The common indication for veno-venous ECMO is ARDS [8], with the intention to provide extracorporeal gas exchange while a protective ventilation strategy allows for lung rest and recovery. Usually ECMO is considered in patients with severe forms of ARDS, and the ELSO recommends ECMO initiation with a Horovitz index below 80. However, many centers start at earlier timepoints, such as a Horovitz index below 100–150 or uncompensated acidosis (pH < 7.2). However, optimal timing, duration and weaning of ECMO have not been investigated in large prospective trials yet. Early trials could not demonstrate a survival benefit of ECMO in ARDS patients [9, 10]. These trials have been a matter of intense debate for different aspects, such as the fact that ventilator settings were not adapted after ECMO initiation, i.e., lung protective ventilation was not performed. In contrast, the conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR) trial demonstrated safety and efficacy of veno-venous ECMO compared to conventional ventilation in ARDS patients [11], albeit the trial design has been discussed controversially [12]. Nevertheless, veno-venous ECMO has gained a central role in ARDS with a low Horovitz index, and the emergence of H1N1 has further strengthened the role of ECMO as a lifesaving tool in severe lung failure [13]. Recently the use of veno-venous ECMO in non-intubated patients (“awake-ECMO”) has gained attention, mostly in patients with terminal lung disease awaiting transplantation in a bridge-to-transplant strategy [14] or with ARDS in a bridge-to-recovery strategy [15].

A relative contraindication for veno-venous ECMO are bleeding disorders, since all ECMO configurations require systemic anticoagulation [5]. The use of veno-venous ECMO is contraindicated in patients with terminal respiratory failure, once there is no perspective of organ recovery or lung transplantation.

For veno-venous ECMO usually the femoral and jugular veins are used as vascular access, with the former for drainage and the latter for supply (Fig. 1). Sufficient diameters of right-sided femoral and jugular veins usually allow introduction of ECMO cannulas without problems due to the straight route. The correct position of both cannula tips is the border between the right atrium and the superior and inferior caval veins, respectively (Fig. 1). Malposition may facilitate recirculation, i.e., drainage of freshly oxygenated blood back into the extracorporeal circuit, which may become a substantial problem during therapy. Hence it is essential to verify optimal cannula position by fluoroscopy, chest X-ray or transesophageal echocardiography [16], and modifying the tip of the supplying cannula [17] or positioning it in the right ventricle [18] have been proposed to reduce recirculation.

In principle, veno-venous ECMO drains blood from a caval vein and returns an equal volume of oxygenated and decarboxylated blood by the other caval vein back to the right atrium. Hence oxygen saturation in the central aorta is the result of a mixture of ECMO-derived blood and residual venous blood returning to the pulmonary circulation, and remaining gas exchange in the lungs. The contribution of both the ECMO and the lung to the final aortic oxygen content varies from patient to patient and over time. Eventually all organs are perfused with approximately the same oxygen saturation, thus a radial or femoral arterial line on either side of the body are sufficient for assessing systemic oxygenation. This is in sharp contrast to all configurations with an arterial cannulation (see below). Another striking difference is that veno-venous ECMO, while profoundly supporting gas exchange, does not influence hemodynamics: The volume of blood drained from the right atrium is replaced by an equal volume of blood from the supplying cannula, resulting in a neutral volume and pressure balance in the right atrium (Table 1). Notwithstanding, during veno-venous ECMO function of the right heart must be closely monitored, and right heart failure in patients with veno-venous ECMO is a potential indication for veno-arterio-venous ECMO (triple cannulation, see below).

A promising recent development is to cannulate only veins of the upper body, in particular by using a bicaval dual-lumen cannula (Fig. 2) [19]. This special cannula drains blood from the superior and inferior caval veins, and supplies oxygenated blood to the mid-right atrium directed to the tricuspid valve, thereby minimizing recirculation. A dual-lumen cannula requires puncture of only one large vessel, which is a great advantage in terms of bleeding risk. Upper body cannulation potentially allows for discontinuation of mechanical ventilation and awake-ECMO, active physical therapy and mobilization on the intensive care unit. Despite these benefits there is a risk of right atrial or ventricular perforation of the cannula, which can be reduced by fluoroscopy or echocardiography guided placement, but needs to be determined in larger studies [20]. Furthermore, currently available dual-lumen cannulas are limited in terms of maximal blood flow and hemolysis may emerge on higher flow rates.

Veno-arterial ECMO can be used in a variety of conditions. The most frequent indications are failure to wean from cardiopulmonary bypass or early decompensation after cardiac surgery, referred to as postcardiotomy cardiogenic shock [22]. The classical non-surgical indication is cardiogenic shock caused by myocardial infarction [23], decompensated non-ischemic heart-failure [24] or fulminant myocarditis [25], in many cases in a bridge-to-recovery strategy. It is further employed during pulmonary embolism prior to embolectomy [26, 27], or in a bridge-to-transplantation strategy for right ventricular failure during decompensated pulmonary arterial hypertension [28]. Another indication is stabilization of patients with cardiogenic shock to enable their transport to a tertiary cardiovascular center [29]. For this application transportable ECMO systems are available. Veno-arterial ECMO has also been successfully used in a provisional setting for high-risk percutaneous coronary intervention [30]. However, in elective high-risk coronary interventions a percutaneous microaxial pump appears to be equally effective with lower procedural risk [31].

Veno-arterial ECMO can be useful for preconditioning the patient prior to implantation of a permanent left ventricular assist device (LVAD) [32], or in a bridge-to-transplantation setting. It can be continued until patients are awake, e.g., to evaluate neurological outcome after resuscitation (bridge-to-decision), or even be inserted in completely awake patients [28]. After lung transplantation for pulmonary hypertension, veno-arterial ECMO is sufficient for bridging the early postoperative phase while the heart is not ready to manage reconstituted left ventricular preload [33]. Recently the use during resuscitation [34] is increasing, with impressive outcome data: in an observational study of 117 patients without spontaneous ROSC after prolonged resuscitation in whom ECMO was initiated, 15 % survived with favorable neurological outcome [35]. However, extracorporeal cardiopulmonary resuscitation should be considered primarily in scenarios with a reasonable exit strategy, e.g., embolectomy in pulmonary embolism or emergency coronary revascularization [36].

Overall, despite promising data for veno-arterial ECMO from smaller studies, large prospective studies are not reported. Contraindications for arterial cannulation can arise from aortic dissection, aortic regurgitation, left ventricular thrombi or bleeding disorders.

For veno-arterial ECMO usually a femoral vein and the ipsilateral femoral artery are used for vascular access (Fig. 3). The venous cannula may also be placed into a jugular vein. The correct position of the venous cannula tip is the mid-right atrium (Fig. 3) to enable homogenous drainage of venous blood from both caval veins. If placed in the femoral artery, the arterial cannula should be fully introduced resulting in a tip position in the common iliac artery in adults. Upper body cannulation is also possible (see below).

Once the femoral artery is cannulated during ECMO, some essential differences to veno-venous ECMO have to be considered.

The first and most important aspect is the so-called watershed phenomenon (Fig. 4): if the failing heart is not able to ensure a critical blood pressure for organ perfusion, flow support by the ECMO unit will result in enhanced blood pressure as long as the vascular system has sufficient resistance (Table 1). However, in most patients on a veno-arterial ECMO the left ventricle still has some output and thus delivers an antegrade blood flow towards the descending aorta. This ‘native’ flow meets the retrograde blood flow from the arterial ECMO cannula at a point called the ‘watershed’ [26]. It is located somewhere between the ascending aorta and the renal arteries in most cases. Importantly, the particular location of the watershed is determined by the competition between left ventricular output and ECMO flow and thus varies during therapy [37] and between patients. In the presence of an antegrade flow through the aortic valve the coronaries and mostly the first branches from the aortic arch will be perfused with blood originating from the left ventricle. All areas distal to the watershed, i.e., the lower half of the body including the kidneys, receive blood oxygenated by the ECMO unit. While oxygen saturation of ECMO-derived blood will be nearly always sufficient, oxygen saturation of blood originating from the left ventricle depends on respiratory function of the lung, which can be severely compromised by edema, pneumonia or other pulmonary conditions. Accordingly, respiratory failure during veno-arterial ECMO may result in hypoxic damage of the heart and brain-despite good perfusion pressure. Therefore, it is mandatory to establish an arterial line at the right upper half of the body (preferably at the right radial artery) for monitoring upper body oxygenation. A femoral arterial line would reflect ECMO oxygenation and is therefore never sufficient for monitoring brain oxygenation. Rarely, the watershed may be located more proximally in the ascending aorta just between the coronaries and the right brachiocephalic trunk [26], which renders monitoring of oxygen saturation for the coronaries virtually impossible. This condition is a possible indication for veno-arterio-venous cannulation (triple cannulation, see below) to ensure coronary oxygenation or implantation of a microaxial pump (see below) to enhance antegrade flow. For the above described reasons it is essential to evaluate pulse pressure (as a surrogate of left ventricular output) and upper body oxygenation immediately after veno-arterial ECMO insertion and continuously thereafter [37].

Second, femoral arterial cannulation reduces perfusion distal to the puncture site. This potentially causes lower limb ischemia and may result in vascular surgery, compartment decompression or amputation [4, 38]. Therefore, an additional sheath is required to ensure distal arterial perfusion (Fig. 3, inset). This sheath should ideally be placed before introducing the arterial cannula, as arterial filling distal to the cannula may be diminished after cannulation. If ECMO cannulation is performed in the cath lab, we prefer to place the antegrade sheath with angiographic guidance. Of note, arterial cannulation generally harbors the risk of arterial injury, e.g., by dissection, rupture or occlusion [39], potentially requiring emergency vascular surgery.

Third, left ventricular distension and pulmonary congestion may occur after in patients with veno-arterial ECMO, especially in cases of extremely low left ventricular output or aortic regurgitation. Retrograde aortic ECMO flow increases afterload, and some blood still arrives in the left heart returning from bronchial and thebesian veins [40] even with full ECMO speed, ultimately resulting in left ventricular distension. In such cases a second venous draining cannula for enhanced preload reduction can be helpful (veno-veno-arterial cannulation, see below) [5]. A novel promising solution to compensate for insufficient or missing antegrade flow across the aortic valve is percutaneous left ventricular unloading by a microaxial pump (Impella ^® ) in addition to veno-arterial ECMO [41]. Such a pump can easily be implanted in the catheterization laboratory without the need for open surgery, facilitating profound left ventricular support and decompression.

It has to be noted that the above described aspects are of critical importance during ECMO with femoral arterial cannulation; however, they do not apply to central and only in part to subclavian arterial cannulation.

Some centers have described accessing the right internal jugular vein and the subclavian artery for veno-arterial ECMO [42]. This results in upper body cannulation, allowing for awake-ECMO, mobilization and active physical therapy. In this case the watershed problem is reduced, at least with respect to brain oxygenation. However, subclavian artery cannulation requires direct surgical arterial access by applying a vascular end-to-side graft, is much more invasive and harbors the risk of injuring vessels or nerves of the arm.

Unloading by veno-arterial ECMO may be insufficient in selected patients, e.g., in grown-up patients with congenital heart defects and the coexistence of intracardiac shunts and pulmonary arterial hypertension: intracardiac right-to-left shunt and two-circulation syndrome contribute to hypoxemia in the ascending aorta and possibly result in myocardial and cerebral hypoxic damage. Optimized unloading, upper body drainage and shunt reversion may then be achieved by adding a second draining cannula to the system, which drains blood from the right atrium or the right ventricle (veno-veno-arterial ECMO, Fig. 5). Another indication for a second draining cannula may arise from left ventricular distension due to suboptimal drainage during veno-arterial ECMO as described above. Furthermore, in selected cases of veno-arterial ECMO drainage with a single venous cannula may not be sufficient, e.g., in the presence of small vein diameters or hemolysis due to high flows. Then a veno-veno-arterial cannulation strategy can be helpful to increase venous drainage and to enable high flows [40, 45].

The second venous cannula should be placed under echocardiographic guidance. This can best be achieved by fluoroscopy or transesophageal echocardiography. Both venous cannulae are then connected outside the body using a Y-connector (Fig. 5, inset), so that venous blood eventually returns through one tubing to the ECMO unit.

It has to be noted that no study data for veno-veno-arterial ECMO exist and that this configuration has yet been used only in highly selected adult patients and in children (Table 2). Hemodynamic consequences of veno-veno-arterial ECMO are comparable to veno-arterial cannulation (Table 1).

Veno-arterio-venous ECMO has a potential indication either in cardiac and secondary respiratory failure and vice versa. During heart failure veno-arterial ECMO aims to unload the heart and to maintain arterial blood pressure. However, when respiratory failure develops during ECMO support, e.g., due to pulmonary edema, severe pneumonia or ventilator-associated lung injury, myocardial and cerebral oxygenation may be compromised resulting from the watershed phenomenon described above: The upper body appears cyanotic and the lower body appears pink, also referred to as “two-circulation syndrome” or differential hypoxia [43, 44]. In such situations a third cannula can be added for supplying arterialized blood into the pulmonary circulation.

Another potential indication is heart failure developing in patients on veno-venous ECMO support [46, 47]. In this case, an arterial cannula must be added to provide circulatory support, for maintaining systemic blood pressure and unloading the heart.

To date, a few case series and small observational studies have demonstrated reasonable safety and efficacy of veno-arterio-venous ECMO [43, 46‐53] (Table 2); however, prospective or controlled data are not reported yet.

Veno-arterio-venous cannulation is usually implemented as an “upgrade” of a veno-arterial or veno-venous ECMO. In both cases the arterialized ECMO outflow is divided via a Y-connector, for one arterial cannula supplying towards the central aorta and one venous cannula supplying towards the pulmonary circulation (Fig. 6). An adjustable clamp and a separate flow sensor on one of the two outflow tubings allow for balancing the flows between both cannulae (Fig. 6, inset). The preferred position of central venous cannulas in veno-arterio-venous ECMO is the border between the caval veins and the right atrium, like in veno-venous ECMO (Figs. 1, 6). Cannulation can also be achieved with two vascular access points: For this a bicaval dual-lumen cannula is used for venous cannulation. The drainage lumen of the cannula is then connected to ECMO input and the supplying lumen to ECMO output.

Every patient with a veno-arterio-venous ECMO has an individual demand of arterialized blood flow for each supplying cannula, which will also vary during therapy. It is important to carefully adjust the balance, since every change will influence preload, afterload, the position of the watershed and oxygenation at the same time (Table 1). Therefore, routine control of right and left ventricular filling and systolic function by transthoracic echocardiography is critical during veno-arterio-venous ECMO, especially after modification of the flow balance. As with flow balance, changes in oxygenator and sweep gas settings at the ECMO will influence oxygenation and decarboxylation in both reinfusion cannulas and should thus be carefully adjusted. Respiratory support by this cannulation is usually strong and facilitates lung protective ventilation. However, circulatory support during veno-arterio-venous ECMO is lower (nearly half the support) compared to veno-arterial and veno-veno-arterial cannulation, since not the whole arterial flow is directed towards the aorta [47].