The advent of ECMO and pumpless extracorporeal lung assist in ARDS.

Despite advances in critical care facilities and ventilation therapies acute respiratory distress syndrome (ARDS) is associated with high mortality rates. The condition can stem from a multitude of causes including pneumonia, septicemia and trauma ultimately resulting in ARDS. ARDS is characterized by respiratory insufficiency with severe hypoxemia or hypercapnia. The treatment strategy depends on the knowledge of the underlying disease. But lung-protective ventilation with adjusted positive end-expiratory pressure remains the most effective therapeutic tool despite advances in prone positioning, inhalation of nitric oxide and the use of steroids. Newer modalities including extracorporeal membrane oxygenation (ECMO) and pumpless extracorporeal lung assist (PECLA) are being increasingly introduced in critical care settings as rescue therapies in patients who fail to respond to conservative measures. We describe here the introduction and advances of both ECMO and PECLA in the management of ARDS.

INTRODUCTION

The first description of acute respiratory distress syndrome (ARDS) was probably by Laennec in 1821 who described pulmonary edema without heart failure in “A Treatise on Diseases of the Chest”.[1] In the 1960s, since acute, diffuse and dense bilateral infiltrates were almost never observed except in patients requiring prolonged mechanical ventilation, the condition gained the term “respirator lung”.[2] It was only in 1967 that Ashbaugh and his colleagues first described the clinical entity that they called “acute respiratory distress in adults”.[3] ARDS was recognized as a group of pathophysiological abnormalities common in patients whose lungs sustained injury by a wide variety of unrelated insults—for example, gastric aspiration, sepsis, blunt trauma, near-drowning, etc. Clinically, acute lung failure is characterized by respiratory insufficiency with severe hypoxemia or hypercapnia.

ARDS technically is defined as a significant inflammatory response to a local (pulmonary) or remote (systemic) insult which results in hypoxemia and marked alterations to pulmonary mechanics. By definition four clinical criteria must be met to establish a diagnosis of ARDS: 1) Acute disease onset, 2) bilateral pulmonary infiltrates on chest X-ray, 3) pulmonary capillary wedge pressure <18mmHg or absence of clinical evidence of left atrial hypertension and 4) ratio between arterial oxygen partial pressure (PaO2) and the fraction of inspired oxygen (FiO2) <200. Patients that meet criteria 1-3, but exhibit a PaO2/FiO2 ratio >200 and <300 are defined as having acute lung injury (ALI), a process physiopathologically similar to ARDS but of lesser clinical severity.[4] Table 1 presents the three most commonly used definitions.

Table 1

Three widely used definitions of acute respiratory distress syndrome[4]

Based on the above criteria, it is estimated that ARDS has an incidence of 13.5 cases per 100,000 people.[5] Despite significant advances in general intensive care therapies, the dramatic alterations that are characteristic of ARDS are associated with an elevated mortality, varying between 35 and 71%.[6] The overall mortality rate in acute respiratory failure leading to mechanical ventilation is still high.[7]

PATHOPHYSIOLOGY

ARDS is characterized by platelet activation and aggregation, microthrombi and intra-alveolar deposition of fibrin. In the 1990s, a procoagulant tendency was observed as concentrations of anticoagulant proteins (protein C and S) fall and there is increased expression of procoagulant proteins (tissue factor) and antifibrinolytic proteins (plasminogen activator inhibitor-1).[8] Survival in ARDS varies widely depending upon age, chronic disease burden and non-pulmonary organ dysfunctions such as shock and hepatic failure. Younger trauma patients have the best outcomes.[9]

MANAGEMENT

The treatment strategy depends on the knowledge of the underlying disease. Lung protective ventilation with adjusted positive end-expiratory pressure (PEEP) remains the most effective therapeutic tool.[10] However, in the most severe cases of acute respiratory failure profound hypoxemia or respiratory acidosis may contradict the sole use of protective ventilation strategies and necessitate additional non-pharmacological interventions strategies such as positioning manoeuvres, inhalation of nitric oxide, [Figure 1] partial liquid ventilation or high-frequency ventilation techniques.[11]

Figure 1

Frequently adjunct therapies such as nitric oxide is used to further manage ARDS as in this Indonesian boy. Although low flow tidal volumes and positive pressure ECCO2 removal remain the therapeutic basis for ARDS in these patients with Novalung, modalities such as steroids, nitric oxide and others are continued if indicated

Pharmacological interventions have been mainly studied in the use of corticosteroids and NSAIDs (non-steroidal anti-inflammatory drugs). The ARDSNet has recently completed a large randomized, blinded trial of methylprednisolone versus placebo. Results presented indicate no difference in 28 or 60-day mortality despite improvements in gas exchange, blood pressure and time on ventilator among patients given methylprednisolone.[12]

The use of prone positioning has thus far proven inconclusive pending further studies to establish the optimal ventilatory setting to be selected before, during and after positioning; to determine the duration and frequency of positioning; and to standardize the maneuver . Studies involving tidal volume have had severe limitations with regard to the statistical power needed to detect a difference. However, Amato et al,[13] was able to show a survival benefit from the use of smaller tidal volumes (6 ml/kg actual body weight) in conjunction with other strategies designed to protect the lung such as lung recruitment maneuvers.

It has been postulated that the lack of adequate functional surfactant makes reinflation very difficult, requiring high airway pressures. Thus in established ARDS, PEEP has been adopted for routine management to recruit, reduce oxygen requirements and improve compliance. Further, by keeping alveoli open throughout the respiratory cycle, damage produced by the repetitive opening and closing may be prevented.[14] Fluid management has assumed greater importance in the management of ARDS as under conditions of microvascular injury, lung water accumulates to a greater degree compared with normal lung at the same microvascular pressures.

Two other non-pharmacological interventions that have gained greater prominence in the treatment of ARDS as a result of Severe Acute Respiratory Syndrome and H1N1 have been the use of extracorporeal membrane oxygenation (ECMO) and pumpless extracorporeal lung assist (PECLA) which is the focus of this review. These modalities facilitate oxygenation and carbon dioxide (CO2) removal without the harm associated with aggressive mechanical ventilation.

EXTRACORPOREAL MEMBRANE OXYGENATION

ECMO is a technique for providing life support for patients experiencing both pulmonary and cardiac failure by maintaining oxygenation and perfusion via oxygenators until native organ function is restored. [Figures 2–6]. In 1972, Hill et al,[15] first reported the use of ECMO in a young pa tient who suffered from ARDS after trauma. A milestone in the technical evolution of cardiopulmonary bypass and ECMO was the development of membrane oxygenators instead of bubble oxygenators in the 1960s, leading to increased short- and long-term biocompatibility. Bartlett and colleagues reported the first case series of 28 patients (14 children, 14 adults) who were treated with ECMO in 1977.[16] Although only five of 28 patients were long-term survivors, the early successes in near-moribund patients led to the first randomized trials of ECMO therapy for respiratory failure in neonates. The first of these trials used a non-traditional “play-the-winner” randomization technique, where the chance of assigning an infant to a treatment was influenced by the outcome of previous patients in the study. All 11 high-risk patients who were treated with ECMO survived (although 1 patient had a cerebral hemorrhage), while the single patient who received conventional therapy died. For newborns with severe respiratory failure, a prospective, randomized study clearly demonstrated that ECMO improved clinical outcome and is cost-effective compared with conservative therapy.

Figure 2

ECMO flow diagram

Figures 3–6

Figures show a centrifugal pump used for ECMO. Children will have cannulas left in the aorta and right atrium for post-op cardiac surgical indications such as low output syndrome. In general the circuit contains a pump which receives venous blood and pumps it into an oxygenator with a side line to a hemofilter past a flow probe and back to the arterial side of the patient. Cannulation sites for adults are the Internal Jugular Vein (IJV) Femoral vein (FV) for VV ECMO and IJV and/or FV, and Femoral artery for VA ECMO

However, in 1979 a randomized controlled trial using ECMO in ARDS were published showing mortality rates of more then 90% in both the ECMO and conventional ventilation arms.[17] Proponents of ECMO argued that this NIH-sponsored study had several problems. A veno-arterial (VA) perfusion with reduced pulmonary blood flow, no adjustment of mechanical ventilation to protect the lungs after starting ECMO, high-dose heparinization with a daily blood loss of 2.5 L and termination of ECMO after 5 days regardless of lung function are possible reasons for the disappointing results in this trial.

It was Gattinoni and co-workers[18] who were the first to introduce the use of extracorporeal CO2 removal (ECCO2R) to support protective ventilation strategies. They developed an alternative approach: a veno-venous (VV) perfusion route and a blood flow of only 20-30% of cardiac output combined with low-frequency mechanical ventilation and additional oxygen insufflations, known as ECCO2R. He believed keeping the activated clotting time (ACT) low and using heparin-bonded tubing to minimize heparin use were important features in reducing the morbidity associated with the technique. In 43 patients with severe ARDS according to the same entry criteria as used in the first ECMO study were treated with ECCO2R, demonstrating a 51.2% mortality rate.

However, once again a randomized controlled trial in 1994 failed to show a survival benefit in ARDS patients treated with ECCO2R.[9] Shortfalls in this trial included the fact that only 40 patients were in the trial as against the ARDS Network trial on low tidal volumes which recruited >800 patients. Setbacks also included the technical devices used which were not sufficiently developed and therefore prone to complications, such as thrombosis, hemorrhage and infections. In addition, protective ventilation strategies differed substantially from what is being used today. Gattinoni et al,[18] used a ventilatory concept based on low breathing frequencies and high tidal volumes. Today it has been shown that low tidal volumes and airway pressure gradients are the key determinants of a protective ventilatory strategy.[13]

Since these negative trial results, there has been a growing body of non-randomized reports supporting the use of ECMO in adults with severe hypoxic respiratory failure. Other centres enhanced the usage of ECMO therapy for most severe cases of ARDS with life-threatening hypoxemia, demonstrating an average mortality of 44% in various case studies.[19-21]

Hemmila et al, reviewed ECMO usage in 255 adult patients from the University of Michigan from 1989 to 2003. These patients nearly all had “severe” ARDS with a Pao2/Fio2 ratio of ≤100 despite receiving optimal conventional treatment and were thus more ill than those patients reported in other ARDS trials. Despite an expected survival rate of <20%, the actual survival rate of patients treated with ECMO was 52%.[20]

To address these contradictions, a prospective, randomized trial of 180 patients comparing ECMO to conventional ventilation (the Conventional Ventilation or ECMO for Severe Adult Respiratory Failure trial) was recently completed in the United Kingdom. Patients randomized to the ECMO arm of the trial were transferred to a single ECMO center to receive treatment, while patients randomized to conventional ventilation remained in regional treatment hospitals experienced in managing severe respiratory failure. Death or disability in the group randomized to receive ECMO was only 37% at 6 months compared with 53% in patients who were randomized to the control arm.[22]

ECMO can be instituted via the VA or VV route. Both require the use of a pump to generate flow rates of 3-5 L/min to ensure sufficient organ perfusion and oxygenation, respectively. For respiratory failure, VV cannulation (usually via the femoral vein and internal jugular vein) is preferred. Since there is no arterial cannulation in VV ECMO, this eliminates complications secondary to arterial embolic events. This is significant since strokes represent a leading cause of mortality in adult ECMO patients, occurring in up to 10% of patients receiving VA cannulation.[20] After a patient is placed on ECMO, protective ventilation strategies are used to minimize further ventilator-induced lung injury while the lungs recover.

ECMO is an intensive therapy with a learning curve in its application and its practice is best suited to centers where the expertise exists in daily management. For this reason, regionalization is appropriate to ensure that adequate volumes are present at each ECMO center. Currently, ECMO is a routine procedure with a 35-year experience, usually carried out in patients with severe ARDS as a rescue therapy. Unfortunately, ECMO therapy often has to be restricted with regard to support duration for its negative side effects, such as hemolysis, coagulation disorders and technical complications.

EXTRACORPOREAL LUNG ASIST

Patients presenting predominantly with hypercapnic respiratory failure may be treated with an arterio-venous-assist device. In contrast to ECMO, no pump is needed for the arterio-venous approach since low-resistance devices are available which allow sufficient blood flow driven by the patient's own blood pressure [Figures 7–12]. The aim of PECLA insertion is to allow lung-protective ventilation and to improve gas exchange. Thus, native lung function is supported, and the diseased lung may recover better as artificial ventilation can be downgraded. Accordingly, additional iatrogenic lung injury such as barotrauma and volutrauma caused by mechanical ventilation with high tidal volumes and high peak inspiratory pressures can be reduced.[23]

Figure 7

Scheme of the simple pumpless extracorporeal lung assist device: arteriovenous shunt with membrane oxygenator, continuous flow measurement in the venous blood line[27]

Figure 12

The iLA membrane oxygenator up close. Note its compact size. It allows a narrow pressure drop and has 1.3m2 of membrane to facilitate gas exchange. In respiratory failure, it is used mainly for CO2 diffusion

Pumpless extracorporeal lung assist device in use in a 7-year old child with lung failure after near drowning[27]

PECLA used in a 17 year old Indonesian boy who developed ARDS following pulmonary embolism after internal fixation of a fractured tibial fracture following an accident. Note the arterial cannulation from the femoral artery and to the femoral vein. The flow meter is on the femoral vein line. The oxygen is delivered through the green tubing to the membrane oxygenator.This patient required two changes of the Novalung as the first clotted after a week's use

Note placement of the Novalung between the patient's legs. There has been concern that long term patients will not be turned regularly for bed sore prevention. The use of other preventive measures such as ripple mattresses become important. Failure to adhere strictly about movement has resulted in femoral artery cannulae being dislodged and patients sustaining hypovolemic shock

The Novalung's flow meter showing typically the low flows provided in these patients with respiratory failure

PECLA devices achieve flow rates of 0.8-1.5 L/min which is sufficient to allow effective CO2 removal. Vascular access is usually obtained via 13-15 F arterial cannulas and 15–17 F venous cannulas inserted into the femoral vessels. PECLA was developed by an interdisciplinary group of perfusionists, cardiac surgeons, internists and anesthesiologists in cooperation with the industry (Novalung GmbH, Hechingen, Germany). The first clinical use took place in 1996.[24] With the introduction of this minimized pumpless lung-assist system using the blood pressure gradient between arterial and venous circulation as the driving force, a reduction of the negative side effects, eg, blood trauma and coagulation disorders and the high costs of pump-driven membrane oxygenation, could be achieved with a comparable mortality to ECMO therapy in selected patient groups.[25]

The main component of the PECLA is a membrane oxygenator (iLA Membrane Ventilator, Novalung GmbH) with a low resistance (of approximately 15 mmHg at 2.5 L/min blood flow) between inflow and outflow. The diffusion membrane of the oxygenator is manufactured of poly-4-methyl-1-penten which allows long-term application and has a surface of 1.3 m2 to which an oxygen flow of 1-12 L/min can be administered. The system is primed with 250-300ml of Ringer's lactate solution. The PECLA system as well as the tubing is coated with high molecular-weight heparin, which allows minimizing anticoagulation and surveillance of it with the ACT (target range, 130-150 seconds).

Analysis for arterio-venous iLA has demonstrated that total ECCO2R is possible with a blood flow of 10-15% cardiac output with a gas flow of 5 L/min and an adequate diffusing capacity of the oxygenator. Blood flow depends on the diameter and resistance of cannulae as well as mean arterial pressure (MAP). Although the membrane could act as the perfect oxygenator, oxygen transfer is limited due to the fact that arterial blood is flowing into the oxygenator. Therefore, the main mechanism of the device is CO2 removal. However, in profound hypoxemia the oxygenation effect becomes more obvious when the inflowing arterial blood is no longer completely oxygenated.

The pumpless arterio-venous approach is increasingly being used in patients with ARDS, although there is still no data from randomized controlled trials to support this concept. But with the help of PECLA, a low tidal volume, positive pressure ventilation can be effected. The results of the ARDS Network have demonstrated that a less invasive ventilation strategy with low tidal volumes of 6ml/kg and inspiratory plateau pressures of 30 cm H2O (3 kPa) resulted in a better survival rate than conventional ventilation with tidal volumes of 12 ml/kg and inspiratory plateau pressures up to 50 cm H2O (5 kPa).[26]

Bein et al, reported the largest series on the use of PECLA in 90 patients with ARDS. They placed 159 patients with an age ranging from 7 to 78 years from 1996 on ECLA. The main underlying lung diseases were ARDS (70.4%) and pneumonia (28.3%). ECLA lasted for 0.1 to 33 days, Successful weaning and survival to hospital discharge was achieved in 33.1%. The best outcome was obtained in patients after trauma. They concluded that the best indication for use of PECLA is severe hypercapnia and moderate hypoxia. A significant improvement of oxygenation was notable during PECLA support in all but three patients (98%).

As the PECLA is a pumpless device, a cardiac index greater than 3 L/min/m2 and a MAP of greater than 70 mmHg is considered necessary because an arterio-venous shunt volume of 1.0-2.5 L/min has to be tolerated by the patient's circulation. If these requirements could not be met with or without catecholamine support (epinephrine, norepinephrine) a pump-driven device was used instead.

The advantages of the PECLA are the avoidance of all pump-related complications. Disadvantages include indirect control of blood flow, which is the result of the arterio-venous pressure gradient; low oxygen transfer capacity, since the already oxygenated arterial blood is flowing into the device; arterial cannulation, which might pose local problems to the cannulated vessel and distal blood flow; and arterio-venous shunt perfusion up to 25% of cardiac output, which needs to be sustained by the left ventricle. Accordingly, the contraindications for the PECLA are heart failure, septic shock with low MAP and severe peripheral arterial occlusive disease. PECLA is generally used in patients with severe acute respiratory failure and severe hypercapnia. It enables a more protective ventilation strategy with reduced airway pressures and tidal volumes, while providing adequate gas exchange in many of the most severe cases of respiratory failure, such as chest deformation, chest trauma, post-surgery, bronchospasm and asthma.[27-29]

CONCLUSION

Although these new modalities show promise in the difficult management of ARDS, patient selection is frequently important. But in a deteriorating patient treated with conventional therapy and especially in instances where the ARDS is rapid and potentially reversible particularly in young patients with trauma or the current viral pneumonia with H1N1, these treatment modalities may potentially gain more importance. More studies, however, will be required to reduce complications associated with these therapies. Cost is an important factor. Although ECMO has been proven to be cost-effective, PECLA awaits further studies.

One of the most important limitations when using PECLA or ECMO is the technical complexity and the personnel required to install and maintain the technique at the bedside without causing major complications such as bleeding, clotting and complement activation as a result of mechanical and contact activation. The development of miniaturized systems with improved bioactive and heparin-bound surfaces will certainly help toward the widespread clinical use of extracorporeal support systems.

Many case reports and small series have shown the clinical feasibility and physiological benefit of PECLA. But unlike ECMO, bigger clinical studies are necessary to evaluate the advantages, complications and indications as well as contraindications of the PECLA. Over the past few decades, VV PECLA has been an important therapy for the management of severe ARDS. But for now both therapies will probably be seen as rescue therapies for the most severe of ARDS cases due to the highly demanding technical and personnel requirements.