Ventricular dysfunction despite normal or elevated filling pressures associated with hypoperfusion of end organs and tissue hypoxia defines cardiogenic shock (1–3). Acute myocardial infarction (AMI) represents the most common trigger of CS. Other common causes include acute valvular heart disease, ventricular arrythmias, fulminant myocarditis, post-cardiotomy shock and acute or chronic heart failure (HF).

Despite multiple advances including early revascularisation strategies, mortality rates in CS patients remain high (up to 50%) (4, 5). The cornerstones of contemporary CS management include prompt diagnostic workup and initiation of directed therapy aiming to re-establish tissue perfusion and halt the shock spiral. Therapeutic options remained limited for decades, and generally only involved inotropes, vasopressors, ventilatory support and reperfusion therapies. However, the introduction of mechanical circulatory support (MCS) has fundamentally changed CS management over the last decade. This is also reflected by the current European Society of Cardiology (ESC) guidelines with a IIa recommendation for short-term MCS (6). Whereas, particularly in the early MCS era, counterpulsation with an intraaortic balloon pump (IABP) as well as extracorporeal membrane oxygenation (ECMO) represented the preferred devices for refractory CS, the micro-axial Impella™ (Abiomed, Danvers, Massachusetts) is an emerging percutaneous ventricular assist device (pVAD), that has increasingly been used in Western countries (7). In fact, there is a paradigm shift in CS management, which not solely aims for enhancing coronary blood flow (IABP) and maintaining systemic perfusion (ECMO), but also incorporates ventricular unloading ultimately aiming for myocardial recovery.

With this background, this comprehensive review highlights the rationale for ventricular unloading in CS. Moreover, it summarizes important practical aspects, possible complications and current evidence one needs to be aware of, when managing patients requiring hemodynamic support with an Impella™ device.

CS represents a complex interplay between the heart and all other organ systems. Rapidly deteriorating myocardial contractility results in a spiraling process of ventricular dysfunction, hypotension, reduced venous return and diminished coronary perfusion leading to pulmonary congestion, hypoxia, decreased organ perfusion and worsening ischemia (3). Compensatory peripheral vasoconstriction initially improves coronary and peripheral perfusion. However, it contributes to increased cardiac afterload that overburdens damaged myocardium further diminishing circulating oxygenated blood flow (3, 8). Systemic hypoperfusion triggers endothelial dysfunction, systemic inflammatory response syndrome (SIRS) and coagulopathies, which all promote multiorgan dysfunction syndrome (MODS) (3). Activated systemic inflammatory mediators (e.g., interleukins, TNF-alpha) result in vasodilation and additional hypotension. Consequently, these mechanisms add up to the high mortality associated with cardiogenic shock (9).

The management of CS should focus on preventing and reversing organ failure through hemodynamic resuscitation and simultaneously addressing treatable causes.

Vasoactive and inotropic drugs, especially those with adrenergic mechanisms, have the burden to increase afterload, aggravate myocardial ischemia and trigger arrhythmias, which all ultimately worsen the patient's prognosis. Therefore, they must be cautiously titrated in the setting of CS (10, 11). Consequently, in patients presenting with impeding or already established cardiogenic shock, immediate MCS may be the first choice to rapidly re-establish stable hemodynamics and potentially prevent related MODS.

To date, three basic concepts have commonly been used for percutaneous MCS in acute CS management: (1) counterpulsation using the IABP, (2) ventricular unloading provided by Impella™ technology or by the pulsatile PulseCath iVAC2L device, and (3) veno-arterial extracorporeal membrane oxygenation (VA-ECMO) circulatory support. The mechanisms and hemodynamic effects of currently available MCS are highlighted in Table 1.

The Impella™ is a percutaneous, microaxial pump that continuously draws blood from its inlet inside the ventricle and expels it in the ascending aorta (Central Illustration) (12–15). Owing its properties, the Impella™ unloads the left ventricle (LV) while simultaneously augmenting cardiac output (CO). The power connections for the pump motor and sensors are contained inside the 9F guiding catheter. The end of the catheter is connected to an external console consisting of an integrated controller for the pump and purge system. Unlike IABP, the Impella™ does not require ECG or arterial waveform triggering, facilitating stability even in the setting of ongoing tachyarrhythmias or electromechanical disassociation.

Currently, four devices are available: Impella™ 2.5, Impella™ CP and Impella™ 5.0/5.5 and Impella™ RP (Table 2). While the Impella™ 2.5 and CP are inserted percutaneously, the Impella™ 5.0 requires a surgical cutdown for insertion. Thus, in many institutions, the Impella™ 2.5 or CP reflect the first choice for mechanical support. The Impella™ RP is a 22 French, three-dimensional catheter-based micro-axial pump approved for use in acute right heart failure (RHF). The inflow of the Impella™ RP is positioned in the inferior vena cava (IVC) and the outflow in the pulmonary artery (PA) expelling blood from the IVC into the PA at a rate of up to 4.6 L/min.

RHF is a characterized by the inability of the right ventricle (RV) to sustain pulmonary flow caused by increased RV afterload (e.g., acute pulmonary embolus, severe hypoxia, acidemia, or increased intrathoracic pressures) or decreased RV contractility (e.g., RV ischemia, myocarditis, post-cardiotomy CS, or LVAD support) (34–36). RHF is associated with high morbidity, mortality, and longer hospital length of stay (37). The thin walled RV differs markedly from the LV in architecture, mechanics, metabolism, and recovery from injury (38). The RV is exquisitely susceptible to failure under conditions of ischemia and pressure overload. However, the RV is remarkably resilient and tends to recover once hemodynamics improve and the underlying insulting cause is eliminated. But in some patients RHF persists and, similar to LV related shock, outcome in patients requiring multiple and prolonged inotropic and vasopressor support is poor (10, 11). Moreover, 10–40% of patients undergoing isolated left ventricular assist device (LVAD) implantation experience some degree of RHF (39). While RHF associated with LVAD insertion may be partially caused by the underlying cardiomyopathy, the pathophysiology of RHF after LVAD implantation is complex.

In this context, the Impella™ RP provides an opportunity for mechanical support in the downward spiral of refractory RHF and may serve as a bridge to recovery or heart transplant. Since survival after impella™ RP insertion strongly depends on timing and patient selection (37, 40, 41), early identification of RHF and careful consideration of patient's clinical status and comorbidities is key to obtain the best clinical outcomes. Device implantation requires some expertise and, in contrast to LV pumps, can only be performed under fluoroscopy guidance. Frequent monitoring of RV function using echocardiography and pulmonary artery catheter measurements is crucial to guide Impella™ RP therapy. Based on the inclusion and exclusion criteria of the RECOVER RIGHT trial (37) and a series of smaller clinical studies and case series (42–45), a dedicated checklist for patient selection has been proposed, see Table 4.

The only two randomized clinical trials comparing the Impella™ vs. IABP have both been neutral with respect to survival. However, both were underpowered, the ISAR-SHOCK trial mainly targeted hemodynamic improvements (46). The small IMPRESS trial also showed similar outcomes with both Impella CP and IABP in patients with ST-elevation myocardial infarction (STEMI) and CS undergoing primary percutaneous coronary intervention (PCI) (47). One must take in account that this trial included critically ill patients and the major cause of death was anoxic brain injury, suggesting that mechanical hemodynamic support may be of limited utility in this patient cohort. Also, the trial was underpowered (47). Although, some centers have reported better survival rates in CS after implementation of a comprehensive shock protocol using pVADs (48, 49), the use of Impella™ has been associated with higher risks of bleeding, stroke, and death, as well as higher costs compared to IABP in propensity-matched analyzes from registry data (7, 50, 51). However, confounding due to the use of pVADs in sicker patients cannot be ruled out (51). Despite neutral results in randomized clinical trials and the remaining high mortality rates in this severely ill population there is some evidence that the use of larger Impella™ pumps (e.g., Impella™ CP), the initiation of Impella™ prior to PCI and its use in patients without cardiac arrest may be correlated with outcome improvements (52).

In comparison to VA-ECMO, the incidence of major complications, such as bleedings, might be lower with Impella™ use (53). The data supporting the use of RV pVADs, namely the Impella™ RP, is even more limited and randomized data is not yet available. The RECOVER RIGHT study was the first to suggest feasibility and safety of the Impella™ RP in patients with severe RHF (13). A series of recent studies indicated possible clinical benefit with the Impella™ RP demonstrating 30-day survival rates of of 64–72% (37, 40, 41). However, the survival rate was much lower among patients in whom Impella™ RP was implanted as salvage support (41). This caused the U.S. Food and Drug Administration to issue a warning advice. This controversy highlights the need for proper patient selection and early initiation of hemodynamic support.

In addition to its application in high-risk PCI and cardiogenic shock complicating AMI, the Impella™ technology has been successfully introduced in a broad variety of clinical scenarios requiring left or right ventricular support. Indication for ventricular unloading and issues to be considered when selecting patients for pVAD support are depicted in Table 5.

Timely implantation is often key. Considering the rapidly progressing shock spiral, early identification and treatment are crucial to increase chances of survival. This seems underlined by observational data suggesting that Impella™ implantation before revascularization maximizes the potential benefit (61) and that survival decreases by about 10% for every 60 min of delay (49).

Overall, the type of complications related to the use of the Impella™ device are similar to those encountered with the IABP. The most common complications include limb ischemia, vascular injury and bleeding requiring blood transfusion (15). The reported incidence of limb ischemia ranges from 0.07–10% and for significant bleeding from 0.05 to 54% (70). The risk of bleeding is also related to the administration of antithrombotics (e.g., unfractionated heparin), thrombocytopenia or consumption of coagulation factors (e.g., von-Willebrand factor) related to shear-stress with the impeller. Moreover, shear stress from the impeller (especially at very high “P” levels) can lead to clinically relevant hemolysis, which in worst case scenario can cause renal failure. This phenomenon has been observed in 5–10% of patients during the first 24 h on Impella™ support. The risk of hemolysis and aortic valve injury may be diminished by proper positioning of the inlet cannula, and thus limited flow turbulences.

Ischemic or hemorrhagic cerebrovascular accidents following Impella™ insertion have also been reported (2.4–6.3%) (70, 71). As with any percutaneous device, there is a risk of access site infection and sepsis, which increases with the duration of support. In the early experience, device migration and malfunction rarely led to injury of the aortic valve or ventricle causing tamponade due to LV perforation. Also, mitral regurgitation secondary to injury of the papillary muscles or chordae have been reported (32). Finally, the pigtail end of the Impella™ within the LV can provoke ventricular arrhythmias potentially further impairing CO and deteriorating CS.

MCS is a key element of most modern cardiogenic shock care pathways (3). It is recommended to define triggers for initiation of MCS, choice of MCS modality, and escalation steps in CS patients. Such pathways should certainly be tailored to local MCS availability and experience. Irrespective of MCS modality, the adequacy of hemodynamic support and ventricular unloading needs to be closely monitored.

Adequate monitoring including a pulmonary artery catheter (measurement of central venous pressure (CVP), PCWP, CO) in combination with standard clinical measures such as blood pressure, lactate and urine output is mandatory. Frequent echocardiographic assessments of LV/RV size, function, and aortic valve opening can help to optimize pharmacologic treatment and guide escalation of mechanical circulatory support.

According to the anticipated degree of support required, the Impella™ 2.5, Impella™ CP, or the surgically implanted Impella™ 5.0/5.5 may be considered. The support requirements depend on body size as well as the degree of hemodynamic compromise. It is crucial to be aware, that due to the Anrep effect the intended Impella™ flow cannot be simply added to the pre-insertion native CO. Reduced contractility of the ventricle after pump insertion will result in a smaller total CO than expected. Among patients with profound LV dysfunction an Impella™ pump might unload the LV to the point of continuous aortic valve closure resulting in a non-pulsatile arterial curve on the monitor.

The Impella™ 2.5 and CP, which can rapidly be inserted percutaneously, are usually the first choice in the setting of CS. However, in patients with severe LV failure, low CO might persist for several days, sometimes even weeks or months. In such cases, upgrading to a larger device (e.g., Impella™ 5.0 or 5.5) might be a wise strategy (72). With these devices the patient can even be ambulated while awaiting recovery, cardiac transplant or LVAD implantation.

Simultaneous RHF results in reduced LV preload and therefore limits the flow of the LV Impella by recurrent suction events, which necessitates down-titration of the Impella™ pump power level. In case of inadequate hemodynamic response after LV unloading and recurrent suction alarms irresponsive to volume challenge, the insertion of an VA-ECMO or Impella™ RP may be considered. The latter augments RV output and therefore increases LV preload (BiPella approach), which in turn improves CO. Although, there are only small case series available (45, 73–78), the BiPella approach seems to be feasible and safe und might be used as a salvage treatment modality for refractory biventricular failure. VA-ECMO might be primarily considered in the setting of inappropriate oxygenation due to acute lung congestion or MODS. Also, VA-ECMO implantation might be evaluated in case of refractory shock and inadequate support from the Impella™.

Conversely, some patients on VA-ECMO support may benefit from additional LV unloading by an Impella™ device. Although potentially lifesaving in patients with CS, VA-ECMO burdens the already impaired LV by increasing afterload. This may further compromise the LV contractile function due to ventricular distension and impaired myocardial blood flow (79, 80). When deployed in combination with VA-ECMO, the Impella™ (ECMELLA approach) reduces filling pressures, ventricular distension, and maintains flow from the LV to the aorta even in the absence of LV ejection and a closed aortic valve (81–83). There is data proposing the combined use of VA-ECMO with an Impella™ device in severe CS cases to unload the LV, facilitate myocardial recovery and improve clinical outcomes. Yet, the evidence supporting the ECMELLA approach derives only from observational studies and has accordingly some limitation (81–84). Also, the increased risks of hemorrhagic and vascular complications due to the additional large bore vascular access required need to be considered.

Finally, there are small case series endorsing the combination of an Impella™ device and IABP as a bail out strategy in refractory CS (28, 85). However, further clinical investigations will be needed to assess if the combination of LV unloading and counterpulsation using the IABP brings any incremental physiological and clinical benefit. Possible combinations of different MCS devices, their indications, clinical effect and possible pitfalls are depicted in Table 6.

With respect to the limited evidence supporting the use of the Impella™, especially in patients with AMI and/or CS, there are several trials in progress. For instance, the DanGer Shock trial (ClinicalTrials.gov Identifier: NCT01633502) is a prospective, multicenter, open-label trial randomizing AMI patients with CS 1:1 to Impella™ CP support or current guideline-driven therapy with a planned enrollment of 360 patients (86).

Also, following encouraging pre-clinical studies (87, 88), which suggest a reduction in infarct size by applying early ventricular unloading in patients with AMI, the STEMI-DTU trial (ClinicalTrials.gov Identifier: NCT03947619) will study the impact of ventricular unloading by the Impella™ device during 30 min before primary PCI on infarct size in patients with acute anterior MI.

Besides new treatment concepts, also new devices are currently under investigation or development. Since the actual versions of percutaneously implanted LV Impella™ devices bear the risks of bleeding and vascular injury, there have been efforts to downsize the catheter size. There is now a nine french device – the Impella™ ECP – under clinical investigation (ClinicalTrials.gov Identifier: NCT04477603). Also, new devices allowing LV unloading with integrated batteries are under development, ensuring long-term hemodynamic support for several months and enabling patients to leave the hospital while awaiting heart transplant or as a destination therapy.

Albeit randomized evidence supporting its clinical use remains scarce, the Impella™ device is an emerging MCS device for treatment of CS. The Impella™ actively unloads the impaired left or right ventricle and maintains systemic pressure. If immediately applied, these devices not only unload the ventricle but also improve myocardial and peripheral oxygen supply and therefore have the potential to halt the shock spiral and reverse MODS. Owing to its design, the Impella™ relieves the battered ventricle, which appears to improve myocardial recovery. Profound understanding of the device, its physiologic impact, but also its limitations are important when considering a CS patient for percutaneous circulatory support.

AA-T has drafted and corrected the manuscript. MB, GC, GT, MM, AB, RK, and FC revised the manuscript critically for important intellectual content. All authors contributed to the article and approved the submitted version.

MB has received speaker fees from Abbott Vascular, Abiomed, and SIS Medical. FC has received speaker and/or consultant fees from Abbott Vascular, Abiomed, Boston Scientific, and SIS Medical. RK has received institutional grants from Abbott, Biosense-Webster, Biotronik, Boston, Medtronic, SIS Medical, and consultant fees from Biosense-Webster and Biotronik. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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