Mechanical ventilation and good critical care are mainstays of therapy when treating patients with ARDS.

The use of extracorporeal technology to accomplish partial or total gas exchange (O2 and/or CO2), with or without cardiac support, is based on the premise that “lung rest” facilitates repair and avoids the volu/barotrauma of ventilator management. The basic technique involves a permeable membrane gas exchanger, either extracorporeal or intracorporeal, which may or may not be driven by a pump. Large vessel cannulation is typically needed in patients with extracorporeal support. Depending on the design and application of the technology, the circuit orientation can be venovenous (VV) or venoarterial (VA), as with extracorporeal membrane oxygenation (ECMO), or arteriovenous, as with arteriovenous carbon dioxide removal (AVCO2R). Recent techniques have employed percutaneous access to simplify AVCO2R with significant reductions in ventilator settings.1 Intracorporeal devices are limited by the surface area of the oxygenator within the vena cava.

Extracorporeal Membrane Oxygenation
ECMO, a modification of cardiopulmonary bypass, has been shown to decrease the mortality of neonatal respiratory distress syndrome (RDS) and is capable of total gas exchange. Patients with a predicted mortality of 90% have been treated with ECMO and nationwide experience with more than 19,500 patients shows a greater than 75% survival.2 Adult ECMO also has improved survival compared to historical controls; however, one recent study comparing ECMO with conventional support shows no superiority of either technique. Bartlett et al3 began clinical trials in 1972 and reported the first successful use of ECMO in newborn respiratory failure in 1976. During the initial experience, ECMO had an overall survival rate of 75%-95% and these results helped to establish the therapeutic effectiveness of ECMO in infants having met criteria predicting 80%-100% mortality.

Other adverse effects associated with ECMO include intracranial hemorrhage (ICH), cardiovascular complications, sensorineural hearing loss, and immune system impairment. ICH is a major concern during ECMO. ICH has been described with an incidence of 9.9%-14.9%.4,5 Hardart and Fackler4 demonstrated an increased risk in neonates who had a low gestational age, acidosis, sepsis, coagulopathy, and treatment with epinephrine, with a gestational age of < 34 weeks being a major barrier for use of current ECMO technologies (odds ratio of 12.1). Kasirajan et al6 identified an incidence of ICH in adults of 18.9% with increased risk for females (odds ratio 6.5), use of heparin (odds ratio 8.5), creatinine > 2.6 mg/dL (odds ratio 6.5), need for dialysis (odds ratio 4.3), and thrombocytopenia (odds ratio, 18.3). Khan et al5 reported that 93% of ICH during ECMO occurs within the first 5 days of therapy; therefore, unless there is a clinical suspicion, daily cranial ultrasonography after the fifth day of ECMO is not cost-effective because subsequent examinations are unlikely to yield information significant enough to alter management.

Cardiovascular complications include hypertension, myocardial stun, arrhythmias, cardiac arrest, pericardial effusion, and noninfective thrombosis. Becker et al7 reports decreased survival in infants with myocardial stun, arrhythmias, and cardiac arrest, but no decreased survival was seen in infants with hypertension and pericardial effusion. Mann and Adams8 reported 24% of ECMO survivors were confirmed to have sensorineural hearing loss with 8% having progressive hearing loss. Additionally, Kawahito et al9 reported that the lymphocyte counts of ECMO survivors returned to normal levels within 5 days after being weaned from ECMO, while the lymphocyte counts of nonsurvivors remained at low levels.

Although ECMO had been used since 1975, systematic collection of data did not begin until 1985. Since 1989, participating ECMO centers have voluntarily registered all patients with the Neonatal, Pediatric, and Adult ECMO Registry of the Extracorporeal Life Support Organization (ELSO). Information concerning patient demographics, pre-ECMO clinical features, ECMO indications, medical and technical complications, and outcome have been collected and updated continuously as new patients undergo ECMO.

Neonatal ECMO
ECMO has become the standard treatment for acute respiratory failure (ARF) in newborn infants based on successful phase 1 studies,3 two prospective randomized studies,10,11 and worldwide application in more than 14,543 patients with an overall 84% survival rate in neonates who were thought to have a survival rate of 20% without ECMO.2

Pediatric ECMO
Concurrent with the adult collaborative study, ECMO was evaluated in children. Bartlett et al12 and Kolobow et al13 reported an ECMO survival rate of 30% in children and infants beyond the neonatal period with ARF whose predicted survival rate with conventional therapy was thought to be < 10%. Green et al14 reported the results from the Pediatric Critical Care Study Group multicenter analysis of ECMO for pediatric respiratory failure. ECMO was associated with a significant reduction in mortality versus conventional or high-frequency ventilation (74% survival with ECMO vs 53% survival in controls). As of July 1999, ECMO had been used in more than 1,711 children with respiratory failure, achieving an overall survival rate of 62%.2 ECMO has also been used for children needing cardiac support with a survival rate of 52%.2 As currently applied to children and adults, ECMO is indicated in acute, potentially lethal respiratory failure that does not respond to conventional therapy when the underlying condition is potentially reversible.

Adult ECMO
In 1972, Hill et al15 reported the first successful clinical use of ECMO in adults. Gattinoni and coworkers,16 using a modified ECMO technique (low-frequency positive-pressure ventilation with extracorporeal carbon dioxide removal [LFPPV-ECCO2R]), achieved 49% survival in adult ARF. Improvement in survival is also in part due to better patient selection, VV perfusion, better regulation of anticoagulation, and ventilator management directed toward “lung rest.” With this information at hand, Morris initiated a controlled trial of a three-step therapy for ARDS.17 Patients were randomly assigned to a control arm of protocol-controlled continuous positive-pressure ventilation or a new treatment arm of pressure-controlled inverse-ratio ventilation; if the patient failed to improve, LFPPV-ECCO2R was used.17 The overall survival rate was 39% in ECCO2R and conventional therapy groups. Bartlett’s experience, initially reported by Anderson et al18 in 1993, reported 47% survival in adults with ARF and 40% survival with ECMO for cardiac support. Most recently, in a retrospective review of 100 adult patients with ARF treated by Bartlett’s group, Kolla et al19 reported a 54% overall survival. Pre-ECMO variables found to be significant independent predictors of outcome included pre-ECMO number of days of mechanical ventilation, pre-ECMO P/F ratio, and patient age. Rich et al20 also retrospectively evaluated Bartlett’s standardized management protocol for ARF utilizing “lung protective” mechanical ventilation and ECMO in 141 patients. Forty-one patients showed improvement with the initial protocol of ventilator management (83% survival), while 100 did not and required ECMO support (54% survival). Overall, lung recovery occurred in 67% of the ARF patients with a 62% survival. Detailed and specific protocols for respiratory management to ensure consistent and uniform respiratory care may yield superior results to historical or nonprotocol-controlled critical care and may decrease the need for ECMO. As of July 1999, 483 adults treated with ECMO for respiratory failure have been entered in the ELSO Registry. The overall survival rate in those patients was 52%.2

The indication for ECMO in pediatric and adult patients is ARF of a few days’ duration with a predicted mortality rate of > 80%. However, current techniques of ventilatory management are often associated with high inspiratory airway pressures (barotrauma), overdistending normal lung regions (volutrauma), and toxic levels of inspired oxygen, leading to exacerbated lung injury manifested by progressive deterioration in total lung compliance, functional residual capacity, and arterial blood gases. High positive airway pressure also contributes to cardiovascular instability. Disappointing results with conventional management of ARDS patients have resulted in an increased urgency for developing alternative strategies that provide sufficient oxygenation, CO2 removal, and “lung rest.” It has been recognized that the primary goal of respiratory support focuses on CO2 removal and O2 exchange with avoidance of high tidal volumes and airway pressures.21 ECMO allows this goal to be maintained even when the lung is incapable of sufficient gas exchange.

Venovenous ECMO
The technique of VV ECMO, as performed by Gattinoni16 and Kolobow,22 is different from VA ECMO.23 This technique prevents damage to diseased lungs by reducing their motion (pulmonary rest), although three to five “sighs” with LFPPV are provided each minute to preserve the functional residual capacity. With this method, oxygen uptake and CO2 removal are dissociated: oxygenation is accomplished primarily through the lungs, whereas CO2 is cleared through ECCO2R. LFPPV-ECCO2R is performed at an extracorporeal blood flow of 20%-30% cardiac output. VV ECMO has the advantage of maintaining normal pulmonary blood flow and avoiding arterial cannulation with the risk of systemic microemboli or stroke. In a recent retrospective review of 94 patients, Bartlett’s group concluded that percutaneous cannulation can be utilized for VV ECMO in adults.24

Outcome
Since the 14-Fr venovenous dual lumen (VVDL) catheter became commercially available in 1989, more than 2,180 neonates have been treated with a 88% overall survival.2 A multicenter retrospective comparison of VA access to VVDL for newborns with respiratory failure undergoing ECMO was undertaken.26 Overall survival in patients undergoing VA bypass was 87%, whereas survival in patients undergoing VVDL was 95%. Therefore, during the initial experience, VVDL ECMO had a higher survival rate and a lower rate of major neurologic complications.27 As of July 1999, VA versus VVDL survival is 77% versus 88%, respectively.2

Although cases in which this technique was used may have been more carefully selected and “more stable” than VA ECMO cases, early success may lead to an important conceptual change in the use of ECMO technology. The current practice of waiting until the natural lungs become severely dysfunctional and then having to support cardiopulmonary function almost completely, as with VA ECMO, may give way to the concept of early lung assistance. Single-site cannulation may soon become the method of choice for most newborn patients. Likewise, continued catheter development will allow percutaneous access for VVDL ECMO. A single cannula tidal flow VV ECMO system has been developed that allows percutaneous access.28,29

Cardiac Support
ECMO’s use has been extended to cardiac and pulmonary support after cardiac surgery in children and infants.30,31 VA cannulation provides the optimal cardiac support when ventricular dysfunction predominates the clinical picture. However, studies have also shown that VV bypass, primarily by improving venous oxygenation, may improve myocardial oxygenation and decrease pulmonary vascular resistance in selected patients, thus providing adequate cardiac recovery and support.32

During ECMO support, it is important to maintain adequate pulmonary ventilation to prevent atelectasis while recognizing this may also create hypocarbia and excessive PaO2. This should be controlled by reducing ventilatory rate (not tidal volume) and adjusting the O2 and CO2 flow to the membrane. Adequate tidal volume and extracorporeal flow rates should never be altered to manage PaO2 or PCO2. VV cannulation provides oxygenation support to venous blood. When myocardial dysfunction is primarily due to inadequate oxygenation or elevated pulmonary vascular resistance, improvement may be accomplished by increasing the saturation of the venous blood. Such situations are uncommon in pediatric cardiac surgery, and therefore VV ECMO has infrequently been used in this patient population.

The preoperative use of ECMO in infants with congenital heart disease is controversial. Other groups have described the successful use of ECMO as a bridge to transplant in pediatric patients33 and a lifesaving therapy after lung transplantation.34 Intraoperative ECMO is used when the child cannot be weaned from cardiopulmonary bypass (CPB) despite maximal inotropic therapy and optimal operative repair. Decisions about venting of the left ventricle at the time of initiation of ECMO in the operating room depend on the measurement of left atrial pressure on full ECMO support.

Clinical Results
Early survival was 40%-44%, with somewhat better survival (43%-54%) when the lesion was tetralogy of Fallot, truncus arteriosus, atrioventricular canal, or total anomalous pulmonary venous return. Lower survival rates (14%) have been reported for single ventricle, hypoplastic left heart syndrome, and other malformations requiring a Fontan procedure. Difference in survival rates suggests improved survival is associated with a complete biventricular operative repair, while an operation with shunt-dependent pulmonary blood flow is associated with lower overall recovery rates. A decreased survival rate of 0%-27% is found when the patient is unable to be weaned from CPB, suggesting a greater degree of myocardial damage in these patients. Current survival rates of ECMO for cardiac support are 55% (neonates), 52% (pediatric), and 36% (adult).2

Future
Most ECMO for respiratory support will be carried out in the VV mode using a single catheter with two lumens or a single lumen tidal flow system. Percutaneous access has become the standard approach for almost all patients over age 2. With improvement in technique and simplification of ECMO, the indications may be expanded. With improved circuit safety, single vein access, and minimal anticoagulation, indications for ECMO will change from moribund patients to patients with moderate respiratory and cardiac failure. ECMO will become an adjunct to conventional ventilation and pharmacologic management rather than something to try when standard ventilation and pharmacology are failing. At the same time, simpler methods of treatment of acute pulmonary and cardiac failure may significantly decrease the need for ECMO.

ECMO has led to better understanding of pulmonary pathophysiology. It has changed the management of congenital diaphragmatic hernia from a rush to the operating room to ICU management until the pulmonary hypertension has been resolved with elective repair of the defect days or even weeks after birth. ECMO permits the evaluation of innovative approaches to lung hypoplasia in the newborn, and earlier and more extensive use of ECMO will lead to the study of pharmacologic agents to reverse fibrosis and growth factors to enhance lung generation or re-generation. The study of ECMO has brought the proper emphasis to the separation of oxygenation from CO2 removal and the realization that high peak airway pressure during attempted hyperventilation for CO2 clearance is the major culprit in ventilator-induced injury. A return to pressure limited mechanical ventilation has occurred, with ECMO acting as an adjunct when low pressure mechanical ventilation does not achieve adequate CO2 clearance.

Different techniques (nitric oxide, pressure-controlled inverse-ratio ventilation and permissive hypercapnia, intravenous oxygenation [IVOX], AVCO2R, and liquid ventilation) highlight the fact that the tools used to sustain gas exchange in the patient with respiratory failure in the near future may be very different from now. The availability of ECMO has made it possible to study these innovative and numerous methods of lung management. Currently, ARDS is primarily treated with mechanical ventilation, aimed at restoring normal blood gases by manipulating minute ventilation and oxygen concentration and by adding or adjusting PEEP (positive end-expiratory pressure) whil the lungs recover from the initial injury or disease process.

The array of alternative ventilator management strategies that can be used in the management of ARDS is impressive. Despite the religious zeal with which many such strategies are defended, few prospective clinical trials can confirm the effectiveness in terms of improving survival. “Cousins” of ECMO, intravascular (intra-venacaval or IVOX) gas exchange devices and AVCO2R, are designed to supply supplemental gas exchange with the potential for percutaneous access and “routine” ICU management. Despite spectacular results in reported individuals, the multicenter trials on IVOX, nitric oxide, and partial liquid ventilation have all been disappointing.

Extracorporeal Carbon Dioxide Removal
Gattinoni and Kolobow introduced the use of ECCO2R in both animals35-37 and humans,38,39 where the focus was CO2 extraction in order to facilitate a reduction in ventilatory support. CO2 removal is facilitated via extracorporeal circulation through the membrane lung, while oxygenation was maintained by simple diffusion across patent alveoli. Kolobow et al37 demonstrated the validity of “apneic oxygenation” as O2 was supplied via constant flow to alveoli maintained with PEEP, and no deterioration in oxygenation was observed. Others have demonstrated a decrease in mortality in patients managed with ECCO2R and low frequency-pressure limited ventilation using ECMO survival as the historical control.16,35,40,41 This improvement in survival has been duplicated at various centers utilizing ECMO criteria as historical controls, with an overall rate of 46%. Morris and colleagues,21 however, compared conventional ventilation with pressure-controlled inverse- ratio ventilation with or without ECCO2R in 40 ARDS patients. No significant difference in survival was found between the two groups with rates of 42% and 33%, respectively, and an overall survival rate of 38%. Of note, the majority of patients were hypercapnic at randomization and though mean peak airway pressures were significantly lower in the new therapy group, they remained elevated (57.8 vs 49.5 cm H2O). Lewandowski et al42 reported on the management of 38 patients with severe ARDS (lung injury score > 2.5) using an integrated approach that included permissive hypercapnia, pressure-controlled ventilation, frequent body position changes, and inhalation of nitric oxide (seven patients). Eighteen patients were treated with ECCO2R, with bypass being used initially if they fulfilled fast ECMO criteria or subsequently if they worsened on the standard therapy. The overall survival rate was 84% (100% in the patients who did not require ECCO2R and 66% in the ECCO2R group).

Intracorporeal Gas Exchange
The concept of an intravenacaval oxygenation and carbon dioxide removal device (IVOX) involves a miniature membrane lung that consists of multiple hollow fibers placed within the vena cava to provide blood oxygenation and CO2 removal without the need for extracorporeal circulation.43-48 The amount of CO2 removal represented approximately 30% of the CO2 production of an adult sheep (150-180 mL/min). Later clinical studies also demonstrated 40-70 mL/min O2 and CO2 exchange, approximately 25%-30% of metabolic demand.47-49 Use of IVOX allowed some reduction in ventilator settings: FiO2, PEEP, mean or peak airway pressure, and minute ventilation were decreased by > 10% in over 60% of patients, and by > 25% in over 40% of patients.49

IVOX is a membrane oxygenator whose CO2 removal capacity is dependent on the transmembrane PCO2 gradient. With permissive hypercapnia, the CO2 pressure gradient across the IVOX membrane can be increased and thus CO2 removal can be enhanced.48 In addition, application of IVOX with permissive hypercapnia allowed a further reduction in ventilatory settings that could help minimize barotrauma inflicted with conventional ventilatory treatment. Our clinical results show that as arterial PCO2 is allowed to increase into the 60-80 mm Hg range, IVOX efficiency can double to further reduce required ventilator support.47,48,50 Permissive hypercapnia and active blood mixing are also effective strategies to reduce surface area requirements.51 Such concepts have been incorporated in designs of other intracorporeal devices such as the intravenous membrane oxygenator (IMO).52

Arteriovenous Carbon Dioxide Removal
AVCO2R was developed as a less labor- intensive, costly, and complex technique of extracorporeal gas exchange to minimize blood surface interactions yet allow an exchange membrane of sufficient surface area for near total CO2 removal. The use of a simple arteriovenous shunt eliminates a substantial portion of tubing and ECMO-related components, reducing the foreign surface area, priming fluid, and blood transfusion volume. A pumpless arteriovenous system of CO2 removal avoids the use of a pump and functions with lower flow rates, expected to produce less hemodynamic or hematologic disturbances. In addition, the amount of CO2 exchange is not limited by surface area (as with intravascular devices such as IVOX) and moderate hypercapnia can be used to advantage. AVCO2R can be utilized to supplement mechanical ventilatory support for ARDS patients, allowing reduced positive pressure ventilation, and therefore decreasing hemodynamic compromise and barotrauma while promoting lung rest and healing. During AVCO2R, CO2 removal and O2 transfer are uncoupled (CO2 is secreted through the membrane gas exchanger whereas O2 diffuses through the native lungs). This process of providing systemic oxygenation with extremely low tidal volumes and respiratory rates is called apneic oxygenation.37

Awad et al53 and Young et al54 first demonstrated the feasibility of arterio-venous gas exchange but were limited by the high resistance in the oxygenator. Recent developments in computational fluid dynamics using computer-assisted dynamic modeling to target maximal gas exchange at low device resistance have provided guidelines for the design of very low-resistance oxygenators.55 One device incorporates fiber crossing, flow directions, and supporting structures iterated repeatedly to achieve low resistance with high gas transfer properties. Conrad et al56 applied mathematical modeling and bench testing on oxygenators designed by computer-reiterated principles and showed that the pressure gradient across this oxygenator was extremely low (approximately 10 mm Hg).

Using our experience from venovenous ECMO and IVOX, our group developed a simple AVCO2R technique in order to achieve near total extrapulmonary CO2 removal and allow lung rest in animal models of ARDS. In our initial studies of the performance characteristics of AVCO2R, we determined that the quantity of CO2 removed is directly dependent on blood flow through the gas exchanger.57 AVCO2R with an 18-Fr arterial cannula via surgical cutdown in adult sheep can achieve 1,400-1,500 mL/min flow (up to 29% cardiac output). Such flow levels are capable of achieving total CO2 removal; however, the flow needed to achieve adequate lung rest with moderate hypercapnia can be as low as 500 mL/min. A 10-Fr arterial and 12-Fr venous percutaneous cannula will allow arteriovenous shunt flow greater than 500 mL/min and provide some lung rest with permissive hypercapnia.58 Our data confirmed that, despite a 20%-26% cardiac shunt, AVCO2R can be used for total CO2 removal for up to 7 days, without hemodynamic compromise or instability, in an adult sheep model of severe respiratory failure.59 Brunston et al,57 investigating the performance characteristics of a low-resistance membrane gas exchanger, reported normal PCO2 could be maintained with minimal ventilator support at blood flows of 500 mL/min or higher. In our ovine model of smoke inhalation injury, AVCO2R achieved total CO2 removal and significantly reduced minute ventilation (MV) and peak inspiratory pressure (PIP) while maintaining normocapnia.

In our clinically relevant, large animal model of ARDS secondary to smoke inhalation and cutaneous flame burn injury,60 percutaneous AVCO2R achieved near total CO2 removal and allowed significant reductions in MV, tidal volume VT), and PIP.61 Using percutaneous 10-Fr arterial and 12-F venous cannulas, AVCO2R flows of 800-900 mL/min (11%-13% cardiac output) achieved 77-104 mL/min of CO2 removal (95%-97% total CO2 production) while maintaining normocapnia. Significant reductions in ventilator settings were VT, 450 to 270 mL; PIP, 25 to 14 cm H2O; MV, 13 to 6 L/min; respiratory rate, 25 to 16 breaths/min; and FiO2, 0.86 to 0.34. In a phase 1 clinical trial evaluating AVCO2R safety, our initial five patients required percutaneous 10-12 Fr arterial and 12-15 Fr venous cannulas to provide mean flows at 24, 48, and 72 hours of 837.4+/-73.9, 873+/-83.6, and 750+/-104.5 mL/min, respectively. They were all safely cannulated and connected to the AVCO2R device and received good support. All patients survived the experimental period without adverse sequelae and achieved approximately 70% CO2 removal.62

Summary
Techniques used to sustain gas exchange in the patient with respiratory failure in the near future may be very different from now. Currently, ARDS is primarily treated with mechanical ventilation, aimed at restoring normal blood gases by manipulating minute ventilation and oxygen concentration and adjusting PEEP while the lungs recover from the initial injury or disease process. The concept of “kind gentle ventilation” is being applied more frequently, while peak inspiratory pressures and fraction of inspired oxygen are minimized to avoid ventilator-induced lung injury; inspiratory times and positive end-expiratory pressure are increased to recruit collapsed lung regions; and higher levels of partial pressure of carbon dioxide and lower levels of arterial oxygen percent saturation are considered acceptable. Future techniques of extracorporeal gas exchange will be designed to supply supplemental gas exchange by percutaneous access for “routine” ICU management and as a bridge or rescue from less invasive respiratory management techniques.

Joseph B. Zwischenberger, MD, is professor of surgery, medicine, and radiology and director of the general thoracic surgery and extracorporeal membrane oxygenation programs, Division of Cardiothoracic Surgery, University of Texas Medical Branch, Galveston. Scott K. Alpard, MD, is a surgical research fellow in the division. Pablo Pritchard, BS, is a medical student at the university. Steven A. Conrad, MD, PhD, is professor and chief of the Division of Critical Care Medicine, Louisiana State University Medical Center, Shreveport.

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