Extracorporeal circulation in acute respiratory failure (Circulación extracorpórea en la Insuficiencia Respiratoria Aguda (IRA))

INTRODUCTION ECMO (Extra Corporeal Membrane Oxygenation) provides extracorporeal temporary respiratory and/or cardiac support by the use of an artificial lung and/or heart in case of cardiopulmonary failure refractory to conventional treatment. It is important to note that ECMO does not treat the underlying pathology but it provides a life support system during the evaluation, diagnosis and resolution of the disease. ECMO is indicated in case of high mortality risk and if the underlying pathology is potentially reversible. In case of cardiac failure the initial etiology to treat the patients with ECMO are quite general. The ELSO registry in 1995 categorized 7 etiologies in the adult: cardiac arrest, post-cardiotomy cardiac arrest, cardiogenic shock, post cardiotomy cardiogenic shock, hypothermia, pulmonary insufficiency, other causes [1]. Indications in case of respiratory failure are Adult Respiratory Distress syndrome (ARDS), pneumonia, trauma, bridge or following lung transplantation but it has also been used, in combination with tracheal intubation and mechanical ventilation to resolve acute asthma attacks and dynamic hyperinflation. In this paper we will primarily discuss the use of ECMO in respiratory failure where the common approach is the veno-venous (VV) bypass in contrast with the veno-arterial (VA) bypass which is used in presence of heart failure. ECMO HISTORY AND TECHNICAL EVOLUTION The first experience of oxygenating blood by an extracorporeal device was performed in 1885 during the perfusion of isolated organs by von Frey and Gruber [2]. After 2 decades, in 1916, MacLean isolated heparin, the primary anticoagulant used in the ECMO circuit. The first laboratory investigation into Extracorporeal Life Support (ECLS) were made in 1930 by John Gibbons, who developed an heart-lung machine in 1937 [3] to allow open heart surgery. In this system the anticoagulated blood was directly exposed to oxygen (“bubble” or “film” oxygenators), unfortunately with severe limitations as hemolysis, thrombocytopaenia, hemorrhage and organ failure. In 1944 Kolff and Berk performed blood oxygenation in cellophane chambers of artificial kidney [4]. From the fifties the technologies evolved and new techniques were introduced, as hypothermia and cross-circulation. In 1950 there was the early development of cardio-pulmonary bypass (CPB) and Gibbon performed the first intervention using CPB in 1953. In 1956 the oxygenators evolved due to the introduction by Clowes of membranes separating the gaseous and the liquid phase, reducing the negative effects of bubble oxygenators [5]. The next year Kammermeyer introduced silicone-membrane lung [6]. Kolobow introduced in the seventies a spiral coil membrane lung [7], widely used for over 30 years. In 1983 Larm [8] introduced a technique that allowed heparinization of all surfaces that come in contact with blood. A recent innovation has been the non-porous hollow fiber devices, characterized by low resistance to blood flow and by polymethylpentene fibers that combined with non-thrombogenic coatings decrease the need of platelets infusion and of continuous heparin infusion. Even the access devices have evolved through the time and the wire-reinforced walls now allow very thin cannula walls, reducing resistances to blood flow. Double lumen catheters reduced the risks of re-circulation and of the placement [9]. TECHNIQUE, CRITERIA and COMPLICATIONS During ECMO venous blood is drained from the venous system through catheters percutaneously inserted either peripherally, via cannulation of a femoral vein, or centrally, via cannulation of the right atrium. The blood is pumped through an artificial lung to oxygenate it and to extract carbon dioxide. The circuit is warmed and heparinized. Blood is then returned back to the patient either in an arterial (aorta, VA) or venous access (right atrium, VV). The VA mode substitutes both heart and lung function, and can be achieved by either peripheral or central cannulation, the VV configuration provides respiratory support only and it is preferred in case of respiratory failure as it leaves normal hemodynamics, it is achieved by peripheral cannulation, usually of both femoral veins. The pumps inserted in the circuit may be of centrifugal or roller type. The centrifugal pump is gravity independent and the inflow is generated by negative pressure at the pump head. Negative pressure should not exceed -20 mmHg to avoid excessive hemolysis, cannula displacement, thrombus at the inflow and inadequate inflow pressures in the patient. The roller pump is gravity dependent, so it must be positioned below the patient level. The inflow is regulated by a bladder regulated by a servomechanism while the forward flow is generated by the compression of the tubing by the heads of the pump and the back plate of the housing. The flow depends on the rotations per minute of the pump, on the occlusion degree and on the tube diameter. Problems may be due to rupture at the tube/heads interface and blow out in the arterial line. New generation circuits are characterized by all surfaces coated with covalently bound heparin and the catheters are wire-reinforced. The system is primed first with a balanced crystalloid and protein coating then the blood is inserted into the circuit using with packed red blood cells and fresh frozen plasma. The support starts quite slowly to allow an adequate mixing of the prime with patient’s blood, the gas flow into the oxygenator is set at an appropriate rate and pressure to avoid apparatus rupture and it is set to maintain adequate CO2 tension. Oxygenation is obtained by the combination of minimal mechanically ventilating the patient natural lung. Several ventilator approaches have been described in association with ECMO. We believe that the most convenient are the ones which try to minimize the potential harm of mechanical ventilation. Therefore, whatever approach is used, attention should be paid to minimize FiO2, plateau pressure and frequency. In our experience, immediately after starting ECMO we keep FiO2 and mean airway pressure as before the bypass. As we decrease the ventilation down to 4-5 bpm this implies an increase of PEEP in order to maintain mean airway pressure. During the bypass, as soon as the patient improves, we first decrease the FiO2 down to 0.4, afterward we decrease PEEP at a rate not greater than 1 cmH2O every 2 hours. When reasonable ventilator set is reached, as an example FiO2 equal to 0.4 and PEEP between 10-15 cmH2O the formal weaning begins by decreasing the gas flow throughout the membrane lung. We decannulate the patient when he is able to tolerate mechanical ventilation without any extracorporeal support (gas flow in the membrane lung equal to 0). Several aspects must be considered evaluating the institution of ECMO. The first one, as previously told, is the likelihood of organ recovery with therapy and during ECMO. Accepted exclusion criteria include contraindication to anticoagulation, (despite the use of surface heparinized apparatus requires reconsideration of this criterion), multiple organ failure, advanced age or poor final prognosis of the underlying pathology, left ventricular failure, immunosuppression, unwitnessed cardiac arrest or cardiac arrest of prolonged duration, aortic dissection or aortic incompetence, sever damage of the central nervous system [10]. The inclusion criteria depend on the centers that performs ECMO [10]. Patients should have been mechanically ventilated for less than 14 day, although some centers exceeded this limit, maximal medical management must have been failed, the disease must be reversible and the mortality risk must be high, although its definition is not easy. Centers usually apply a set of criteria that are modification of the criteria reported by Zapol et al. [11]. They include oxygenation, shunt, compliance and sometimes Murray score. Complications are related to technical aspects and to patient complications [10]. Technical aspects include tubing rupture, pump/heater malfunction, oxygenator failure, cannula related problems. Patient related problems are bleeding, neurological complications, additional organ failure due to non-pulsatile perfusion at end-organs, barotrauma, infection and metabolic disorders. The major complication is bleeding which occurs in 10-30% [12] of the patients and that can be reduced reducing heparinization o f the circuit. It must be noted that whatever maneuver, which is usually without risk, as an example the insertion of naso-gastric tube, may be, in these patients, a source of bleeding. Great attention, therefore, should be paid to all the maneuvers which potentially may damage the tissue surface. It worth to underline, however, that the real nightmare of this treatment is the occurrence of intracranial bleeding. ARDS Acute Respiratory Distress Syndrome (ARDS) has been first described in 1967 in the cornerstone paper published by Ashbaugh on Lancet [13]. ARDS may be caused by a noxious stimulus of either pulmonary or extra-pulmonary and it is characterized by acute pulmonary inflammatory states and acute hypoxemic respiratory failure arising from widespread diffuse injury to the alveolar-capillary membrane. The definition of ARDS evolved through the years and, to date, the routinely used definition is the one introduced by the American European Consensus Conference in 1994 [14]. This definition includes: • the sudden onset of acute hypoxemic respiratory failure • presence of diffuse pulmonary infiltrates that are not caused by hydrostatic pulmonary edema • absence of left atrial hypertension. According to this definition a cut-off value of the PaO2/FiO2 ratio equal to 300 has been defined to indicate Acute Lung Injury (ALI)/ARDS patients: patients with a value comprised between 200 and 300 are define as ALI, while a ratio lower than 300 indicates ARDS. Despite the great advantage of this definition of being a standard way to select patients it is affected by a series limitations (variability of chest X-rays interpretation [15], exclusion of the cardiogenic origin of pulmonary edema [16] and the alteration of the oxygenation staus by PEEP use [17]). Moreover, it has been showed that over half of patients initially classified as ARDS did not met the criteria after 30 min of ventilation with a standardized PEEP [17]. Accordingly the ARDS definition should be updated even considering the results provided by CT scan quantitative analysis, as the amount of lung tissue involved in the pathology, as indicated by the amount of pulmonary edema, and the potential for lung recruitment, defined as the percentage of tissue regaining aeration from 5 cmH2O PEEP to 45 cmH2O end inspiratory plateau pressure [18]. Even the response to PEEP or pronation should be evaluated. ARDS has always been considered a rare pathology, however data on incidence are characterized by a great variability due to the criteria used to identify the patients and to logistic. Studies published in the eighties and nineties reported values between 1.5 and 8.3 case/100000 population, while the most recent studies reported an incidence of 17.9 case/100000 population in Scandinavia [19], 34 in Australia [20] and 78.9 in the King County (United States) [21]. Patients with ARDS are treated with different advanced methods of intensive care developed during the years, including mechanical ventilation, permissive hypercapnia, prone position, fluid resuscitation, vasodilators. The primary treatment of ARDS used since the first description in the sixties is mechanical ventilation. It is used as a buying time maneuver waiting the resolution of the underlying pathology. Through the years modalities and techniques have been sensibly modified to provide ventilatory support improving oxygenation while avoiding augmentation of the existing lung damage. In the seventies ALI/ARDS patients were ventilated with high tidal volumes and low PEEP levels [22-24]. Lung damages due to mechanical ventilation were not known at that time and the only concerns were high inspiratory oxygen concentration and hemodynamics. Clinical and experimental studies led to the development of the concept of Ventilator Induced Lung Injury (VILI) and the goal of mechanical ventilation progressively shifted to the improvement of gas exchange to avoiding lung damages [25]. At the moment, in clinical practice it is widely accepted to ventilate ARDS patients with low tidal volumes normalized on patient ideal body weight (VT/IBW) to avoid excessive strain of the lung parenchyma and to limit plateau airway pressure [26]. The optimum PEEP level has not yet been established as 3 randomized trials on unselected ALI/ARDS population did not find mortality differences testing high versus low PEEP levels [27-29]. It is conceivable that these results are due to the variability of patients severity, the positive effects of high PEEP level on the most severe patients may be cancelled by the nil or negative effects on the less severe ones [30]. This suggest that a correct patients characterization is needed before tailoring mechanical ventilation. There is a residual number of patients, however, in which mechanical ventilation, even at very low volumes is not applicable and the goal of maintaining an adequate oxygenation is not compatible with a “lung protective strategy”. In these patients the use of Extracorporeal Membrane Oxygenation (ECMO) may be an additional treatment during the acute phase. ECMO in ARDS PATIENTS The first successful application of ECMO in a patient with respiratory failure was reported by Hill in 1972 [31] and Bartlett published in 1976 the experience of a newborn treated with ECMO who survived [32]. The enthusiasm risen by ECMO application led to the first large randomized trial launched in 1974 to compare VA ECMO versus conventional therapy in adult ARDS patients [11]. After 90 patients the trial was stopped for futility. The study revealed a 90% mortality both in the ECMO and in the conventional treatment group. This result discouraged the use of ECMO and further research in the field for years. However the idea of supporting the impaired lung by extracorporeal gas exchange was followed by Gattinoni and the group of Kolobow. They proposed to prevent further damage to the natural lung and “resting” it reducing respiratory rate, tidal volume and peak pressure (Low Frequency Positive Pressure Ventilation, LFPPV). Moreover they popularized the idea that the main function of breathing is CO2 removal and that it can be dissociated from oxygenation. Oxygenation was granted by apneic oxygenation while carbon dioxide was removed by the artificial lung. (ECCO2-R). In 1977 [33] the group published their results obtained on experimental animals spontaneously breathing, in which various amounts of CO2 were removed through an extracorporeal membrane lung. Ventilation was reduced proportionally to the amount of CO2 removed and it almost ceased when the extracorporeal CO2 removal approximated the CO2 production (VCO2). The technique was then used even for clinical application in ARDS patients. In 1980 Gattinoni et al published on Lancet their result on 3 patients in which terminal respiratory failure was reversed resting the lungs with diffusion oxygenation (3 bpm), avoiding possible pulmonary and extrapulmonary complications of conventional mechanical ventilation and removed CO2 through a membrane lung by low flow VV bypass [34]. In 1986 Gattinoni et al reported the results of a study designed to evaluate the effects of LFPPV-ECCO2-R in a group of 43 patients with severe acute respiratory failure. Lung function improved in 31 (72.8%), and 21 patients (48.8%) eventually survived [35]. They did not report major technical accidents in more than 800 hours of perfusion, suggesting that this technique may be a reliable alternative to conventional treatments. These results led to many investigations into the technological development of extracorporeal support. Among these works Zwischenberger et al. refined the LFPPV-ECCO2-R technique developing a simplified arterio-venous extracorporeal CO2 removal, called AVCO2-R, with a low-resistance membrane gas exchanger [36]. In 1984 Gattinoni et al found that in a group of 36 ARDS patients meeting mortality rate criteria (90%) for LFPPV-ECCO2R total static lung compliance (TSLC) was the best predictive factor in deciding the management of severe ARDS patients unresponsive to conventional treatment [37]. Patients were ventilated for 48 hours with PEEP and pressure controlled inverted ratio ventilation (PC-IRV) before the connection to bypass, and, if possible they were allowed to spontaneously breathing or to were switched to CPAP. After 48 hours 19 patients still required LFPPV-ECCO2R, 5 were still on PC-IRV and 12 were on CPAP. The authors found that patients with TSLC lower than 25 ml/cmH2O did not tolerate PC-IRV or CPAP, patients with TSLC higher than 30 cmH2O were successfully treated with CPAP while the other patients (TSLC comprised between 25 and 30 cmH2O) had to be treated with PC-IRV for more than 48 h, or were then placed on LFPPV-ECCO2R if PaCO2 rose prohibitively. At that time it was not clear the meaning of the TSLC, which became clear after the quantitative CT scan was introduced in the assessment of respiratory failure. This technique clearly showed that the intrinsic lung characteristics of the ventilatable lung (specific lung compliance) are normal, therefore TSLC just reflects the size of the “baby lung” [38]. This concept fully accounted for the association between the need of ECMO and the low TSLC. ECMO was in the nineties the standard treatment for neonatal respiratory failure refractory to conventional treatments and it was extended even to premature, low birth weight infants, children and adults. The Extracorporeal Life Support Organization (ELSO) registry (introduced in the eighties) reported in July 1994, 9258 neonates (overall survival rate 81%), 754 pediatric (49%), and 130 adult patients (38%) with respiratory failure treated with ECMO. In 1994 [39] Morris published the results of a second randomized clinical trial in which pressure-controlled inverse ratio ventilation followed by LFPPV-ECCO2-R (21 patients) was compared to positive pressure ventilation (19 patients) in ARDS patients. Again they found that the survival rate was not significantly different between the two groups (42% in the control group versus 33% in the ECMO group), however the survival rate was significantly improved compared to the 1979 report. The results of the trial, however, rose a lot of criticism, mainly regarding the inhomogeneous ventilation used in the ECMO group, the high peak pressure used and the methodology used that did not reach the modern standards as indicated by the elevate number of blood loss complications. The results of the trial stopped the research of ECMO application in ARDS. A retrospective case review of the ELSO registry from 1986-2006 published by Brogan et al. [40] showed a mortality rate of ARDS patients treated with ECMO of 50%. Between 2001 and 2007 another prospective randomized trial was conducted in the United Kingdom [41]. The trail compared conventional ventilatory support performed in various centers versus extracorporeal membrane oxygenation for severe adult respiratory failure performed at Glenfeld Hospital. The study included 180 patients from 68 centers, 90 patients in the ECMO group (68 effectively treated with ECMO) and 90 in the conventional treatment group. In the control group the intensivists could use any type of management they felt appropriate but the NIH ARDS strategy was recommended. The authors found that the primary endpoint, the survival at 6 months free of disabilities, was 63% in the ECMO group vs 47% in control group. It is important to note that the intervention in CESAR was referral to an ECMO center not treatment with ECMO (only 75% of ECMO-referred patients actually received ECMO). However it was impressive how the treatment of patients affected by respiratory failure in a center with ECMO capabilities can significantly increase survival rate. The study shows that ECMO referral is beneficial, however, as the Glenfeld Hospital is an expert high case volume center it is not certain that the result would be similar in smaller or less experienced centers. Even the non standard treatment of conventional treatment group rose some criticism. The recent H1N1 flu epidemics led to an increase of respiratory failure with patients considered not safely ventilable with current clinical criteria (i.e. tidal volume 6-8 ml/Kg and plateau pressure below 30-35 cmH2O) leading to renewed interest for extracorporeal support and hundreds of ARDS patients worldwide received ECMO, according to the ELSO registry. Typing “H1N1 and ECMO” in PubMed the displayed results are 93 from 2009 to January 2011. The most relevant report was the one performed by australian and New Zealand investigators [42]. The authors reported that, between June and August 2009, 68 patients with severe H1N1 influenza-associated ARDS were treated with ECMO. Before ECMO these patients, characterized by a median age of 34.4 years, had severe respiratory failure despite advanced mechanical ventilatory support. The authors reported a mortality rate of 21%. Freed et al. reported a mortality rate of 33% of 6 patients only 6 patients were treated with ECMO for influenza H1N1 related ARDS in Canada [43]. A prospective observational study of patients treated in Marseille South Hospital from October 2009 to January 2010 reported the data about 22 patients requiring mechanical ventilation [44]. Eighteen were admitted to ICU for ARDS and 10 patients met the criteria for ECMO; of them nine received it whereas one patients died of cardiac arrest due to hypoxemia before ECMO could be organized. These 9 patients were compared with other 9 patients treated without ECMO. Mortality rate was 56% in both groups (5 patients died in each group while 4 survived). In the ECMO group cause of death was intractable respiratory failure in 2 patients and multi-organ failure in 3 patients while in the group treated without ECMO the cause of death was intractable respiratory failure in 1 patient and multiorgan failure in 4 patients. In Italy between August 2009 and March 2010, 151 patients were admitted to the ICUs of 14 selected centers with suspected H1N1 (courtesy of Dr. Patroniti, data submitted for publications). Sixty patients were treated with ECMO; among them 49 patients had ARDS caused by H1N1, while 11 patients had ARDS because of other causes. Overall survival at hospital discharge was 41/60 (68%), while survival for confirmed H1N1 was 35/49 (72%) versus 6/11 (54%) for non confirmed H1N1. The report of the incidence of hemorrhagic complications seems the major limit of ECMO diffusion. However both the CESAR trial [41] and Italian data reported that only 1 patient died for hemorrhagic complications. The experience gained in the last years taught that new generation devices and the promotion of support from experienced centers seems relevant for a successful ECMO treatment. CONCLUSION After almost 40 years since the first ECMO application this technique is increasingly used. As dr. Bartlett said (email, personal communication): “did more pigs for ECMO than whatever randomized trial”. We believe that all the centers applying for the first time this support (which is now technically advanced and relatively simple) for H1N1 flu discovered how the system is powerful. We are presently investigating the feasibility of extracorporeal support as bridge to lung transplant, in re-exacerbation of COPD and in ARDS, without associated mechanical ventilation. If the preliminary results will be confirmed we will plan a randomized trial in which 2 treatment will be compared in the ARDS patients: mechanical ventilation according to lung protective strategy versus ECMO without intubation. 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