ECMO

Introduction

The term extracorporeal life support (ECLS) denotes the use of prolonged extracorporeal cardiopulmonary bypass, usually via extrathoracic cannulation, in patients with acute, reversible cardiac or respiratory failure who are unresponsive to conventional medical or pharmacologic management. Although extracorporeal membrane oxygenation (ECMO) is the traditional term associated with this technique, ECLS is the current, preferred mnemonic since the term "life support" encompasses functions other than "oxygenation", including cardiac and hemodynamic support as well as carbon dioxide elimination. It is important to recognize that ECLS is not a therapeutic intervention. Instead, ECLS simply provides cardiopulmonary support so that the patient is spared the deleterious effects of high airway pressure, high FiO2, and perfusion impairment while "reversible" pathophysiologic processes are allowed to resolve either by spontaneous means or by medical or surgical therapeutic intervention.

Three prospective randomized trials have compared the effectiveness of ECLS with conventional mechanical ventilation (CMV) in fullterm newborns with severe respiratory insufficiency. One of these was a randomized prospective study performed in the United Kingdom which demonstrated a significant difference in survival between fullterm newborns managed with ECLS (72%) and those managed by conventional means (41%). Other studies have demonstrated a significant increase in survival among pediatric respiratory failure patients managed with ECLS (74%) when compared to carefully matched patients managed with CMV (63%).

Indications for ECLS

In the majority of newborns, pulmonary disease processes result in the pathophysiology associated with pulmonary hypertension and persistent fetal circulation (PFC). Conventional methods such as mechanical ventilation, induced respiratory alkalosis, surfactant administration, nitric oxide administration, and high frequency oscillatory ventilation (HFOV) may be applied in order to decrease the PFC and respiratory insufficiency. When these interventions fail, ECLS may allow reversal of the cycle of increasing pulmonary hypertension while minimizing the complications of high pressure mechanical ventilation and FiO2. In contrast to the newborn, infants and children with respiratory failure and patients of all ages with cardiac failure frequently have pathophysiologic processes which are based on parenchymal organ dysfunction.

For optimal application of ECLS, one would wish to define criteria which would allow identification of those who will ultimately succumb at the earliest moment while excluding those patients who would eventually survive by more conventional means. Two such criteria have been developed in neonates. The first is an oxygen index (O.I.) which is based on arterial oxygenation and mean airway pressure (MAP) and computed according to the following formula:

OI = (MAP x FiO2 x 100)/PaO2

It has been suggested that an OI > 40 in three of five postductal arterial blood gases each drawn one-half to one hour apart is predictive of a mortality of > 80%. A randomized, controlled study suggested that "early" initiation of ECLS based on an O.I. > 25, which is predictive of a 50% mortality rate, is associated with a trend toward a higher mental developmental score and a lower incidence of morbidity at one year of age when compared to a control group of patients in whom ECLS was initiated at an O.I. > 40. Many centers, therefore, currently consider institution of ECLS when a series of postductal arterial blood gases demonstrate an O.I. > 25 with mandatory application of ECLS when the O.I. > 40. The other criterion used to indicate initiation of ECLS is based on the alveolar-arterial oxygen difference [(A-a)DO2]: an (A-a)DO2 value of > 610 torr despite 8 hours of maximal medical management is associated with a mortality of 79% while excluding only 6% of subsequent deaths. Newborn patients with CDH are frequently placed on ECLS at O.I. criteria = 25 to 30 based on a series of postductal arterial blood gases.

Criteria for high mortality risk among non-neonatal children with respiratory failure have been less well-defined. Some centers employ fast entry criteria (PaO2 < 50 mmHg for > 2 hours) and slow entry criteria (pulmonary shunt fraction > 30%) measured at an FiO2 = 1.0 and positive end-expiratory pressure (PEEP) - 5 cmH2O to indicate need for ECLS. However, the ELSO registry would suggest that the indication for ECLS is simply classified as "failure to respond" in >90% of pediatric respiratory failure patients.

Many of the "absolute" exclusion criteria have been relaxed as experience with ECLS has allowed reduction in activated clotting time (ACT) levels and refinement and standardization of various aspects of the ECLS technique:

Previously, an estimated gestational age (GA) - 34 weeks was considered a contraindication to ECLS due to the high incidence of intracranial hemorrhage (ICH). However, ECLS has been successfully applied in the preterm newborn with EGA > 32 weeks, although the incidence of ICH may be as high as 40%.
Although intracranial hemorrhage has been considered an absolute contraindication to ECLS in the past, reasonable outcome has been demonstrated when ECLS has been instituted in the setting of grade I or II ICH.
Mechanical ventilation for longer than 7 to 10 days in newborn and pediatric patients with respiratory insufficiency has been considered a contraindication to ECLS because of the high incidence of bronchopulmonary dysplasia and irreversible fibroproliferative lung disease. However, reviews of the ELSO registry data have suggested that survival in patients who have been managed with mechanical ventilation for up to 10 to 14 days may still be reasonable.
Cardiac arrest which requires cardiopulmonary resuscitation (CPR) in the pre-ECLS period has been considered a contraindication to institution of extracorporeal support. However, survival rates of up to 60% have been observed among neonates and pediatric cardiac patients who sustain a cardiac arrest prior to or during cannulation. Based on these data, many centers now consider patients who sustain pre-ECLS cardiac arrest candidates for extracorporeal support.
In order to avoid application of ECLS to newborn patients with CDH and "irreversible" severe lung hypoplasia, extracorporeal support in the past was withheld from those patients who could not demonstrate a best postductal PaO2 > 50 mmHg. However, following the demonstration that a number of patients who met this exclusion criteria still survived, most centers will now consider any patient with CDH as a candidate for ECLS.
Finally, as an ethical consideration, those patients with profound neurologic impairment, multiple congenital anomalies, or other conditions not compatible with meaningful life are excluded as candidates for ECLS.

Additional relative exclusion criteria which apply specifically to pediatric patients with respiratory failure are the presence of multiorgan system failure, major burns, immunodeficiency, active bleeding, chronic lung disease, and the presence of an "incurable" disease process. It should be noted that preoperative cardiac anomalies in newborns represent a relative contraindication to ECLS since they should be treated operatively, although they may be supported with extracorporeal support until surgical intervention may be accomplished.

Methods of Extracorporeal Support

The goal of ECLS is to provide perfusion of warmed, arterialized blood into the patient. In order to achieve this goal, three configurations of extracorporeal blood flow are used clinically: 1) venoarterial (VA), 2) venovenous (VV), and 3) double lumen venovenous (DLVV) bypass (see Figure 1). In the early experience ECLS was almost always performed using venoarterial support since it offered the potential to replace cardiac and lung function. However, there are significant disadvantages to the use of venoarterial bypass: a major artery must be cannulated and at least temporarily sacrificed; the risk of dissemination of particulate or gaseous emboli into the systemic circulation is substantial; pulmonary perfusion may be markedly reduced; cardiac output may be compromised due to the presence of increased ECLS circuit-induced afterload resistance; and the coronary arteries are predominantly perfused by the relatively hypoxic left ventricular blood. In contrast, both VV and DLVV support provide adequate gas exchange without these disadvantages. One significant problem with VV and DLVV ECLS, however, is that a fraction of recently infused blood recirculates back into the extracorporeal circuit. As a result, oxygenation levels are relatively reduced and extracorporeal blood flow rates must be increased approximately 20% to account for this effect. The VV and DLVV extracorporeal circuit configurations also do not provide cardiac support. However, because of the numerous advantages VV and DLVV ECLS have become the preferred method for patients of all age groups who do not require cardiac support. Even neonates, as well as older pediatric and adult patients, who require pressor support prior to initiation of bypass often do well with a VV or DLVV configuration once hypoxia and acidosis are resolved and high ventilator pressures reduced. The DLVV configuration of bypass has now been used in over 1200 newborn cases with a 90% survival rate; only 15% of patients required conversion from DLVV to VA ECLS. Unfortunately, double lumen cannulas appropriate for use in patients over 4-5 kg in weight are not available. However, VV ECLS with drainage from the internal jugular vein and infusion into the femoral vein is an effective means of providing support in adults and children over three years of age.

The ECLS Circuit

The ECLS circuit is comprised of three basic components: a roller pump, a membrane lung, and a heat exchanger (Figure 2). The remainder of the devices associated with the extracorporeal circuit serve safety and monitoring functions. Right atrial blood is drained to the pump by gravity siphon via a cannula placed through the right internal jugular vein. Roller pumps are the perfusion devices most frequently used and require continuous servoregulation and monitoring to prevent application of high levels of negative pressure to the drainage circuit and high levels of positive pressure, with a risk of circuit disruption, to the infusion limb of the circuit should occlusion occur. Application of high negative pressures to the drainage circuit results in hemolysis; damage to the endothelium of the right atrium or vena cava; and cavitation as air is drawn out of solution. To prevent generation of negative pressures a small (30 mL) distensible bladder which compresses a spring loaded mechanical switching device that interrupts flow of power to the roller pump is frequently interposed between the venous cannula and the roller pump. The bladder remains distended as long as venous return is adequate for the current pump flow rate and the bladder pressure remains > -20 mmHg. If the pump flow rate exceeds venous return or if venous drainage is impeded for any reason the bladder will collapse, resulting in discontinuation of pump flow. An alternative method for roller pump servoregulation involves the use of a pressure monitor which signals a reduction of roller pump speed or interruption of power to the pump as negative pressures are applied to the pre-pump circuit.

Once blood passes through the roller pump it is then perfused through the artificial lung. The membrane lung, which is the one most commonly used, consists of two sheets of silicone which are sealed at the edges. Oxygen gas flows through connector tubing segments at opposite ends which are in continuity with the inside of the silicone envelope. The envelope is wound up on a polycarbonate spool and blood is distributed, via a manifold, lengthwise through the interstices of the wound up envelope. Gas exchange takes place across the silicone membrane. Membrane lungs are available from 0.4 m2 to 4.5 m2 in surface area: the size of the artificial lung is selected to provide total cardiopulmonary support.. Hollow fiber artificial lungs are highly efficient with regard to gas exchange, of low resistance to blood flow, and easy to prime. The disadvantage of the hollow fiber lung is the increased rate of condensation of water in the gas phase and the frequent need for replacement due to development of plasma leak.

Once through the artificial lung, blood passes through a heat exchanger as the arterialized blood is then perfused at body temperature either through 1) the internal carotid cannula into the aortic arch or 2) via a femoral venous cannula or the second lumen of the internal jugular DLVV cannula into the right atrium. A bridge between the drainage and infusion tubing exists in most ECLS circuits. The purpose of this bridge is to allow temporary dissociation of the patient from the extracorporeal circuit during emergencies and during trial periods off of ECLS. The volume of the neonatal circuit is approximately 400-500 mL which is 1-2 times the newborn blood volume. The circuit, therefore, must be primed carefully in order to perfuse the neonate at onset of bypass with blood containing appropriate pH, hematocrit, calcium, clotting factors, electrolytes, and temperature. However, ECLS may be instituted in those patients over 35 kg in weight without addition of blood to the prime.

Patient management on ECLS

Cannulation in general is performed in the intensive care unit. All procedures such as placement of chest tubes and appropriate intravenous, pulmonary arterial, or intraarterial catheters are performed prior to cannulation and administration of heparin. Paralyzing agents are administered in order to prevent air embolus during placement of the venous cannula. Intravenous morphine or fentanyl and local lidocaine infiltration provide anesthesia.

The size of the venous cannula is the factor which determines the blood flow rate and, therefore, the level of extracorporeal support. As such, the largest possible venous access cannula should be placed. It should be of sufficient size to provide adequate blood flow with the assistance of a 100 cm H2O gravity siphon pressure. The flow-pressure characteristics of a given cannula are determined by a number of geometric factors including length, internal diameter, and side hole placement. The "M-number" provides a standardized means for describing the flow-pressure relationships in a variety of vascular access devices.

Transthoracic cannulation may be appropriate in the post-cardiac surgery patient with cardiac and/or pulmonary dysfunction. In general, however, access for ECLS is provided via extrathoracic cannulation. The first choice of venous access is the internal jugular vein since it is a large vein which provides easy access to the right atrium via a short cannula. The femoral vein is the second choice for venous drainage access during ECLS and the first for reinfusion during VV support. In children under 5 years of age the femoral vein is too small to function as the primary drainage site. Therefore, the iliac vein should be considered the second choice of access in young children. A proximal venous drainage cannula (PVDC) may be placed into the proximal internal jugular vein to enhance venous drainage to the extracorporeal circuit.

The size of the reinfusion cannula is less critical than that of the venous cannula, although it must be large enough to tolerate the predicted blood flow rate at levels of total support without generating a pressure proximal to the membrane lung of > 350 mmHg. Infusion cannulas typically have a single end hole while venous drainage cannulas have additional side holes. The first choice for placement of a cannula into the arterial circulation is the carotid artery in all age groups since it provides easy access to the aortic arch. Few complications have been associated with carotid artery cannulation and ligation in newborns, children and adults. The second choice for arterial access is the femoral artery in those patients over 5 years of age. In patients under 5 years of age, the femoral artery is of insufficient size to provide arterial access; therefore, the iliac artery is the preferred site after the carotid artery. Distal perfusion of the lower extremity arterial circulation is sometimes required when the femoral artery is cannulated, although distal perfusion is typically not required after cannulation of the iliac artery in young children.

The cannulation procedure is usually performed by direct cutdown using local anesthesia (Figure 3). The patient is placed supine with the head turned to the left and a roll placed transversely under the shoulders. A 2-3 cm transverse cervical incision is made one finger's breadth above the clavicle over the right sternocleidomastoid muscle (SCM). Dissection between the heads of the SCM exposes the carotid sheath which is opened as the internal jugular vein, common carotid artery, and vagus nerves are identified. Manipulation of the vein should be minimized to avoid induction of venospasm which may preclude placement of a large venous cannula. The common carotid artery lies medial and posterior and may be safely dissected since it has no branches at this level. Heparin (100 units/kg) is administered intravenously. The tips of the arterial and venous cannulas will be optimally located at the opening of the right brachiocephalic artery and the inferior aspect of the right atrium, respectively. The cannulas are inserted a specific distance in the neonate (arterial = 2.5 cm and venous = 6 cm). The DLVV cannula must be placed such that the tip is in the mid-right atrium (advanced 5 cm in the neonate) with the reinfusion ports oriented toward the tricuspid valve to minimize recirculation of reinfused blood.

Percutaneous access to the internal jugular and femoral vein is the preferred approach to cannulation in adults and children over 3 years of age. Sequentially larger dilators are placed over a wire as the Seldinger technique allows final access of the cannula itself into these large veins. The Jostra or Origen 12 or 15 french DLVV cannula is amenable to percutaneous introduction into the internal jugular vein in neonates.

Once on extracorporeal support there typically is rapid cardiopulmonary stabilization. All paralyzing agents, vasoactive drugs, and other infusions are discontinued during use of venoarterial support, although some pressor support may be necessary when venovenous bypass is utilized. Ventilator settings are adjusted to minimal levels in order to allow the lung to rest and any air leaks secondary to barotrauma to seal. The mixed venous oxygen saturation (SvO2) is conveniently monitored by a fiberoptic Oximetrix catheter placed in the venous limb of the circuit which allows determination of the adequacy of oxygen delivery in relation to oxygen consumption. Pump flow is adjusted to maintain oxygen delivery such that the SvO2 is above the 65-70% range. The PaCO2 is inversely proportional to the flow rate of gas ventilating the membrane lung.

Heparin is administered to prevent thrombus formation throughout the ECLS course. The level of anticoagulation is monitored hourly by the whole blood ACT. Many centers maintain the ACT between 180-200 seconds.

During the first few hours on bypass pulmonary function and gas exchange are often observed to deteriorate. This is frequently manifested radiologically as bilateral opacification of the lung fields and is likely secondary to the abrupt decrease in the airway pressures employed after onset of ECLS. Application of PEEP levels of 14 cm H2O may reduce the development of the lung opacification. Aggressive diuresis is frequently instituted approximately 24 hours after initiation of ECLS because total body water is increased in many patients. Renal function may be transiently impaired during ECLS and, therefore, utilization of a hemofilter placed in the circuit to supplement renal water excretion may be necessary. Nutrition remains a high priority in the critically ill patient requiring ECLS, carried out via parenteral nutrition or enteral feeding.

Over the ensuing days on ECLS, as the cardiopulmonary pathology resolves, the inflammatory process subsides, the pulmonary radiographic appearance improves, and the elevated pulmonary vascular pressures normalize, gas exchange increases across the native lung. The ECLS flow rate is weaned as gas exchange improves based on the SvO2 (Figures 4 and 5). Simultaneous increases in lung compliance are frequently observed. Discontinuation of ECLS is associated with a final lung compliance of 0.8 ml/cmH2O/kg. Most practitioners transiently discontinue extracorporeal support in order to determine whether cardiopulmonary function is such that ECLS may be discontinued. This "trial off" is performed during venoarterial bypass by clamping the arterial and venous connectors between the bridge and the patient and allowing recirculation of extracorporeal blood flow through the bridge. Usually it is clear within the first 15-30 minutes whether ECLS may be discontinued, although prolonged trials of up to 2 hours may occasionally be required. During venovenous bypass the gas phase of the membrane lung may simply be capped indefinitely so that the patient remains on extracorporeal support but without contribution of the artificial lung to gas exchange.

Figure 4 (above)

Figure 5 (above)

Once it has been determined that ECLS is to be discontinued, the cannulation site incision(s) are opened and the right carotid artery and/or internal jugular vein are ligated. Percutaneously placed cannulas may simply be removed and pressure applied without concern for the anticoagulation status of the patient. A number of centers have demonstrated the ability to reconstruct the carotid artery following a course on venoarterial extracorporeal support. Controversy still exists, regarding the practice of carotid artery reconstruction since there is no evidence to suggest that it is in fact necessary nor beneficial since cerebral blood flow is normal on long term follow up. In fact, the ratio of right to left hemispheric cerebral blood flow and blood velocities in the right and left internal carotid arteries are no different between newborns with reanastomosed or ligated common carotid arteries.

The mean S.D. duration of the ECLS course is 149 - 162 hours for neonates with respiratory failure and 280 - 204 hours for children with respiratory failure. Considerations for discontinuing extracorporeal support at times other than when indicated by improvement of cardiopulmonary function include the presence of irreversible brain damage, other lethal organ failure, and uncontrollable bleeding. Those neonates with congenital diaphragmatic hernia or pneumonia and pediatric patients with cardiac or pulmonary failure may require substantially longer periods on ECLS before resolution of the cardiopulmonary process is observed.

Complications

In general, the complications associated with ECLS fall into one of three major categories: 1) bleeding associated with heparinization, 2) technical failure, and 3) neurologic sequelae, a majority of which are secondary to the hypoxia and hemodynamic instability which occurs prior to onset of extracorporeal support.

Because of systemic heparinization bleeding complications are the most common and devastating. Intracranial hemorrhage occurs in approximately 13% of neonates, 5% of pediatric patients, and 4% of cardiac patients. It is the most frequent cause of death in newborns managed with ECLS. The incidence of intracranial hemorrhage is clearly increased in patients who are premature, especially in those < 37 weeks gestational age.

The most notable technical complications include the presence of thrombus in the circuit (26%), incorrect cannula positioning (6-15%), oxygenator failure (5-17%), pump malfunction (1-4%), and presence of air in the circuit (6%).

Results and Follow-up

A total of 25,201 cases have been submitted to the ELSO registry since 1975. Of these, there have been 17,536 cases of neonatal respiratory failure and 2,361 cases of pediatric respiratory failure. Overall survival is 77% with the best survival noted among those neonatal patients with the most frequent diagnoses of meconium aspiration syndrome (survival = 94%), respiratory distress syndrome (84%), and PPHN (79%). Congenital diaphragmatic hernia patients continue to have the poorest survival among those for which ECLS is applied likely because of the "irreversible" pulmonary hypoplasia which is associated with that condition. In fact, the survival in patients with CDH requiring ECLS has fallen from a high in 1987 of 71% to the current rate of 54%. The total number of neonatal respiratory ECLS cases peaked with 1,517 cases performed in 1992. There has since been a trend downward such that the total number of neonatal cases in calendar year 2000 was 867 likely due to improved results with neonatal respiratory management which includes the use of nitric oxide and HFOV.

The experience with patients with pediatric respiratory failure at the University of Michigan demonstrates a survival rate of 73% at the University of Michigan since 1988. In addition, patients in the younger age groups demonstrate greater survival rates, including a 100% survival in those infants < 1 year of age. The ELSO registry demonstrates that pediatric respiratory cases are accumulating at a rate of 150-200 cases per year with an overall survival rate of 55%. One of the most frequent diagnoses is viral pneumonia which is predominated by respiratory syncytial virus.

Multiple studies have evaluated the long term follow up of newborn and pediatric patients following a course on ECLS. Most have documented normal neurologic function in 70-80% of patients. Such studies have demonstrated that neurologic morbidity is no different in ECLS-managed when compared to CMV-managed newborns. However, children at school age demonstrate an increased risk for academic difficulties and behavioral problems when compared to their normal counterparts. Bronchopulmonary dysplasia or supplemental oxygen requirement have been observed in 10 to 50% of patients at the time of discharge.

Suggested readings authored by the University of Michigan, Section of Pediatric Surgery

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