Extracorporeal membrane oxygenation for severe respiratory failure

Extracorporeal membrane oxygenation for severe respiratory failure

Chest Surg Clin N Am 12 (2002) 355 – 378 Extracorporeal membrane oxygenation for severe respiratory failure Scott K. Alpard, BS, Joseph B. Zwischenbe...

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Chest Surg Clin N Am 12 (2002) 355 – 378

Extracorporeal membrane oxygenation for severe respiratory failure Scott K. Alpard, BS, Joseph B. Zwischenberger, MD* Department of Surgery, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA

Extracorporeal membrane oxygenation (ECMO) is the term used to describe prolonged extracorporeal cardiopulmonary bypass achieved by extrathoracic vascular cannulation. A modified heart-lung machine is used, most often consisting of a distendible venous blood drainage reservoir, a servoregulated roller pump, a membrane lung to exchange oxygen and carbon dioxide, and a countercurrent heat exchanger to maintain normal body temperature (Fig. 1). The patient must be anticoagulated continuously with heparin to prevent thrombosis within the circuit and potential formation of thromboemboli. Although most ECMO centers are experienced in the treatment of neonatal respiratory failure, institutional expertise and need dictate the availability of pediatric ECMO for respiratory or cardiac support, and adult ECMO for respiratory failure. Principles described in the discussion of neonatal ECMO also apply to the use of ECMO for the pediatric and adult patient populations but pertinent differences are detailed. The expanding use of ECMO for cardiac failure after surgical repair of congenital heart defects and for support in heart and lung transplantation is also described. 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, indications, medical and technical complications, and outcomes on ECMO have been collected and updated continuously as new patients receive ECMO support [1]. Extracorporeal circulation for respiratory failure was first attempted in newborns in the 1960s [2]. Bartlett et al [3] began clinical trials in 1972 and reported the first successful use of ECMO in newborn respiratory failure in 1976. During the initial experience in neonates, ECMO had an overall survival rate of 75% to 95% [4 –6]. These results helped to establish the therapeutic effectiveness of ECMO in infants having met criteria predicting greater than 80% mortality. In

* Corresponding author. E-mail address: jzwisc[email protected] (J. Zwischenberger). 1052-3359/02/$ – see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 1 0 5 2 - 3 3 5 9 ( 0 2 ) 0 0 0 0 2 - 9


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Fig. 1. Extracorporeal membrane oxygenation circuit.

1986, Bartlett et al [7] published his first 100 cases of ECMO for neonatal respiratory failure with an overall survival rate of 72%. The collaborative UK ECMO trial [8] concluded that ECMO support reduces the risk of death without a concomitant rise in severe disability. ECMO has become the standard treatment for unresponsive severe respiratory failure in neonates based on successful phase I studies [3], two prospective randomized studies [9,10], and worldwide application in over 20,638 patients with an overall 77% survival rate [1]. Pediatric patients also may benefit from extracorporeal support because of severe parenchymal lung damage and impaired gas exchange. Most pediatric ECMO patients have received progressive mechanical ventilation with high fraction of inspired oxygen (FIO2), peak inspiratory and mean airway pressures, and positive end-expiratory pressure (PEEP) for several days and have ventilatorinduced lung injury. These factors, along with secondary organ damage that may also be present, contribute to the longer duration of ECMO required for pediatric patients. On average, pediatric patients with unresponsive severe respiratory failure spend about 2 weeks on ECMO, with some survivors receiving ECMO for periods of up to 4 to 6 weeks before lung recovery [11]. Concurrent with the adult collaborative study, ECMO was evaluated in children. Bartlett et al [5] reported an ECMO survival rate of 30% in children and infants beyond the neonatal period with acute respiratory failure whose predicted survival rate with conventional therapy was thought to be less than 10%. Green et al [12] reported the results from the Pediatric Critical Care Study Group multicenter analysis of ECMO for

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pediatric respiratory failure. ECMO was associated with a significant reduction in mortality versus conventional or high-frequency ventilation (74% survival with ECMO versus 53% survival in controls). As of July 2001, ECMO had been used in over 2145 children with respiratory failure achieving an overall survival rate of 63% [1]. ECMO has also been used for children needing cardiac support with a survival rate of 54% [1]. Patients who would have been excluded from ECMO in the past because of such conditions as immunosuppression following treatment for malignancy, burns, meningococcemia, and other diseases are now reported in the literature as ECMO survivors [13 – 16]. If ECMO is to be used to full advantage as a therapeutic option for cardiorespiratory failure, more detailed information is needed on long-term outcome, morbidity, health care costs, and costbenefit analyses.

Adult application In 1972, Hill et al [17] reported the first successful clinical use of ECMO in adults. A number of small patient series soon followed from the United States and Europe [18,19]. Initially, the overall survival rates were relatively low, but the successes were individually dramatic. To reduce mortality from severe respiratory failure, a national study of adult ECMO sponsored by the National Heart, Lung, and Blood Institute of the National Institutes of Health was initiated in 1975 and completed in 1979 [20]. Although 300 patients were to be entered, the study was discontinued after 90 patients, with an approximately 90% mortality in both the control and treatment groups. Following these results, interest in adult ECMO all but ceased. In 1986, however, Gattinoni et al [21] reported a 49% survival in patients with severe respiratory failure treated with a form of ECMO and several investigators regained enthusiasm. Because expected survival with ECMO is approximately 50%, ECMO is appropriate when survival is predicted to be less than 20% [22]. Patients selected for ECMO must have a potentially reversible underlying pathologic process. Indications for ECMO include acute reversible respiratory or cardiac failure unresponsive to optimal ventilator and pharmacologic management with a predicted mortality rate of greater than or equal to 80%, but from which recovery can be expected within a reasonable period (several days to 3 weeks) of extracorporeal support. Despite advances in ventilatory support, antibiotic therapy, and critical care, mortality from adult respiratory distress syndrome (ARDS) remains about 50% [23 – 29]. Current techniques of ventilatory management are often associated with relatively high inspiratory airway pressures (barotrauma), overdistending normal lung regions (volutrauma), and toxic levels of inspired oxygen, leading to exacerbated lung injury (biotrauma) manifested by progressive deterioration in total lung compliance, functional residual capacity, and arterial blood gases [27]. High positive airway pressure also contributes to cardiovascular instability. Limiting airway pressures to avoid barotrauma or volutrauma of mechanical


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ventilation is rapidly gaining acceptance. Multiple studies, most notably the recent ARDS Network Trial, have shown an improvement in survival when using a low tidal volume (6 mL/kg) ventilator management strategy to reduce lung stretch [29,30]. Low tidal volume ventilation, however, may cause alveolar hypoventilation, hypercapnia, and acidosis, with the potential adverse effects of increased intracranial pressure and pulmonary hypertension [31]. Likewise, low tidal volume ventilation may require higher levels of PEEP and FIO2 to maintain minimally acceptable levels of arterial oxygenation, which could contribute to oxidant-induced lung injury. The primary goal of ECMO focuses on CO2 removal and O2 exchange with avoidance of high tidal volumes and airway pressures [32]. ECMO allows this goal to be maintained even when the lung is incapable of sufficient gas exchange. Reversible respiratory failure in adults is difficult to define; adult criteria for ECMO are controversial [20,33,34]. Many use a PaO2-FIO2 (P-F) ratio less than 100 but particular care must be taken to avoid therapy in patients with established pulmonary fibrosis. Bartlett advocates a Qp/Qs greater than 30 as an indication for ECMO. ECMO may also be effective for severe reactive airway disease, because bronchospasm is largely reversible, with most deaths caused by complications of mechanical ventilation [35,36]. All agree the goal is to identify ARDS patients with an estimated 80% mortality having potentially reversible respiratory pathophysiology. Causes of acute respiratory failure supported with ECMO include primary and secondary ARDS of multiple etiologies and reactive airway disease [37]. Another disease once considered a contraindication to ECMO is sepsis accompanying respiratory failure. Rich et al [38], however, demonstrated that sepsis or bacteremia was not predictive of survival. Selection criteria vary somewhat between adult ECMO centers worldwide. Experience plays a major role in patient selection, and cannot be characterized or quantitated. For most adult patients with unresponsive severe respiratory failure, venovenous support is the method of choice including both extracorporeal CO2 removal (ECCO2R) and venovenous (VV) ECMO (Table 1). ECCO2R emphasizes carbon dioxide removal through low-flow (approximately 1 L) bypass, using lowfrequency positive pressure ventilation by the natural lungs [21,34]. With this method, oxygen uptake and CO2 removal are dissociated: oxygenation is accomplished primarily through the lungs, whereas CO2 is cleared through the extracorporeal circuit. Even the most severely injured lungs are capable of oxygen transfer if they are not required to provide any ventilatory function. This is the rationale behind ECCO2R and apneic oxygenation as developed by Kolobow [39] and Gattinoni et al [21]. The lungs are inflated to moderate pressures (15 to 20 cm H20) to maintain functional residual capacity and oxygen concentration is reduced, while CO2 is removed by low-flow partial VV bypass. Low-frequency positive-pressure ventilation with ECCO2R is performed at an extracorporeal blood flow of 20% to 30% cardiac output. Vascular access is achieved by combinations of jugular-femoral, femoral-femoral, or saphenoussaphenous veins.

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Table 1 Comparison of Venoarterial and Venovenous ECMO Venoarterial ECMO

Venovenous ECMO

Cannulation sites

Internal jugular vein, right atrium, or femoral vein plus right common carotid, axillary, or femoral artery or aorta (directly)

Organ support

Gas exchange and cardiac output Circuit flow and cardiac output Reduced pulsatility Unreliable Unreliable Mixed venous into perfusate blood Pulmonary hyperperfusion may shunt

Internal jugular vein alone (double-lumen or single-lumen tidal flow) Jugular-femoral Femorofemoral Saphenosaphenous Right atrium (directly) Gas exchange only

Systemic perfusion Pulse contour CVP PA pressure Effect of R ! L shunt Effect of L ! R shunt (PDA)

Blood flow for full gas exchange Circuit SVO2 Circuit recirculation Arterial PO2 s Arterial oxygen saturation Indicators of O2 insufficiency

Carbon dioxide removal

Oxygenator Ventilator settings Decrease initial vent settings

80 – 100 ml/kg/h Reliable None 60 – 150 mm Hg  95% Mixed venous saturation or PO2 Calculated oxygen consumption

Sweep gas flow and membrane lung size dependent 0.4 or 0.6 Minimal (dependent on patient size) Rapidly

Cardiac output only Normal pulsatility Accurate guide to volume status Reliable None No effect on flow Require increased flow usual PDA physiology 100 – 120 mL/kg/h Unreliable (due to recirculation) 15% – 30% 45 – 80 mm Hg 80% – 95% Cerebral venous saturation Da-VO2 across the membrane Patient PaO2 Premembrane saturation trend Combinations of all of the above Sweep gas flow and membrane lung size dependent 0.6 or 0.8 Minimal to moderate (dependent on patient size) Slowly

Abbreviations: CVP, central venous pressure; PA, pulmonary artery; PDA, patent ductus arteriosus.

Venovenous ECMO emphasizes oxygenation in addition to CO2 removal, achieved through the use of higher flow rates (approximately 5 L) and a parallel configuration of two oxygenators to increase surface area. Patients with more advanced respiratory failure and high transpulmonary shunt fractions require the additional oxygen transfer supplied by VA ECMO. In a recent retrospective


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review of 94 patients, Bartlett’s group concluded that percutaneous cannulation can be used for VV ECMO in adults [40]. Venoarterial (VA) extracorporeal support is reserved for patients with cardiovascular instability or failure to maintain an adequate cardiac output during the course of respiratory failure. Disadvantages of VA ECMO include the need for major arterial access, reduced pulmonary blood flow, arterial discharge of emboli, further impairment of left ventricular function by volume overload, and circulatory dependence on an extracorporeal circuit. Advantages include lack of dependence on cardiac function to maintain oxygenation. If cardiac function improves, then the patient may be converted from VA to VV bypass.

Venovenous extracorporeal membrane oxygenation Venovenous ECMO (Fig. 2) has the advantage of maintaining normal pulmonary blood flow and avoiding arterial cannulation with its risk of systemic microemboli. Total support of gas exchange with VV perfusion, returning the perfusate blood into the venous circulation through the femoral vein or a modified jugular venous drainage catheter, also has the advantage of avoiding carotid artery ligation [41]. Bartlett’s group developed a polyurethane doublelumen (DL) catheter for single-site cannulation of the internal jugular vein [42,43]. A tidal flow VV system with a single-lumen catheter [41] has been developed to aid venous gas exchange. Efficient wire-wound cannulas, which are

Fig. 2. Venovenous bypass using the superior vena cava (SVC) as the venous outflow tract and the femoral vein as the arterial inflow tract. IVC = inferior vena cava. (From Bartlett RH. Extracorporeal life support for cardiopulmonary failure. Curr Probl Surg 1990;27:635; Mosby, with permission.)

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capable of sufficient flow for total gas exchange, can be inserted in large children ( > 15 kg) and adults by percutaneous insertion (Seldinger technique). Since the 14F VVDL catheter (Fig. 3) became commercially available in 1989, over 2248 neonates have been treated with an 87% overall survival [1]. The entire ELSO Registry experience of VA versus VVDL was compared [44]. As of January 2000, VA versus VVDL survival is 76% versus 87%, respectively [1], but the increased survival seen with VV is believed to be caused by selection bias. A multicenter retrospective comparison [43] of VA access versus VVDL for newborns with respiratory failure undergoing ECMO was undertaken and in a matched review with no advantage to either technique of ECMO. The current practice of waiting until the natural lungs become severely dysfunctional, and then having to support cardiopulmonary function almost completely with VA ECMO, may give way to the concept of early lung assistance. Single-site cannulation has already become the method of choice in neonates for ECMO. A single cannula tidal flow VV ECMO system has been developed that even allows percutaneous access [45,46]. Gattinoni et al [21], using a modified ECMO technique (low-frequency positive-pressure ventilation with ECCO2R) achieved 49% survival in adult ARDS. The improvement in survival is also attributed in part to better patient selection, VV perfusion, better regulation of anticoagulation, and ventilator management directed toward lung rest. Bartlett’s experience, initially reported by Anderson et al [47] in 1993, demonstrated a 47% survival rate in adults with severe respiratory failure. In a retrospective review of 100 adult patients treated by Bartlett’s group, Kolla et al [35] reported a 54% overall survival. Pre-ECMO variables found to be significant independent predictors of outcome included

Fig. 3. Double-lumen venovenous cannula. Blood is reinfused through the perforations near the tip of the cannula. The perforations must be aimed toward the tricuspid valve to minimize recirculation. (From Hirschl RB, Devices. In: Zwischenberger JB, Steinhorn RH, Bartlett RH, editors. ECMO: extracorporeal cardiopulmonary support in critical care. 2nd edition. Ann Arbor, Extracorporeal Life Support Organization; 2000. p. 199 – 236; with permission.)


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number of days of mechanical ventilation, P-F ratio, and patient age. Patients with respiratory failure alone had the best prognosis, with a mortality rate of 40%. Mortality increased substantially with increases in the number of organ failures. Each organ system failure was approximately equally contributory to mortality rate. Rich et al [36] also retrospectively evaluated Bartlett’s ‘‘standardized management protocol’’ for acute respiratory failure using lung protective mechanical ventilation and ECMO in 141 patients. Forty-one patients showed improvement with the initial protocol of ventilator management (83% survival), whereas 100 patients required ECMO support because of persistent respiratory failure (54% survival). Overall, lung recovery occurred in 67% of the patients with a 62% survival. As of July 2001, 678 adults treated with ECMO have been entered in the ELSO Registry with an overall survival rate of 56% [1]. A secondary benefit of ECMO is to enable the use of protective ventilatory strategies and other therapies that are not possible without extracorporeal gas exchange. Arteriovenous carbon dioxide removal (AVCO2R) uses a commercially available, low-resistance gas exchanger in a simple percutaneous arteriovenous shunt to achieve near-total extracorporeal removal of CO2 production with only 800 to 1200 mL/min flow. From the authors’ animal and initial patient safety trials, AVCO2R allows decreased respiratory rate, tidal volume, and peak airway pressures such that peak inspiratory pressure is predictably less than 30 cm H2O and respiratory rate four to five breaths per minute with an increase in P-F and no significant decrease in white blood cell, platelets, or increased complement activation while maintaining CO2 and pH homeostasis [48 –58]. The use of a simple arteriovenous shunt eliminates the roller pump and a substantial portion of the tubing and ECMO-related components, reducing the foreign surface area, priming fluid and blood transfusion volume. During AVCO2R, CO2 removal and O2 transfer are uncoupled: CO2 is excreted across the membrane gas exchanger, whereas O2 diffuses across the native lungs at a much lower minute ventilation using the principles of apneic oxygenation [39] similar to low-flow VV ECMO. The authors are currently conducting prospective, randomized, controlled, unblinded, multicenter outcomes studies to compare the effect of percutaneous extracorporeal AVCO2R with low tidal volume (6 mL/kg) mechanical ventilation on all-cause mortality and ventilator-free days in children with acute, severe respiratory failure secondary to burn injury with or without severe smoke inhalation and in adults with ARDS (P-F < 200). Severe progressive ARDS with P-F less than 100 and profound hypoxia exceed the capacity for AVCO2R to reverse the pathophysiology despite CO2 homeostasis. Trauma Respiratory failure adds significant morbidity, mortality, and cost to the care of patients with multiple trauma. ARDS has been reported to occur in between 14% and 35% of trauma patients [59,60] and to have a 50% overall mortality. ECMO has been used primarily for acute cardiac support, rewarming, oxygenation

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during resuscitation [61 –63], and the management of acute and severe respiratory failure [35,36,64 – 66] in trauma patients. ECMO can provide total cardiorespiratory support for the trauma patient, allowing reduction of ventilatory support to less-damaging levels [64,67,68].The primary risk with ECMO in trauma patients is severe bleeding because of the need for systemic heparinization. Hill et al [17] successfully applied ECMO to a trauma patient suffering from acute posttraumatic pulmonary insufficiency 6 days after repair of a transected aorta. Anderson et al [64] published Bartlett’s experience with 24 moribund pediatric and adult patients who received ECMO support for respiratory failure from trauma. Fifteen patients (63%) survived and were discharged from the hospital. Early intervention was thought to be a key factor in their successful outcome. ECMO with heparin-bonded circuits can aid the resuscitation and cardiopulmonary support of massively injured patients while their primary injuries are being evaluated [63]. In children and adults, the challenge is to identify the causes of respiratory failure that may be reversible within the safe time limits (2 to 3 weeks) of ECMO. Conditions treated successfully by ECMO include bacterial and viral pneumonias, fat and thrombotic pulmonary embolism, thoracic or extrathoracic trauma, shock, sepsis, and near-drowning. As in neonates, lung rest from the harmful effects of excessive positive-pressure ventilation (high FIO2, PEEP, peak inspiratory pressure, and minute ventilation) may be the universal benefit of ECMO in children and adults [69]. When ECMO is initiated, ventilatory settings are rapidly decreased to prevent further barotrauma from overdistention, and to prevent local tissue alkalosis. A low respiratory rate and normal inspiratory pressure or continuous PEEP can be used during ECMO. A few sustained inflations above the alveolar opening pressure are provided periodically to prevent total lung collapse. During VV ECMO right ventricular output is normal and probably higher than before ECMO, because cardiac output increases after severe hypoxia is corrected. This exposes the pulmonary arterioles to blood with a relatively high PO2, which may be beneficial in the treatment of pulmonary hypertension. VV ECMO depends solely on cardiac output to provide flow and is most useful in pure respiratory failure.

Techniques and management Extracorporeal membrane oxygenation has evolved into several formats including ECMO (VA and VV); traditional cardiopulmonary bypass; ECCO2R; AVCO2R; and the developing artificial lungs. Each presents advantages and disadvantages depending on the physiology to be corrected and the expertise of the ECMO team. A comparison of the different extracorporeal treatment modalities is shown in Table 2 [70,71]. In general, all age groups are cannulated with VA access if cardiac support is required for acute hemodynamic compromise (cardiac arrest) or for transport on


Table 2 Comparison of ECMO, CPB, ECCO2R, AVCO2R, and Artificial Lung CPB



Artificial Lung


Respiratory or cardiac failure

Cardiac surgery

Respiratory failure

Location Type of support

Extrathoracic VA (cardiac) VV (respiratory) VA: neck VV: neck and groin Two cannulas (surgical or percutaneous) One cannula (VVDL) High (70% – 80% CO) Pressure-controlled ± High PEEP 10 – 12 breaths/min small (50 mL) No Roller or centrifugal ACT 200 – 260 Days to weeks

Intrathoracic VA (total bypass)

Extrathoracic VV (respiratory)(CO2)

Respiratory failure (investigational) Extrathoracic AV (respiratory)(CO2)

Respiratory failure (experimental) Extrathoracic PA-PA or PA-LA

Direct cardiac Two cannulas (surgical)

Neck and groin Two cannulas (surgical or percutaneous) One cannula (VVDL)

Groin Two cannulas (percutaneous)

Transthoracic to major vessels

Total (100% CO) None (anesthesia)

Low (10% – 15% CO) Volume controlled (algorithm driven)

Total (100%) None necessary

Yes (> 1 L) Yes Roller or centrifugal ACT > 400 Hours

Med (30% CO) High PEEP 2 – 4 breaths/min High FIO2 Small (50 mL) No Roller or centrifugal ACT 200 – 260 Days to weeks

No No None ACT 200 – 260 Days to weeks

No No None ACT 200 – 260 Days





Intraoperative Air embolism

Multiorgan failure Septic shock Hemorrhagic

Respiratory failure

Right heart failure


Blood flow Ventilatory support

Blood reservoir Arterial filter Blood pump Heparinization Average length of extracorporeal support Complications Causes of death

Bleeding Organ failure Support terminated: PAP > 75% systemic Irreversible lung disease. Cardiac dysrhythmias

Abbreviations: ACT, activated clotting time; AV, artriovenous; AVCO2R, arteriovenous carbon dioxide removal; CO, cardiac output; CPB, Cardiopulmonary bypass; ECCO2R, extracorporeal carbondioxide removal; LA, left atrium; LFPPV, low-flowpositive pressure ventilation; PA, pulmonary artery; PAP, pulmonary artery pressure; PEEP, positive end-expiratory pressure; VA, venousarterial; W, venovenous; WDL, venovenous double-lumen.

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ECMO. VV access is used in most cases without hemodynamic compromise and is the method of choice for neonates or patients with primary respiratory failure. For VV access in neonates the authors prefer the right internal jugular vein for drainage and reinfusion using a DL catheter. For children and adults, the authors prefer the right internal jugular vein for drainage and the right femoral vein for reinfusion. Rich et al [72], however, recently compared atrial-femoral and femoral-atrial flow in adult VV ECMO. Femoral-atrial bypass provided higher maximal extracorporeal flow, higher pulmonary arterial mixed venous oxygen saturation, and required less flow to maintain equivalent mixed venous oxygen saturation than atrial-femoral bypass. In adults, 80 to 100 mL/kg/min is an adequate blood flow rate. Once ECMO is established and appropriate pH, PaO2, and PaCO2 values are obtained, ventilator settings are reduced to minimize barotrauma and oxygen toxicity (peak inspiratory pressure, 15 to 20 cm H2O; rate, 10 breaths per minute; FIO2, 0.3). The optimum PEEP level is uncertain, but many programs use high PEEP (12 to 15 cm H2O) with mean airway pressures of 13 to 16 cm H2O, based on experimental studies in a neonatal lamb model of meconium aspiration [73] that showed decreased time on ECMO without increased barotrauma. A prospective, randomized study in neonates has also concluded that higher PEEP safely prevents deterioration of pulmonary function during ECMO and results in more rapid lung recovery [74]. Because the patient is on extracorporeal support and does not have to breathe, airway management techniques unique to ECMO can be evaluated. For a large bronchopleural fistula, selective ventilation of the opposite lung for a period of time, selective occlusion of the offending bronchus with a balloon catheter for 1 or 2 days, or cessation of ventilation altogether while the air leak seals are available management options. Once the air leak has been sealed for 48 hours, alveoli are recruited by hourly lung conditioning with application of continuous static airway pressure in the range of 20 to 30 cm H2O. If the primary problems include excessive exudate or occlusion of the airways, flexible bronchoscopy with lavage can often help to clear the airway. ECMO can be used in patients with severe airway obstruction secondary to status asthmaticus or airway occlusion caused by blood clots or other foreign material [75]. In these circumstances, oxygenation is usually more than adequate and the major problem is CO2 retention, high intrathoracic pressures with cardiovascular compromise, or barotraumas with uncontrolled pneumothorax. Occasionally, surgical procedures are necessary while patients are on ECMO. Evacuation of hemothorax, open lung biopsy, and congenital diaphragmatic hernia repair have been performed during ECMO. Michaels et al [15] reported on 30 adult trauma patients, of which 19 (63.3%) underwent operative procedures while on ECMO. Procedures on ECMO for ongoing critical care include open reduction and internal fixation, repair of iatrogenic laceration, diagnostic peritoneal lavage, tracheostomy, abscess drainage, and gastrointestinal reconstruction [15,76]. Extracorporeal membrane oxygenation has been reported to allow unrushed, precise reconstruction during complex tracheal surgery and provide brief post-


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operative support [77,78]. ECMO has been reported for the perioperative management of congenital tracheal stenosis [77]. Recently, Kamata et al [79] reported using ECMO to support 6 of 11 infants in whom they performed tracheal reconstruction with costalcartilage grafts. Laryngotracheoesophageal cleft repair is a complicated procedure, first reported by Geiduschek et al in 1993 [80], whose major challenge was maintaining oxygenation, both during the surgical repair and the postoperative healing period. An additional postoperative complication is trauma to the fresh tracheal repair from ventilatory pressures and endotracheal tube motion. Geiduschek et al [80] used ECMO to facilitate surgical exposure of the defect and for postoperative respiratory support to avoid trauma to the fragile tracheal suture lines. Amakawa et al [81] reported on using ECMO to provide gas exchange during placement of metallic stents in a patient with tracheobronchial stenosis secondary to a large metastatic tumor. ECMO eliminated the need for an endotracheal tube and maximized exposure of the operative field. Trauma to the tracheal side of the repair is minimized by maintaining ECMO postoperatively, thereby eliminating the barotrauma of positive pressure ventilation and the mechanical trauma to the posterior tracheal wall that are produced by a larger endotracheal tube. Liver transplantation, lung transplantation, heart transplantation, and evacuation of intracranial hematoma in patients on ECMO have also been performed. Congenital diaphragmatic hernia In 1981, the first cases of infants with congenital diaphragmatic hernia (CDH) treated with ECMO were reported [82]. CDH has the lowest survival rate of all categories of neonatal respiratory failure for which ECMO is used [83 – 94]. The impact on mortality, however, has been institution specific with survival rates ranging from 43% to 87%. Aggregate survival data in the ELSO registry [1] are 62%. At first, infants were placed on ECMO after they developed severe respiratory failure following immediate repair of the diaphragmatic defect. Currently, with the increasing role of delayed surgical repair following preoperative stabilization, infants are now being placed on ECMO as part of the stabilization strategy before and after surgery. Wung et al [95] reported 85% overall survival with a strategy based on surgery delayed until pulmonary hypertension is minimized by respiratory care based on spontaneous respiration, permissive hypercapnea, and no chest tube. ECMO is required in only 14% preoperatively or postoperatively. Although the role of ECMO as a treatment for CDH has been widely accepted, the timing of the surgical repair of the defect in relation to ECMO therapy remains controversial. Operative repair of the defect has been proposed while on ECMO [96 –100] but survival rates have been variable and as high as 80% [96,99,101]. Delaying repair until the infant is off ECMO is another option in which favorable results have been reported [102,103]. Unfortunately, the overall mortality rate of CDH has remained approximately 50% even with the increased use of ECMO support [88,104 – 107]. Evolution of mechanical ventilation

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techniques, extracorporeal support, use of surfactant, nitric oxide, and different timing of surgical intervention have all contributed to variable survival rates from different institutions.

Complications during extracorporeal membrane oxygenation and their management Complications during ECMO are the rule, not the exception [44,108], because the management of the patient on ECMO, including patient-related complications, spans the entire field of critical care. This section is limited to complications unique to ECMO. Cannulas are inserted with great care to avoid vascular damage during insertion, because loss of control of the internal jugular vein can result in massive mediastinal bleeding, and dissection of the carotid artery intima can progress to a lethal aortic dissection. Minor surgical procedures may be required during ECMO; however, they should not be taken lightly because of the risk of bleeding with systemic anticoagulation. Tube thoracostomy may be required to drain hemothorax or pneumothorax. At the time of these minor invasive procedures, skin incisions can be made with the cutting mode of an electrocautery. Muscles should be cauterized and not torn. Although bleeding may be a significant problem, liberal use of cautery, application of fibrin glue, and a low threshold for re-exploration permit nearly any procedure to be performed. Thrombocytopenia is expected during the use of ECMO because platelets are altered and platelet aggregates in the extracorporeal circuit are preferentially sequestered in the lung, liver, and spleen [109 – 111]. Thrombocytopenia must be avoided by using platelet transfusion as often as necessary to maintain adequate platelet counts during and after ECMO when thrombocytopenia may occur. The development of heparin-bonded, nonthrombogenic surfaces is attractive, but the initial experiences with heparin-bonded tubings have not shown significant advantages. Catastrophic hemodynamic deterioration is unusual while a patient is on VA ECMO. The factors that deserve immediate evaluation when this occurs include venous catheter displacement, inadequate systemic volume status, and the possibility of ECMO circuit failure. Pericardial tamponade and tension hemothorax or pneumothorax show a similar pathophysiology of increasing intrapericardial pressure and decreasing venous return. With decreased venous return to the heart, pulmonary blood flow and the native cardiac output are decreased. The relative contribution of the extracorporeal circuit to peripheral perfusion is increased, and peripheral perfusion is initially maintained by the nonpulsatile flow of the ECMO circuit (postoxygenator PO2 > 300 mm Hg). The triad of increased PaO2, decreased peripheral perfusion (as evidence by decreased pulse pressure and decreased SvO2), followed by decreased ECMO flow with progressive hemodynamic deterioration is consistently associated with tension pneumothorax and pericardial tamponade [112]. Tension hemothorax and


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pneumothorax are initially identified by chest radiograph. An echocardiogram demonstrates a pericardial effusion or hemothorax with or without cardiac compression. For emergency drainage of tension hemothorax, pneumothorax, and pericardial tamponade, a percutaneous drainage catheter should be placed to remove the blood or fluid and reverse the pathophysiology. Sepsis is both an indication for and a complication of ECMO. According to the ELSO Registry, however, only 5% of all patients requiring ECMO demonstrate positive blood cultures. This is a remarkably low incidence given the duration of cannulation, the large surface area involved, and frequency of access to the circuit. The pathophysiology of persistent fetal circulation is a right-to-left shunt and a patent ductus arteriosus (PDA) during severe respiratory failure in the newborn. When ECMO is initiated, a PDA is often present in the newborn. When pulmonary hypertension resolves, flow through the ductus reverses (becomes left-to-right shunting). A persistent left-to-right shunt across the ductus arteriosus may lead to pulmonary edema. Decreased systemic oxygenation may result both from pulmonary edema and decreased systemic blood flow. Both of these conditions require increasing ECMO flow to maintain adequate gas exchange and perfusion. A PDA on ECMO may present with various signs: (1) a decreased PaO2, (2) decreased peripheral perfusion, (3) decreased urine output, (4) acidosis, and (5) rising ECMO flow and volume requirements. The clinical diagnosis may be confirmed as with other neonatal patients using Doppler echocardiography or angiography. Some centers have tried using intravenous indomethacin to treat PDA while on ECMO; however, this may increase the risks of bleeding in patients on ECMO because of its effects on platelet function. Once the diagnosis is established, most programs ‘‘run the patient relatively dry’’ while maintaining supportive ECMO flow until the PDA closes. Although this often means a few additional days on ECMO, surgical ligation is rarely necessary. Occasionally, a patient’s respiratory status does not improve despite 2 to 3 weeks of ECMO support. An echocardiogram is repeated to ensure an absence of PDA with predominant left-to-right shunt and congenital heart defect, such as total anomalous venous return.

Cardiac support Extracorporeal membrane oxygenation applied to patients with severe cardiac failure was first reported in the 1950s but it was not commonly used until the 1980s [113]. Since then, the use of ECMO has been extended to both infants and children after cardiac surgery [114 –116]. There have been over 3000 patients supported with ECMO for myocardial dysfunction with overall survival of about 39%. ECMO provides greater flexibility in dealing with some forms of complex congenital heart disease in which pulmonary hypertension and hypoxia contribute significantly to the pathophysiology [117]. The effect of ECMO on the heart includes a decrease in preload, a slight increase in afterload, and a concomitant

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elevation in left ventricular wall stress. Advantages include support of both right and left ventricles, improvement of systemic oxygenation, and ease of placement. VA cannulation provides the optimal cardiac support when ventricular dysfunction predominates in the clinical picture. Studies have also been shown, however, that VV bypass, primarily by improving venous oxygenation, may improve myocardial oxygenation and decrease pulmonary vascular resistance in selected patients, providing adequate cardiac recovery and support [118]. Most patients have received ECMO postoperatively after repair of congenital heart defects [115,117,119]. In these patients, factors associated with poor survival despite ECMO support include residual cardiac defect, single ventricle physiology, initiation of ECMO in the operating room, and failure to return to adequate cardiac function and wean from ECMO within 3 to 7 days. Two changes in the philosophy of cardiac ECMO have occurred with time and experience. Over 100 children have received ECMO either as a bridge to heart transplant or following cardiac transplant. Key points in management of bridgeto-transplant patients include deciding as early as possible to list patients for transplant and avoiding complications that remove patients from transplant consideration. The second change regarding cardiac ECMO involves patients with sudden cardiac arrest. There are several reports of good survival in patients requiring active cardiopulmonary resuscitation at the time of ECMO cannulation. Overall survival ranged from 41% to 53% [120]. Rapid-deployment ECMO has also been shown to be useful in support of patients who suffer cardiopulmonary arrest [121]. Cannulation for cardiac support Venoarterial ECMO may be performed by extrathoracic cannulation (carotid artery and jugular vein, or femoral artery and vein), or more commonly transthoracic cannulation through the median sternotomy incision (the aorta and the right atrium). Carotid-jugular cannulation may be used best in patients who are weaned from cardiopulmonary bypass in the operating room and develop myocardial dysfunction with cardiogenic shock after operation. Advantages of this approach are a separate incision site remote from the median sternotomy wound and a lower incidence of bleeding from the mediastinal wound. Both of these factors may contribute to a decreased risk of mediastinal infection [122]. In patients with a cavopulmonary connection (Glenn or Fontan circulation), direct access from the jugular vein to the right atrium is not feasible; a transthoracic approach is required in these cases. Femoral VA cannulation can be used in certain older children, with placement of intravascular catheters into the inferior vena cava or right atrium through the femoral vein and into the common femoral or iliac artery for arterial return. The venous return with this type of cannulation may be restrictive unless a centrifugal-type pump, which provides active venous drainage, is used. The advantage of this peripheral technique includes the noninvasive surgical approach and more secure cannula fixation. Transthoracic cannulation is preferable in patients who cannot be


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weaned from cardiopulmonary bypass in the operating room or in those circumstances where the chest was opened for the purpose of resuscitation in the postoperative period. The major disadvantage of the transthoracic approach includes the potential risks of mediastinal hemorrhage, infection, and cannula dislodgment during repositioning or transport. The prevention of cardiac distention, minimization of myocardial energy expenditure, is vital to potential myocardial recovery. When left atrial pressures remain elevated despite optimal flow, it is critical to vent the left atrium to the venous drainage system either by direct left atrial cannulation in the operating room or transatrial septal cannulation in the cardiac catheterization laboratory. The preoperative use of ECMO in infants with congenital heart disease is controversial. In patients with cyanotic heart disease and cardiopulmonary collapse associated with hypercyanotic spells, pulmonary hypertension, or sepsis, indications for ECMO include arterial oxygen saturation less than 60% on maximal medical therapy, with hypotension and metabolic acidosis [122]. The potential uses of ECMO in lung transplant patients include the support of severe pulmonary insufficiency immediately before transplant, the support of the lung transplant patient in the immediate postoperative period, and support of late graft dysfunction during an acute rejection episode [123]. Lung transplantation in a patient placed on ECMO for severe ARDS may represent the only option for those patients who fail to recover adequate pulmonary function. The most common indication for ECMO in the lung transplant patient is in the immediate postoperative period as a means of support following primary graft failure or severe ischemic reperfusion injury [123 – 126]. Primary graft failure is a potentially lethal complication of lung transplant that occurs in 6% to 20% of recipients [127]. ECMO in this scenario relinquishes the lungs from high pressure and high oxygen concentration requirements during ventilation, thereby allowing the lung to heal without additional barotrauma or oxygen toxicity. A final role for ECMO in the lung transplant patient is as a supportive measure during a period of late graft dysfunction (lung failure > 7 days after transplant) [125,128]. The interval between surgery and initiation of ECMO may provide sufficient time for recovery of normal coagulation, an important factor that may positively affect the outcome of these infants and children [129]. The ability to decrease inotropic support along with improvement in renal function and diuresis of retained fluid are initial indicators of myocardial recovery. With reasonable inotropic support, ECMO flow is gradually lowered to 10% to 20% of supportive flow. If myocardial contractility remains satisfactory, and the filling pressures are low, decannulation may be accomplished. Complications The major complication of postcardiotomy ECMO in pediatric patients is hemorrhage. Approximately 40% to 50% of children require re-exploration for hemorrhage during the time of support. To minimize the magnitude of bleeding, the activated clotting time is maintained at approximately 200 seconds and the

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platelet count is kept greater than 100,000/mm3. The primary determinant of significant hemorrhage is the duration of ECMO [130]. Keeping the chest open is sometimes necessary to facilitate re-exploration and to prevent periods of cardiac tamponade. The use of heparin-coated circuits and oxygenators presents promising possibilities with improved biocompatibility, and less complement activation [131]. Another important complication of prolonged ECMO is mediastinal infection and sepsis. This is a result of continued bleeding from mediastinal structures, multiple cannulae, and catheters in the mediastinal cavity, exiting through the skin; low cardiac and renal output; and multiple transfusions. To decrease the incidence of infection, broad-spectrum coverage with antibiotics and aseptic technique, together with attempts to minimize the time on ECMO, are encouraged. Clinical results The results of ECMO for pediatric cardiac support reported early survival was 40% to 44%, with somewhat better survival (43% to 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 [115,117,119]. Certain factors seem to be related to the likelihood of hospital survival following extracorporeal life support (ECLS). Patients with two ventricles are more likely to survive than those with one, ECLS initiation in the operating room seems to be associated with lower survival, and postoperative patients on ECLS more than 200 hours rarely survive. Difference in survival rates suggests that the improved survival is associated with a complete biventricular operative repair, whereas an operation with shunt-dependent pulmonary blood flow is associated with lower overall recovery rates.

Future The future of extracorporeal support depends on the development of techniques and devices to make the technique less invasive, safer, and simpler in management. Using percutaneous catheters without surgical exploration can reduce potential bleeding wounds. 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. The use of the Seldinger wire-guided technique with sequential dilators and placement of large catheters directly or with peel-away sheaths has had an impact on decreasing the incidence of bleeding complications from cannulation sites. Cannulation can be accomplished quickly and easily under a variety of circumstances, including on-ECMO transport and emergency access. Heparin-bonded oxygenators, pump chambers, and extracorporeal circuits may allow ECMO for days without bleeding, complications, or formation of clots. Various groups have tested heparin-coated circuits and reported reduced


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thrombogenicity and reductions in required systemic heparinization for prolonged support [132 – 135]. New applications of ECMO will include emergency room and catheter laboratory resuscitation in cardiac failure, resuscitation in trauma and hemorrhagic shock, and use as an adjunct to perfusion and temperature control. The ECMO experience has stimulated the development of artificial lung prototypes, which are being evaluated in large animal trials [136 – 138]. The future of ECMO also includes laminar flow oxygenators; safe, simple automatic pumps; nonthrombogenic surfaces to eliminate bleeding complications; advances in respiratory and cardiac care; and new approaches to clinical trials.

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