease (CS) and a therapeutic modality (VA-ECMO), many factors can combine to produce LV overload that requires LV unloading. Variable hemodynamic statuses and courses caused by the heterogeneity of CS etiology and treatment decisions such as the flow of VA-ECMO and volume status management could all affect the incidence of LV overload. In addition, the absence of validated criteria for diagnosing LV overload and inconsistent indications for LV unloading could also explain why the incidence of therapeutic LV unloading varies with the data source.
Therapeutic LV unloading is generally indicated when medically refractory signs of LV overload appear (Figure 3). Pulmonary edema in a chest x-ray or frothy or foamy secretion in an endotracheal tube are the most frequently encountered and convincing clinical signs of LV overload. These signs are usually accompanied by hemodynamic or echocardiographic changes. Pulse pressure, for example, is proportional to stroke volume [29] when other factors can be controlled, and a pulse pressure <10 mm Hg in the early course of VA-ECMO treatment is known to be related to severe pulmonary edema and poor prognosis [30]. Some clinicians use refractory ventricular arrhythmias during VA-ECMO as a clinical sign of LV overload [13], which is theoretically plausible because an LV overloaded by VA-ECMO could have both higher myocardial O2 demand and reduced coronary perfusion, as explained above. However, only one anecdotal case report has supported refractory ventricular arrhythmias as an indication for LV unloading [31], so recommending LV unloading for all cases of refractory arrhythmia is an empirical approach that requires more evidence. Low pulse pressure is related to aortic valve closure or less frequent aortic valve opening and spontaneous echo contrast [32], which are known to be associated with intracardiac thrombi and stroke during VA-ECMO treatment. Although LV distension can be found with serial echocardiography, the non-linear relationship between diastolic pressure and volume [9] makes this parameter too insensitive to detect LV overload. The relationship between LVEDV and LVEDP can be appreciated in Figure 1D, which shows that the PV loops have more rightward and upward movement as the VA-ECMO flow becomes higher. The relationship between LVEDV and LVEDP is non-linear, with a steeper increase of LVEDP at the extreme range of LVEDV. When higher ECMO produces higher afterload, a smaller amount of change in LVEDV could produce a larger change in LVEDP. Expecting higher LVEDP status based on the echocardiographic measurement of the LV chamber size, therefore, would be inadequately sensitive, especially if the chamber compliance is low due to high ECMO flow. Variability in LV diastolic function caused by chronic heart failure or the etiology of CS, which changes the relationship between LVEDP and LVEDV (EDPVR) [33,34], is thus another obstacle to using chamber size with a uniform cut-off as an indicator of LV overload.
Sometimes, it might be difficult to determine whether LV unloading is needed by using clinical, hemodynamic or echocardiographic findings because of discrepancies among the parameters. Some advocate for invasive hemodynamic monitoring using a Swan-Ganz catheter during VA-ECMO treatment [2,13,35] and taking a PCWP above 15 mm Hg as an indication for LV unloading [13,36]. PCWP is known to be a surrogate for preload, and PCWP higher than the normal range is associated with the development of pulmonary edema [37]. Most available LV unloading measures are known to reduce PCWP and ameliorate pulmonary congestion [38,39]. Although PCWP has historically been regarded as a surrogate for LVEDP, many studies suggest significant discrepancies between them [40-44]. Most studies about that discrepancy have focused on populations with pulmonary hypertension, but the discrepancy between PCWP and LVEDP has been consistently observed regardless of pulmonary hypertension [40]. Several factors or situations could be related to the discrepancy. Mitral valve pathologies, for example, can directly alter PCWP and produce this discrepancy. Even in patients without mitral valve pathology, atrial fibrillation, rheumatic valve disease, and a large atrial diameter were shown to be related to overestimation of PCWP, and old age was associated with underestimation of PCWP [42]. Because PCWP has been measured as a mean in most previous studies, the discrepancy between the mean PCWP and LVEDP could be explained, at least in part, by altered atrial or ventricular compliance in some pathologic conditions. In cases of atrial fibrillation, for example, there is loss of a-wave and augmentation of v-wave, especially in cases of reduced atrial compliance, and that mechanism could affect the mean PCWP more than the LVEDP [45]. Although data about the correlation between PCWP and LVEDP in VA-ECMO patients are scarce, the correlation itself seems to be poor and might be affected by ECMO flow, which can directly alter pulmonary circulation and afterload [43]. Given the known discrepancy between PCWP and LVEDP and uncertainty about their correlation in VA-ECMO patients, using PCWP as an indication for LV unloading requires caution and more study.
Lastly, defining indications for LV unloading requires many considerations other than LV overload signs. The procedures for LV unloading have possible complications [23], and the time course for LV function recovery might vary among patients with different etiologies of CS. For that reason, the etiology of CS might be one factor that we should consider before deciding whether (and how) to perform LV unloading. Although it is currently uncertain whether LV unloading is more beneficial for a specific etiology of CS, Kang et al. [34] recently suggested that LV unloading might have differential effects on outcomes of CS with different etiologies, particularly acute myocardial infarction [AMI] vs. non-AMI CS. In their retrospective study, the most frequently used modality for LV unloading was IABP, and the data showed a lower risk of 90-day mortality in non-AMI CS patients treated with LV unloading on top of VA-ECMO than in non-AMI CS patients treated with VA-ECMO alone. However, that finding was not replicated in patients with AMI-CS. Interestingly, non-AMI patients treated with LV unloading were treated with heart transplantation more frequently than AMI patients (45.8% vs. 18.2%, P=0.039), suggesting that LV unloading might have beneficial effects for patients waiting for heart transplantation. On the other hand, in the study performed by Schrage et al. [23], which showed a 30-day mortality benefit from LV unloading using Impella, the subgroup analysis did not show any difference in benefit from LV unloading among the different etiologies of CS, despite a larger sample size.
Therefore, medical treatment to ameliorate LV overload, including optimization of ECMO flow [46], volume status adjustment and increasing positive end-expiratory pressure [47], and the use of medication to reduce afterload (e.g., nitroprusside [48]) or increase contractility(e.g., dobutamine [49]) could be tried [28] (Figure 3) before mechanical LV unloading. Whether those measures ameliorate LV overload might depend on factors such as the native cardiac function remaining, the course of cardiac function recovery, and volume status. The minimal requirement for flow support by VA-ECMO to reverse shock physiology is not well defined, but reducing ECMO flow to lower afterload and increase the frequency of aortic valve opening might not be tolerable in some cases, especially in the early period of VA-ECMO treatment when patients have overt shock physiology without cardiac function recovery. When inotropes are used, an increase in myocardial oxygen demand (rather resting for recovery) might be a concern [50], and its action might depend on cardiac reserve for further contractility. Therefore, efforts to ameliorate LV overload with medical treatment should be based on close monitoring for shock physiology and hemodynamics using multiple modalities (e.g., lactate, echocardiography, and invasive monitoring using Swan-Ganz).
In conclusion, because the two recently published RCTs could not prove the benefit of prophylactic or early LV unloading, despite comparing various timings for LV unloading in patients with LV overload signs [20] or regardless of LV overload signs [19] at the time of enrollment, we do not recommend prophylactic, routine LV unloading at the beginning of VA-ECMO treatment. Instead, we recommend using initial medical therapy to reduce LV overload if any signs of it appear during close monitoring for progression and response to treatment (Figure 3). Others have recommended similar approaches, giving priority to non-invasive or medical treatment before trying invasive LV unloading methods [13,36,47]. Some studies have also advocated that unloading methods be combined, beginning with medical, non-invasive modalities and moving to more invasive options based on the severity of the LV overload signs [47]. Those approaches seem reasonable, though all the suggested approaches require validation before they can be generally recommended. Many uncertainties remain about the benefits of prophylactic (at the beginning of VA-ECMO treatment regardless of LV overload) and early (when LV overload is present but medical treatment has not yet been tried) LV unloading, and these strategies might have unique benefits in some populations with a specific CS etiology (e.g., non-AMI CS) or in some clinical contexts (e.g., relatively long wait for heart transplantation). Further research is needed to determine who could benefit from which strategies. Given the current state of the evidence, determining the refractoriness of LV overload and timing therapeutic LV unloading are still areas of art for physicians who treat patients in this difficult situation.
Despite the publication of many studies exploring how modalities for LV unloading during VA-ECMO treatment affect hemodynamics, LV energetics, and clinical outcomes, no prospective head-to-head comparisons of unloading modalities have been reported. Understanding the accumulated evidence about each modality, however, could give valuable insights for further explorations of LV unloading.
The modalities for LV unloading can be classified based on their modes of action: increasing antegrade flow (IABP and Impella) or not (pulmonary artery drainage [PAD], percutaneous atrial septostomy [PAS], transseptal LA cannulation, and surgical LV venting) (Table 1). Some researchers prefer the term “left heart” unloading or venting over LV unloading because some modalities directly vent the LV, and others vent the left atrium, thus unloading the LV indirectly. This difference could be important in some clinical situations. For example, when severe mitral stenosis produces a difference between PCWP and LVEDP, direct LV unloading might be insufficient to protect the lungs from edema. Furthermore, the risk of Harlequin syndrome might differ between modalities depending on whether they reduce preload without increasing the antegrade flow of unoxygenated blood caused by lungs with pathologic conditions such as pulmonary edema or pneumonia. Detailed explanations for the phenomena of varying unloading modalities have been provided in previous reports [5,51]. We report differences in the degree of LVEDP reduction among the varying LV unloading modalities in Table 1 [15-17,38,47,51].
Although new ways to differentiate LV unloading from venting have been suggested [13,51] based on whether the modality improves LV energetics and myocardial O2 demand, that classification might be arbitrary because most measures benefit LV energetics and LV decompression at the same time, even those that reduce only the preload [16,17]. The modes of action and observed or suggested hemodynamic effects of the various modalities are summarized in Table 1. PV loops from the various unloading modalities, which we reconstructed based on data obtained from animal models [14-17], are shown in Figure 4. A brief review of some representative modalities is provided in this section.
Intra-aortic Balloon Pump
At present, IABP is the device for LV unloading with the most available data [26,28]. Counter-pulsation from IABP during cardiac cycles produces volume displacement within the aorta and decreases the afterload [52]. These actions make IABP feasible for LV unloading during VA-ECMO. In an animal model, IABP on top of VA-ECMO reduced MVO2, mainly by reducing PE [14]. In an observational study in human subjects, IABP seemed to increase the antegrade flow, which was measured using the aortic root volume time integral regardless of the pulse pressure on VA-ECMO (>5 mm Hg or not), with femoral artery flow increasing when the IABP was on [53]. IABP seems to have varying regional hemodynamic effects according to native cardiac function. The left carotid artery flow decreased in patients on VA-ECMO who had pulse pressure ≤5 mm Hg, but not in those with higher pulse pressure [53]. Similarly, cerebral blood flow, measured as the mean of the bilateral middle cerebral artery using transcranial doppler, decreased in patients with pulse pressure <10 mm Hg but increased in patients with pulse pressure ≥10 mm Hg when IABP was turned on [54]. These findings suggest that IABP could have varying regional hemodynamic effects, especially on cerebral blood flow, according to the native cardiac function. IABP also showed PCWP reduction, although the degree of that reduction was smaller than for the other LV unloading measures [38] (IABP: –3.9±1.3 mm Hg vs. PAS: –9.6±2.5 mm Hg vs. transapical catheterization: 17.2±2.1 mm Hg; P<0.001).
The effect of IABP as an LV unloading measure on clinical outcomes is still controversial, and no RCT has tested it. Observational studies and meta-analyses showed that IABP had some favorable effects on short-term mortality (30-day mortality [26] or in-hospital mortality [55]) but none on long-term mortality [26]. Other observational studies [56] and meta-analyses [57] suggested favorable 30-day mortality in patients with AMI-induced CS treated with VA-ECMO and IABP, compared with VA-ECMO alone. Because of its theoretical benefit to coronary perfusion, exploring whether LV unloading using IABP is more beneficial for any specific etiology of CS (e.g., AMI-CS) might be an interesting topic.
Impella
Since the late 2010s, Impella has been a popular modality for LV unloading during VA-ECMO treatment [58]. The Impella CP (Abiomed, providing a maximum flow rate of 3.5 L/min, introducer sheath 14 Fr) is most commonly used [23], but the Impella 2.5 (2.5 L, introducer sheath 13 Fr) and 5.0 (5.0 L/min, introduction sheath 23 Fr) [59] can be used for this purpose in some cases. The combination of Impella and VA-ECMO is called ECMELLA or ECPELLA. The Impella 2.5 and CP can be inserted through the femoral or axillary artery and advanced under fluoroscopic and echocardiographic guidance, but the Impella 5.0 requires surgical placement. All the Impella products actively drain blood from the LV and propel it into the proximal ascending aorta. In addition to the venting effect, which lowers the PCWP in human cases [60], LV unloading with Impella in animal models directly lowers LVEDP and reduces PVA, mainly by reducing PE but not SW, compared with VA-ECMO alone [15]. In that study, the total cardiac work (PVA × heart rate × 10–3) was also reduced by ECPELLA without a reduction in carotid artery flow. Compared with IABP, which depends on remaining LV function for its appropriate action, Impella can increase antegrade flow regardless of LV function because it has an active microaxial pump.
No RCT has shown a mortality benefit from LV unloading with Impella, and previous observational studies [23,58,61] and meta-analyses [62] about ECPELLA show conflicting results about its benefits. Most studies report higher complication rates, including bleeding, access site–related ischemia, and acute kidney injury compared with VA-ECMO alone [23] or IABP [58]. Even in comparisons between Impella and IABP, LV unloading with Impella did not show a mortality benefit [58,61,63,64], but it was consistently associated with a higher complication rate.
Because Impella is currently not available in South Korea, and our group has limited experience with it, we recommend some studies [13,65,66] about using it during VA-ECMO treatment. Some RCTs about LV unloading using Impella are ongoing, and the results of those trials will add more evidence about the safety and efficacy of this device for LV unloading (UNLOAD-ECMO [NCT05577195] and HERACLES [ISRCTN82431978]) (Table 2).
Percutaneous Atrial Septostomy, Transseptal LA Cannulation, and Pulmonary Artery Drainage
PAS can provide LV unloading by reducing the LV preload. Data about PAS are limited to some retrospective analyses with small sample sizes [38,67-69]. In an animal model of CS on VA-ECMO, PAS reduced LVEDP and PVA by reducing both SW and PE [17]. In that study, increasing the VA-ECMO flow elevated LVEDP and PVA in the group without PAS. LVEDP and PVA in the group with PAS, however, was not changed by increased VA-ECMO flow; thus PAS seems to provide a sufficient LV unloading effect even with a high VA-ECMO flow. PAS also reduced PCWP and resolved pulmonary edema [38,68] in human studies.
Another similar LV unloading approach is transseptal LA cannulation. It reduces preload, and thus LA pressure or PCWP [70,71], by actively draining the LA using a cannula connected to a drainage cannula with a Y-connector, which makes a co-drain circuit of both the right and left atria. Although data about this LV unloading measure are limited [72], transseptal LA cannulation is currently in wide use in South Korea and was used for LV unloading in the recently published RCTs from South Korea [20,73]. Transseptal LA cannulation can be used in a form called left atrial-veno-arterial ECMO (LAVA-ECMO), which uses a single transseptal LA cannula for drainage [74] by performing septostomy. LAVA-ECMO can be initiated by removing the original inferior vena cava-right atrium drainage cannula or at the beginning of VA-ECMO treatment if the patient is stable enough for transseptal cannulation without deterioration. Because of the presence of side halls in a drainage cannula, both atria can be drained by a single transseptal drainage cannula. No study has provided information about LV energetics when transseptal LA cannulation is used for LV unloading, though it might be similar to PAS because the principle of unloading is similar. Nonetheless, the effects must be confirmed by an adequate experimental model.
PAD for LV unloading during VA-ECMO has been reported in both pediatric and adult patients using cannulas of various sizes, from 10 Fr [75] or 15 Fr [76] to ProtekDuo [77] (29 Fr to 31 Fr). In a study using an animal model, PAD using a 19 Fr cannula seemed to reduce PVA with SW [16]. In that study, the degree of LVEDP reduction in the PAD group was insignificant but numerically smaller than the reduction in the Impella group (LVEPD; mean: PAD, 0.5 mm Hg vs. Impella, 5.4 mm Hg; P=0.143).
All the modalities for LV unloading mentioned in this section provide some degree of LV unloading by reducing preload to the LV and could provide both venting and unloading effects, with reductions in PCPW and LVEDP and beneficial effects on LV energetics. In addition, these methods can provide direct lung protection in certain circumstances (e.g., severe mitral stenosis) in which Impella or IABP could not provide that benefit. One concern about these unloading methods is their potential to increase the risk of LV or aortic root thrombosis by reducing the preload, stroke volume, and antegrade flow with insufficient aortic valve opening [13]. Although that concern is not supported by the available data, whether these measures can be used to remove or reduce spontaneous echo contrast or blood stagnation is controversial.
Other Methods: Direct LV Venting or Other Surgical Approaches
Direct LV unloading can also be achieved by percutaneous or surgical approaches. Percutaneous transaortic pigtail catheter (7 Fr) insertion under fluoroscopic and transesophageal echocardiographic guidance [78] and a surgical transapical cannula insertion method [79] were introduced, and they both seem effective for resolving LV distension and pulmonary congestion. Variable surgical methods for LV unloading are also available and described elsewhere [80].
The use of VA-ECMO for CS has increased exponentially despite a lack of RCTs to provide supporting evidence. VA-ECMO can produce undesired LV overload via retrograde aortic flow, and LV unloading is indicated in that condition. The goals of LV unloading include reducing both the elevated pressure in the LV that causes clinical signs of LV overload and myocardial energy consumption. The optimal timing, indication, and modality for LV unloading are still uncertain, so further studies are required to create an LV unloading strategy with proven benefit.
▪ Treatment of cardiogenic shock using veno-arterial extracorporeal membrane oxygenation can induce left ventricular (LV) overload through retrograde aortic flow, which increases the afterload.
▪ The goals of LV unloading are to reduce myocardial energy consumption and any elevated LV pressure causing clinical signs of LV overload.
▪ The optimal timing, indications, and modality for LV unloading are still uncertain, and further studies are needed to develop an LV unloading strategy with proven benefit.

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

FUNDING

None.

ACKNOWLEDGMENTS

The authors thank to all the Chonnam National University Hospital ECMO team members for their continuous dedication.

AUTHOR CONTRIBUTIONS

Conceptualization: MCK, ISJ. Methodology: YL, ISJ. Formal analysis: YL. Data curation: MCK, YL. Visualization: MCK, YL. Project administration: MCK, ISJ. Funding acquisition: MCK. Writing-original draft: MCK, YL. Writing-review & editing: MCK, ISJ. All authors read and agreed to the published version of the manuscript.

Figure 1.
Pressure volume curves describing normal left ventricular (LV) hemodynamics (A), pressure-volume area, sum of stroke work, and potential energy (B), cardiogenic shock with a decrease in contractility (arrow a) and stroke volume (b to b’) and an increase in LV end-diastolic volume and pressure (arrow c) (C), and veno-arterial ECMO during cardiogenic shock (D). LVP: left ventricular pressure; LVV: left ventricular volume; Ea: arterial elastance; ESPVR: end-systolic pressure-volume relationship; Ees: end-systolic elastance; EDPVR: end-diastolic pressure-volume relationship; LVEDV: LV end-diastolic volume; PVA: pressure-volume area; PE: potential energy; SW: stroke work; MVO2: myocardial oxygen consumption; ECMO: extracorporeal membrane oxygenation.
acc-2024-00801f1.jpg
Figure 2.
Pressure volume loop simulating left ventricular (LV) venting during veno-arterial extracorporeal membrane oxygenation. LVP: left ventricular pressure.
acc-2024-00801f2.jpg
Figure 3.
Suggestion of possible left ventricular (LV) unloading strategies. “Prophylactic” means unloading before any evidence of LV overload. “Therapeutic” means LV unloading to treat LV overload signs refractory to medical treatment. “Early” means performing mechanical LV unloading prior to medical treatment to ameliorate it. With the currently available evidence obtained from randomized controlled studies, we advocate for therapeutic rather than prophylactic or early LV unloading (the degree of recommendation). VA-ECMO: veno-arterial extracorporeal membrane oxygenation; SEC: spontaneous echo contrast; PCWP: pulmonary capillary wedge pressure: PEEP: positive end-expiratory pressure; CS: cardiogenic shock.
acc-2024-00801f3.jpg
Figure 4.
Pressure-volume loops for varying modalities of left ventricular (LV) unloading. Each modality has a specific mode of action that could have different effects on LV hemodynamics or energetics. CS: cardiogenic shock; ECMO: extracorporeal membrane oxygenation; PAS: percutaneous atrial septostomy; PAD: pulmonary artery drainage. Adapted from data obtained from animal models [14-17].
acc-2024-00801f4.jpg
Table 1.
Characteristics of each LV unloading modality
Modality IABP Impella Direct LV venting PAS PAD Transseptal LA cannulation
Primary mode of action Afterload reduction Active pumping of blood from LV to aorta Preload reduction Preload reduction Preload reduction Preload reduction
Direct LV unloading Yes Yes Yes No No No
Direct lung protection No No No Yes Yes Yes
The risk of Harlequin syndrome Possible Possible Less likely Less likely Less likely Less likely
Increase in antegrade flow Yes Yes No (could decrease) No (could decrease) No (could decrease) No (could decrease)
Dependency on LV function Yes No No No No No
Efficacy for LVEDP reduction + +++++ +++++ +++~++++ +++ ?a)++++
LV energetics
PVA↓ + [14] + [15,16] NAa) + [17] + [16] NAa)
PE↓ (+) (+) NAa) (+) (-) NAa)
SW↓ (-) (-) NAa) (+) (+) NAa)

LV: left ventricular; IABP: intra-aortic balloon pump; PAS: percutaneous atrial septostomy; PAD: pulmonary artery drainage; LA: left atrial; LVEDP: left ventricular end-diastolic pressure; PVA: pressure volume area; NA: not available; PE: potential energy; SW: stroke work.

a)No available data from human or animal experimental model (simulation data was not adopted).

Table 2.
Ongoing RCTs about LV unloading
Trial name (identifier) Inclusion criteria No. of participants Intervention Control Institution Primary outcome Estimated study completion
UNLOAD-ECMO (NCT05577195) Cardiogenic shock 198 Impella+VA-ECMO VA-ECMO only University Heart and Vascular Center, Germany 30-Day all-cause death Dec 1, 2025
HERACLES (iSRCTN82431978) Cardiogenic shock 36 VA-ECMO+Impella CP VA-ECMO+IABP Multicenter, UK Coronary device flow reserve Feb 1, 2025

RCT: randomized controlled trial; LV: left ventricular; VA-ECMO: veno-arterial extracorporeal membrane oxygenation; IABP: intra-aortic balloon pump.

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      Left ventricle unloading during veno-arterial extracorporeal membrane oxygenation: review with updated evidence
      Image Image Image Image
      Figure 1. Pressure volume curves describing normal left ventricular (LV) hemodynamics (A), pressure-volume area, sum of stroke work, and potential energy (B), cardiogenic shock with a decrease in contractility (arrow a) and stroke volume (b to b’) and an increase in LV end-diastolic volume and pressure (arrow c) (C), and veno-arterial ECMO during cardiogenic shock (D). LVP: left ventricular pressure; LVV: left ventricular volume; Ea: arterial elastance; ESPVR: end-systolic pressure-volume relationship; Ees: end-systolic elastance; EDPVR: end-diastolic pressure-volume relationship; LVEDV: LV end-diastolic volume; PVA: pressure-volume area; PE: potential energy; SW: stroke work; MVO2: myocardial oxygen consumption; ECMO: extracorporeal membrane oxygenation.
      Figure 2. Pressure volume loop simulating left ventricular (LV) venting during veno-arterial extracorporeal membrane oxygenation. LVP: left ventricular pressure.
      Figure 3. Suggestion of possible left ventricular (LV) unloading strategies. “Prophylactic” means unloading before any evidence of LV overload. “Therapeutic” means LV unloading to treat LV overload signs refractory to medical treatment. “Early” means performing mechanical LV unloading prior to medical treatment to ameliorate it. With the currently available evidence obtained from randomized controlled studies, we advocate for therapeutic rather than prophylactic or early LV unloading (the degree of recommendation). VA-ECMO: veno-arterial extracorporeal membrane oxygenation; SEC: spontaneous echo contrast; PCWP: pulmonary capillary wedge pressure: PEEP: positive end-expiratory pressure; CS: cardiogenic shock.
      Figure 4. Pressure-volume loops for varying modalities of left ventricular (LV) unloading. Each modality has a specific mode of action that could have different effects on LV hemodynamics or energetics. CS: cardiogenic shock; ECMO: extracorporeal membrane oxygenation; PAS: percutaneous atrial septostomy; PAD: pulmonary artery drainage. Adapted from data obtained from animal models [14-17].
      Left ventricle unloading during veno-arterial extracorporeal membrane oxygenation: review with updated evidence
      Modality IABP Impella Direct LV venting PAS PAD Transseptal LA cannulation
      Primary mode of action Afterload reduction Active pumping of blood from LV to aorta Preload reduction Preload reduction Preload reduction Preload reduction
      Direct LV unloading Yes Yes Yes No No No
      Direct lung protection No No No Yes Yes Yes
      The risk of Harlequin syndrome Possible Possible Less likely Less likely Less likely Less likely
      Increase in antegrade flow Yes Yes No (could decrease) No (could decrease) No (could decrease) No (could decrease)
      Dependency on LV function Yes No No No No No
      Efficacy for LVEDP reduction + +++++ +++++ +++~++++ +++ ?a)++++
      LV energetics
      PVA↓ + [14] + [15,16] NAa) + [17] + [16] NAa)
      PE↓ (+) (+) NAa) (+) (-) NAa)
      SW↓ (-) (-) NAa) (+) (+) NAa)
      Trial name (identifier) Inclusion criteria No. of participants Intervention Control Institution Primary outcome Estimated study completion
      UNLOAD-ECMO (NCT05577195) Cardiogenic shock 198 Impella+VA-ECMO VA-ECMO only University Heart and Vascular Center, Germany 30-Day all-cause death Dec 1, 2025
      HERACLES (iSRCTN82431978) Cardiogenic shock 36 VA-ECMO+Impella CP VA-ECMO+IABP Multicenter, UK Coronary device flow reserve Feb 1, 2025
      Table 1. Characteristics of each LV unloading modality

      LV: left ventricular; IABP: intra-aortic balloon pump; PAS: percutaneous atrial septostomy; PAD: pulmonary artery drainage; LA: left atrial; LVEDP: left ventricular end-diastolic pressure; PVA: pressure volume area; NA: not available; PE: potential energy; SW: stroke work.

      No available data from human or animal experimental model (simulation data was not adopted).

      Table 2. Ongoing RCTs about LV unloading

      RCT: randomized controlled trial; LV: left ventricular; VA-ECMO: veno-arterial extracorporeal membrane oxygenation; IABP: intra-aortic balloon pump.


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