Veno-venous extracorporeal membrane oxygenation (VV ECMO) ensures the restoration of respiratory exchanges in patients suffering from acute lung injury (1). However, it is quite common that patients, despite extracorporeal support, remain extremely hypoxemic (2). This event should trigger the attempt to guarantee an improvement in oxygenation with therapeutic measures on top of VV ECMO. Moreover, when the need of VV ECMO is dictated by acute respiratory distress syndrome (ARDS), some adjunctive therapies can be added to address the underlying pathophysiological mechanism of systemic inflammation, excessive fibro-proliferation and altered vascular permeability (3). For the purpose of this review, we will refer to adjunctive therapies as all pharmacological or non-pharmacological strategies employed to address clinical issues during the course of extracorporeal support. For each of these, the current evidence will be summarized.
Refractory hypoxemia can be defined as the persistence of low levels of blood oxygen content during VV ECMO, which are considered inadequate to match the patient’s metabolic needs (2). The current knowledge about the safe arterial oxygen partial pressure in the blood (paO2) does not allow neither the determination of a threshold triggering interventions nor the value at which the brain is injured (4-8). Therefore, the decision about the need to start adjunctive or rescue therapies on top of VV ECMO is often left to the clinician judgement, arising from a global evaluation of the single patient and his comorbidities. Hypoxemia during VV ECMO occurs as a consequence of phenomena that are partly intrinsic to the veno-venous bypass partly to the underlying lung damage such as: mixture between blood oxygenated by ECMO and patient’s own blood, high recirculating fraction, intrapulmonary shunt (9). Adjustment of ECMO flow and reduction of recirculating fraction are usually the first measures undertaken to increase the oxygen content in the blood. Available strategies to improve peripheral oxygenation can be classified as follows: (I) increase of ECMO flow; (II) reduction of the recirculation fraction; (III) increase of blood oxygen-carrying capacity; (IV) reduction of oxygen consumption; (V) manipulation of native cardiac output (CO) and intrapulmonary shunt; (VI) switch to veno-arterial (VA) ECMO or hybrid configurations (2). We have evaluated only measures not directly involving the management of extracorporeal support, such as regulation of ECMO flow, the reduction of recirculation fraction or the management of mechanical ventilation. Comprehensive reviews on mechanical ventilation and management of refractory hypoxemia during VV ECMO are referenced (2,10).
Increase of blood oxygen-carrying capacity
The frequency of bleeding complications makes ECMO one of the most blood-expensive settings (11). The number of packed red blood cell transfused has been related to patients’ mortality and morbidity (12). These acquisitions drove the attempt to lower the transfusional threshold, while optimizing anticoagulation therapy with the aim to reduce bleeding complications (13). ELSO guidelines state that, during respiratory ECMO, the hemoglobin level should be maintained at 12–14 g/dL (14), owing to the fact that the lower is the hemoglobin level, the higher should be ECMO blood flow to ensure the oxygen delivery. In recent years, many studies showed that good outcomes can be achieved by using a lower than usual threshold for blood transfusion (15,16), provided that this strategy was accompanied by a concomitant blood conservation technique, as reinfusion of circuit blood at the moment of decannulation and by a rigorous titration of anticoagulation (17). To the best of our knowledge, there are no clinical trials with a head-to-head comparison of liberal (around 10 g/dL) versus restrictive (around 7 g/dL) hemoglobin levels triggering red blood cells transfusions in adult patients.
In conclusion, some considerations should be made: firstly, the increase in haematocrit is the first and more effective physiologic mechanism adopted when human subjects are exposed to hypobaric hypoxia (18); in second instance, oxygen delivery during ECMO is closely linked to hemoglobin levels (19); thirdly, the administration of fluids instead of packed red blood cells to treat hypovolemia can lead to fluid overload, which is a significant concern in ARDS patients (20); lastly, the concept of theoretical and transfusion threshold itself could be questioned, as it does not take into account many variables affecting the specific clinical situation (age, comorbidities, concomitant cardiac dysfunction etc.).
Reduction of oxygen consumption: sedation, neuromuscular blocking agents and therapeutic hypothermia (TH)
Deep sedation and neuromuscular blockade (NMB) are widely used in the first phase of ECMO support, until stabilisation occurs. The ACURASYS study randomised 340 patients to receive, within 48 hours from the onset of ARDS, the neuromuscular blocker cisatracurium besylate or placebo for 48 hours. The study showed an improvement of adjusted 90-day survival and a decrease of the length of mechanical ventilation in the treatment arm (21). A meta-analysis, including three RCT comparing NMB versus placebo in ARDS, concluded that a short-term infusion of cisatracurium is associated with a reduced 28-days, intensive care unit (ICU) and in-hospital mortality, without increasing the risk of ICU-acquired weakness (22). The reduction of peripheral and brain metabolic demand during sedation and the suppression of the work of breathing during NMB administration have not been associated, to the best of our knowledge, to better outcomes in ECMO patients. The deliberate and controlled lowering of body temperature above 36 °C is termed TH (23). Many factors, as the speed of induction and rewarming and the duration of TH influence the physiologic response (23). The pathophysiologic rationale is the reduction of oxygen consumption of the whole body and the cerebral protective effects. To date, no studies have explored the effect of mild (34–35.9 °C) TH in ECMO patients. Only anecdotal are the experience of TH in ARDS patients (24-26). TH usually requires sedation to reduce the unpleasant effect of induction and to prevent shivering, which induces a sudden and considerable increase in metabolic rate. On these premises, TH does not seem to offer significant advantage out of selected cases in the first phase of support.
In conclusion, the benefits of sedation, prolonged neuromuscular blocking, and TH are all linked to the need to reduce oxygen consumption and, as regard to NMB, even to allow for a safer mechanical ventilation. Each expected beneficial effect from therapies requiring prolonged sedation out the first phase of stabilization should be weighted with the advantages of an “awake” ECMO strategy, with an early weaning from mechanical ventilation, oral feeding and active physiotherapy (27-29).
Manipulation of intrapulmonary shunt
Seminal studies highlighted the role of CO in determining intrapulmonary shunt, and the consequent possibility to reduce with mechanical [high tidal volumes and high positive end expiratory pressure (PEEP)] and pharmacological modulators the degree of shunt, improving arterial oxygenation (30,31). An emerging technique to reduce the intrapulmonary shunt is the infusion of esmolol, a cardio-selective beta-1 blocker agent, characterized by an ultra-short half-life that allows for a quickly modulation and recovery from its effect (32). The rationale underlying the infusion of esmolol is that, by reducing CO, esmolol increases the ratio between ECMO flow and patient’s CO and, in doing so, prevents the need for dangerous ECMO flow increases during hyper dynamic phases of shock (2); moreover, as stated above, the reduction of CO is a well-known mechanism of intrapulmonary shunt reduction, that is a paramount mechanism of hypoxemia in patients with ARDS (33). Clinical data about the use of esmolol in ECMO patients are limited. A case series of three ARDS patients treated with esmolol for refractory hypoxemia during VV ECMO revealed the feasibility of this strategy to augment the paO2 reducing CO and thereby ameliorating the match between CO and pump flow, without a significant reduction of oxygen delivery (33). More specifically, three patients with ARDS and refractory hypoxemia despite protective mechanical ventilation and high flows of VV ECMO, with a hemodynamic profile characterized by high CO (>7 L/min), were treated with a continuous infusion of esmolol at a dosage of 50–80 mcg/kg/min. Hemodynamic evaluation during the first 12 hours demonstrated a significant reduction of CO and heart rate (HR) and a significant improvement of peripheral oxygenation, as demonstrated by the increase of paO2. Furthermore, calculated oxygen delivery (DO2) did not significantly vary during the treatment. The absence of metabolic acidosis and the decreasing trend of blood lactates during the treatment further confirm the absence of peripheral hypoperfusion because of reduced CO. A possible objection to this approach could be the risk of CO reduction and, consequently, of the peripheral oxygen delivery. However, this technique does no entail the situations of low CO states, which should be strictly monitored and diagnosed by means of markers of tissue hypoxia, such as lactates or metabolic acidosis. Furthermore, the association between esmolol and inotropes, even if limited to sparse reports and experimental studies, could be not lacking a pharmacological and physiologic rationale (34-36). Beta-blockers administration may have other advantages. Myocardial dysfunction is often present in the shocked septic patient, with an incidence of reduced left ventricular ejection fraction ranging from 24% to 50% of affected patients, and there are also consistent findings regarding impaired left ventricular diastolic function and right ventricular dysfunction (37). Chronic therapy with beta-blockers seems to have a protective effect in patient with septic shock (38), and the treatment with esmolol of septic shocked patients on vasopressor therapy has been associated with a strong mortality reduction, even if the latter study was not powered to infer on mortality (39). However, although increasing evidence suggests the possible beneficial role of β-blockers in sepsis, the topic is still controversial.
In patients under mechanical ventilation suffering from ARDS, the use of prone positioning is a well-known system to improve peripheral oxygenation, whose physiologic effects are related to changes in the stiffness of the whole chest wall, redistribution of regional alveolar inflation from dependent to non-dependent regions, relief of the heart pressure on the lungs (3). The PROSEVA trials (RCTs) and meta-analyses established that prone positioning is effective when long sessions are used (duration of more than 12 hours) and in more severe subgroups of ARDS (40). The RCT assigned 466 patients with severe ARDS to prone-positioning session of at least 16 hours daily or supine positioning. The prone group had a significant lower 28-day and 90-day mortality, with an incidence of complications that did not differ between the two groups (41). Guervilly et al. (42) reported the outcomes of series of patients turned to prone positioning during VV ECMO therapy. Fifteen ARDS patients were turned into prone position, without major complications, if they had severe hypoxemia (paO2/FiO2 ratio below 70) despite maximal oxygenation, injurious ventilation parameters with plateau pressure exceeding 32 cmH2O, or failure of attempt to wean from ECMO after at least 10 days on ECMO support. The main findings of the study are significant improvement in paO2/FiO2 ratio at 6 and 12 hours after reversal. The improvement in oxygenation persisted 1 and 6 hours after being turned back to the supine position. Positive results were reported even in the study of Kimmoun et al. (43). Before this experience, the combined treatment of VV ECMO and prone positioning has been reported only in small case series and in a retrospective study involving few patients, without control group (44). Prone positioning has demonstrated its safety if performed by trained personnel (45). A recent review on complications observed during prone positioning of patients on VV ECMO did not report catastrophic complications as cannula dislodgement or major bleeding (46). Analogously, prone positioning requires sedation and the harm of prolonged deep sedation should be kept in mind.
Pharmacological specific treatment of ARDS
The absence of sound evidence about specific pharmacological treatments of ARDS makes this disease substantially orphan of effective therapies (47,48). Indeed, even if the knowledge of pathophysiology of ARDS has enormously increased in the last years (1), the attempts to hit the suggested targets have been disappointing. Statins, corticosteroids, inhaled nitric oxide (iNO), beta-agonists and drugs influencing vascular permeability will be evaluated below.
The discovery of pleiotropic effects of statins (49,50) and the results of meta-analyses studies highlighting their positive effect on outcomes of septic patients (51,52) prompted RCTs, with the aim to establish the effects of statins on sepsis and ARDS. The HARP RCT (53) enrolled 60 ARDS patients, randomized to receive simvastatin at the dose of 80 mg/die or placebo until mechanical ventilation cessation or up to 14 days. The authors found no significant differences in mortality, but reported an improvement in oxygenation, pulmonary mechanics and non-pulmonary organ failure.
These positive results have not been confirmed by larger subsequent trials. Indeed, the HARP-2 trial (54), in which 540 patients have been randomized to receive simvastatin or placebo for a maximum of 28 days. In this trial, no differences in 28-days mortality, mechanical ventilation free days and non-pulmonary organ failure were reported in the two groups. Similar results reported the more recent trial in which rosuvastatin or placebo was tested in a population of 745 patients (55). The study was prematurely terminated before reaching the target of 1,000 patients because of the absence of any mortality benefits in 60-days mortality and mechanical ventilation free days and because of the concern about an increase of hepatic and/or renal failure incidence in the treatment arm. The results of the one-year follow-up of the 275 survived patients registered the high burden in terms of cumulative mortality of ARDS together with the physical and mental impairments in survived patients, but no effect of rosuvastatin was noted on these outcomes (56). To overcome the risk of these trials to be underpowered to infer on mortality, an individual patients data meta-analysis was recently conducted (57). The authors included 1,755 patients from six critical trials on statins and sepsis/ARDS. No significant effects on 28-days mortality and mechanical ventilation free days were reported. At the same time, even if treated patients had an increased incidence of raised creatinine or transaminases levels, no difference in serious adverse events was observed between the two groups. Considering the overall results of the above-mentioned studies, it emerged that statins therapy in critically ill patients is essentially safe, but the lack of positive results in terms of mortality reduction does not recommend their routine use as an adjunctive therapy in ARDS patients. However, many issues remain unclear: statins are not homogenous from the pharmacokinetics point of view, and it is not known whether this could have influenced the results of some trials; the effective dose, if any, in this category of patients is unknown; the fragility inherent to all clinical trials in critically ill patients could have contributed to negative results (58); finally, ARDS is a heterogeneous disease, whose phenotype characterization is at an early phase (59). Therefore, the identification of subgroups of patients who could take advantage from statins could be the object of future studies.
Two main reasons justify the use of corticosteroids in critically ill patients: their powerful anti-inflammatory effects and the high prevalence of cortico-adrenal insufficiency in critically ill patients (64). Corticosteroids are widely prescribed in ECMO patients (65); however, three trials (66-68) did not demonstrate any mortality reduction in treated patients, but all of these studies reported improvements in secondary endpoints, as mechanical ventilation free days, ICU free days, pulmonary and end-organs function. These trials enrolled relatively small numbers of patients, with the risk that difference in mortality could have been not identified. To overcome this risk, Meduri et al. (69) conducted an individual patients-data meta-analysis, showing reduced in-hospital mortality in patients treated with low dose corticosteroids. The effect was more pronounced for the subgroup in which corticosteroids were started within 14 days from the onset of ARDS. On the basis of these results, low dose corticosteroids (equivalent to methylprednisolone 1 mg/kg/day) could be considered during VV ECMO for ARDS.
Beta-2 agonists are a class of drugs that, beyond its well-known bronchodilator effect, promote sodium and water reabsorption, have anti-inflammatory properties and reduce endothelial permeability (48). This complex pharmacological profile suggested the potential benefits in patients with ARDS. The first small RCT, BALTI-1 (70), showed that patients treated with intravenous salbutamol had, at the end of a 7-day treatment, a reduced extravascular lung water index (EVLWI). Nevertheless, two subsequent larger RCTs with intravenous or inhaled beta-2 agonists reported no effects on mortality and a decreased mechanical ventilation and organ failure free days (71,72). Moreover, in the group treated with beta agonists, the incidence of arrhythmia causing the withdrawal of treatment was higher. In light of these results, confirmed in a recent meta-analysis (73), administration of beta-2 agonists should be avoided.
Alteration of vascular permeability
Alveolar fluid clearance is impaired in ARDS (74) and is associated with increased morbidity and mortality (75). The identification of amiloride-sensitive epithelial sodium channel (EnAC) offered a potential target to address this alteration. The synthetic peptide AP301 is able to enhance the activity of EnAC, promoting sodium and water re-absorption from the alveoli. A preliminary proof-of-concept randomized trial employed aerosolized AP301, demonstrating no improvement in EVLWI, paO2/FiO2 ratio, airway pressures, Murray Lung Injury Score nor 28-days mortality (76). However, restricting the analysis to more severe case (SOFA score >11), a reduction of EVLWI and airway pressures were observed. The authors did not report serious adverse events in the experimental arm compared to placebo. Further studies are needed to clarify the potential role of AP301.
iNO is a gas, delivered in the mixture of respiratory gases that the patient breathes. iNO reaches the ventilated alveoli and, through a mechanism mediated by guanylate cyclase, relaxes the pulmonary vessels, reduces pulmonary vascular resistance, right ventricular afterload and the degree of intrapulmonary shunt (77). iNO is able to increase the paO2, but this effect is transient and more pronounced in the first 24 hours of administration (77). Many trials failed in demonstrating that iNO could improve survival of treated patients (78-80); moreover, no significant benefits in surrogate outcomes have been registered. A recent study (81) and a meta-analysis (82) raised the concern about nephrotoxicity of iNO, with unclear mechanism but probably involving lung-kidney cross-talk and metabolites action. Two recent meta-analyses, on the basis of aforementioned studies, do not recommend its routine use in ARDS patients (82,83). Therefore, the administration of iNO as an adjunctive therapy during VV ECMO should derive from hemodynamic rather than respiratory needs. The favourable effect of iNO in reducing right ventricle afterload could be useful in the significant percentage of patients suffering from concomitant right ventricular failure (84). If pulmonary hypertension takes place and determines right ventricular failure and left ventricular underfilling secondary to leftward interventricular septal shift, the administration of iNO could be beneficial (85).
ARDS is a broad category in which many heterogeneous diseases produce similar clinical expressions in their final phase. The definition itself lacks specificity. The characterization of subphenotypes of ARDS is a promising field, but still in its nascent phase. If subgroups of patients with different characteristics were identified, it is conceivable that more specific new or already available therapies could find their definitive role. Nowadays, few drugs or procedures reached enough evidence to be used routinely as adjunctive therapies for a VV ECMO patient. At the same time, we must be aware that the organisation of trials with an adequate power to infer on mortality in this field is challenging. Contrarily, if the clinical need to adjunctive therapies arises from refractory hypoxemia during VV ECMO, the therapeutic panel is wider.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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