Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a temporary mechanical circulatory support system used in patients with refractory cardiogenic shock. Although there have been significant technological advancements in VA-ECMO over the last decade, patient outcomes remain poor.
Levosimendan acts to sensitize myocardial contractile proteins to calcium, improving cardiac contractility without increasing the intracellular calcium concentration. Unlike traditional inotropes, levosimendan neither increases myocardial oxygen consumption nor impairs diastolic function or possess proarrhythmic effects.1 It also influences the opening of ATP-dependent potassium channels, including those in vascular smooth muscle cells, leading to coronary, pulmonary, and peripheral vasodilation.2
Levosimendan does not interact with β-blockers and peculiarly shows long-lasting action (up to 7–9 d), resulting from the formation of active metabolites such as OR-1896, which has a half-life of approximately 80 h.3 Levosimendan also has an anti-inflammatory effect, through the reduction of the levels of proinflammatory cytokines and oxidative stress markers.4 We sought to investigate whether the use of levosimendan improves weaning outcomes in patients on VA-ECMO.
Between January and December 2011, six consecutive patients with refractory cardiogenic shock of varying etiology were placed on VA-ECMO support by femoral vessels cannulation and received levosimendan infusion 24 h before the planned weaning (group A). As control group (group B), we retrospectively reviewed the medical records of VA-ECMO implanted at our institution before the introduction of the levosimendan protocol. These 11 consecutive patients received only traditional inotropes/vasopressors as weaning strategy.
According to ELSO criteria, the indication for VA-ECMO support was cardiopulmonary failure not responding to full pharmacologic and intra-aortic balloon pump (IABP) support but potentially reversible.5
All patients in both groups were under maximal medical therapy with at least two high-dose inotropes. Absolute hemodynamic criteria were not used, and ECMO support was initiated at the discretion of the cardiac surgeon and the intensivist. Table 1 summarizes the patients’ clinical data and preoperative characteristics and Table 2 the ECMO setup details.
The femoral vessels were directly exposed through a small incision in the groin and cannulated using the Seldinger technique. This hybrid approach, in our opinion, reduces the risk of surgical site bleeding. Hemostasis was further ensured applying a Prolene 5-0 purse string suture with mini-pledgets around each cannula.
Distal limb perfusion was provided through selective deep or superficial femoral artery cannulation. The Levitronix CentriMag (Levitronix LLC, Waltham, MA) magnetically levitated rotary pump was used in all cases. The flow was adjusted to meet hemodynamic and oxygen requirements. Intra-aortic balloon pump was used in all patients to ensure pulsatility of flow, reduce afterload, and improve coronary perfusion.
Mechanical ventilation volumes were set at low levels to avoid barotrauma while maintaining alveolar patency. The activated clotting time was maintained between 160 and 180s, hemoglobin kept >12 g/dl, and platelets >100,0009/L.
Levosimendan (Simdax, Orion Pharma, Espoo, Finland) was infused in group A patients 24 h before commencing ECMO weaning at an initial rate of 0.005 and then incremented up to 0.2 μg/kg/min within 1–2 h, depending on the hemodynamic response. We adopted this protocol to minimize the risk of vasoplegia and the consequent use of high-dose vasoactive medications. For the same reason, we did not administer the loading dose, as described by other authors.6
Weaning was carried out by reducing the pump flow by 0.5 L every hour, and it was usually accomplished within 48 h. Echocardiographic monitoring was performed routinely during weaning and repeated before discharge. Patients’ hemodynamic status was continuously monitored using a Swan-Ganz catheter, and the periodic assessment of mixed venous oxygen saturation, arterial blood gas, brain natriuretic peptide, and lactates was performed.
Continuous variables were expressed as the mean ± standard deviation and were evaluated by Student’s t-test; categorical data were expressed as percentages and were evaluated using χ2 or Fisher’s exact test. Statistical significance was set at a p value <0.05.
Detailed outcomes are summarized in Table 3. Table 4 shows inotrope/vasopressor requirement in the periweaning period in the two groups.
Levosimendan was initially used in the treatment of end-stage heart failure although large studies such as the REVIVE-II and the SURVIVE failed to show survival benefit at 90 and 180 d.7,8 In recent years, its use has been extended to the treatment of low cardiac output syndrome after cardiopulmonary bypass (CPB) or myocardial preconditioning in patients with impaired left ventricular function undergoing cardiac surgery.
Several studies indicate that the medication would be of benefit with an increased weaning rate from CPB, increased cardiac output, reduction of filling pressures, reduction of inotropes or IABP requirements, decreased intensive care unit stays, and reduced mortality.2,9–12 Starting from these data, we sought to investigate whether levosimendan improves weaning outcomes in patients undergoing VA-ECMO for cardiogenic shock.
There were no statistically significant differences in the preoperative data of the two groups, except for the renal function (creatinine and clearance), which was more impaired in the control group. This could explain the higher incidence of acute renal failure, requiring dialysis in this group.
There were no significant differences in ECMO support duration, ICU, and total hospital stay as well as in ECMO-related complicances and in other complicances. In our small series, the weaning rate of patients pretreated with levosimendan was 83.3% (5/6 patients) while in the control group it was 27.3% (3/11 patients). This difference was statistically significant (p = 0.0498). Furthermore, the weaning rate in the levosimendan group is higher than that reported in the ELSO registry for adult VA-ECMO13 and in most series.14–17
The survival rate was higher in group A (66.6%) than in group B (36.4%); however, this difference did not reach statistical significance. In group A, there were two inhospital deaths. The first was a patient in whom weaning was not successful because of multiorgan failure. In this case, VA-ECMO was set up during cardiopulmonary resuscitation. The second patient was successfully weaned but died 2 days after ECMO cessation because of a massive myocardial infarction caused by acute coronary stent occlusion.
In group B, there were seven inhospital deaths: six because of weaning failure (three multiorgan failure, two septic shock, and one case of irreversible coma) and one patient because of a refractory cardiogenic shock a few days after ECMO removal.
A second cycle of levosimendan was necessary in one patient to facilitate weaning from inotropic support after ECMO cessation. Nitric oxide was administered to a patient in group A. He was successfully weaned from ECMO and subsequently developed a right ventricle defaillance with increased pulmonary resistance. The use of nitric oxide led to a progressive improvement in right ventricle function. The patient was subsequently extubated and discharged without further problems. In group A, three patients (50%) required inotropic/vasopressor support during or after weaning versus 11 patients (100%) in the control group. This difference was statistically significant (p = 0.00294) and may reflect a possible role of levosimendan in reducing the inotropic requirements in such patients.
Two patients (18.2%) of group B did not recover left ventricular contractility and were switched to left ventricular assist device. Interestingly, this factor did not affect ICU and hospital mean stay of group B, which were similar to those of group A.
In our series, pretreatment with levosimendan seems to facilitate weaning from VA-ECMO through the optimization of cardiac function, thus reducing the need for high-dose inotropes. The long-lasting action (up to 8–9 d) of levosimendan could be a particularly useful tool in this setting. It allows a very gradual weaning and provides a continuous support in the critical immediate post-ECMO period.
However, the retrospective nature of our study and above all the small number of patients do not permit any definitive conclusion. Furthermore, the control group consisted of our first consecutive cases of VA-ECMO; thus, it is possible that the lack of experience in managing such complex patients negatively influenced the outcomes in this group.
To the best of our knowledge, this is the first report to describe this novel potential drug application, and it could serve as a starting point for larger population studies of prospective design.
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