The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–9, 2015 Copyright Ó 2015 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter

http://dx.doi.org/10.1016/j.jemermed.2015.02.010

Clinical Review PEDIATRIC EXTRACORPOREAL MEMBRANE OXYGENATION: AN INTRODUCTION FOR EMERGENCY MEDICINE PHYSICIANS Lynn P. Gehrmann, MD,* John W. Hafner, MD, MPH, FACEP,†‡ Daniel L. Montgomery, MD,§ Klayton W. Buckley, CCP, RN,k and Randall S. Fortuna, MD, FACS{**†† *Department of Emergency Medicine, Ministry Medical Group Saint Mary’s Hospital, Rhinelander, Wisconsin, †Department of Emergency Medicine, University of Illinois College of Medicine at Peoria, Peoria, Illinois, ‡Department of Emergency Medicine, Children’s Hospital of Illinois at OSF Saint Francis Medical Center, Peoria, Illinois, §Emergency Medicine Residency Program, University of Illinois College of Medicine at Peoria, Peoria, Illinois, kDepartment of Perfusion, Children’s Hospital of Illinois at OSF Saint Francis Medical Center, Peoria, Illinois, {Department of Pediatrics, University of Illinois College of Medicine at Peoria, Peoria, Illinois, **Extracorporeal Life Support (ECMO) Services, Congenital Heart Center, Children’s Hospital of Illinois at OSF Saint Francis Medical Center, Peoria, Illinois, and ††Department of Surgery, University of Illinois College of Medicine at Peoria, Peoria, Illinois Reprint Address: John W. Hafner, MD, MPH, FACEP, Department of Emergency Medicine, Children’s Hospital of Illinois at OSF Saint Francis Medical Center, 530 NE Glen Oak Ave., Peoria, IL 61615

, Abstract—Background: Extracorporeal membrane oxygenation (ECMO) therapy has supported critically ill pediatric patients in the intensive care unit setting with cardiac and respiratory failure. This therapy is beginning to transition to the emergency department setting. Objective of Review: This article describes the fundamentals of ECMO and familiarizes the emergency medicine physician with its use in critically ill pediatric patients. Discussion: ECMO can be utilized as either venoarterial (VA) or venovenous (VV), to support oxygenation and perfusion in respiratory failure, sepsis, cardiac arrest, and environmental hypothermia. Ó 2015 Elsevier Inc.

ECMO use has become standard of care with survival rates > 85% in neonates as a final rescue therapy, with severe and refractory hypoxemia secondary to meconium aspiration, respiratory distress syndrome, and primary pulmonary hypertension prompting uses from the neonatal population to the pediatric (1). Most of the literature on ECMO use with pediatrics relates to its use in the pediatric intensive care unit (PICU), but with this expanded patient selection criteria and simplified, more compact systems, ECMO is now a possible treatment option for more pediatric patients who are failing conventional treatment in the emergency department (ED). The purpose of this article is to review the evidence and describe the fundamentals of ECMO to familiarize the emergency medicine physician with this modality for the treatment of the critically ill pediatric patient.

, Keywords—ECMO; extracorporeal membrane oxygenation; respiratory failure; pediatric; E-CPR

INTRODUCTION

DISCUSSION

Extracorporeal membrane oxygenation (ECMO) is the use of a modified cardiopulmonary bypass machine that provides cardiac support, blood oxygenation, and carbon dioxide removal in patients with reversible cardiac or respiratory failure. In the neonatal intensive care unit (NICU),

History The story of ECMO’s transition from the NICU and the PICU to the ED is a complicated journey that spans

RECEIVED: 2 October 2013; FINAL SUBMISSION RECEIVED: 19 December 2014; ACCEPTED: 17 February 2015 1

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Figure 1. VV and VA ECMO circuits.

over several decades. ECMO is a mechanical technique that provides a circuit outside the body where blood oxygenation and carbon dioxide removal can occur for patients with reversible cardiac or respiratory failure. ECMO machines are a modified cardiopulmonary bypass circuit, conceptually similar to the one invented by John Gibbon in 1936 and in current use during cardiac bypass surgery in the operating suite. One of the major modifications that expanded the use of the original historical bypass circuit was the addition of a silicone membrane in the 1950s that enabled prolonged use by limiting the direct interface between the blood and oxygen during cardiac surgery (2–5). In the 1960s there was extensive research on materials and techniques, with the goal to increase the length of time a patient could remain on bypass. The first reported successful use of extracorporeal circulation for a patient in acute respiratory failure was for the treatment of an adult blunt chest trauma patient in 1971 that developed acute respiratory distress syndrome (ARDS) after a motorcycle accident (6,7). This was the beginning of moving cardiopulmonary bypass from the operating suite to the bedside. In the early 1970s, the concept of intensive care units development and advanced care for patients with ARDS stimulated further research of bedside extracorporeal circulation techniques. It was a few years later that Bartlett et al. reported success in treating the first newborn with respiratory failure, fostering the hope that there was a new possible therapy for the treatment of severe hypoxia (2,8). In 1974, a multicenter randomized trial was launched to test venoarterial ECMO vs. conventional mechanical ventilation therapy in adult ARDS patients. Unfor-tunately, the study revealed mortality rates in the ECMO therapy group as high as 90%, not significantly different from those in the conventional ventilator treatment group (9). These results decreased the interest of ECMO for adult

ARDS therapy at the time, but utilization continued with neonates. In the late 1970s, neonates with respiratory failure treated with ECMO yielded survival rates of 56%. This success was attributed to the fact that in neonatal respiratory failure, the lungs require only a short time for recovery (9). Subsequently, ECMO has been used in NICUs for the treatment of respiratory failure due to primary pulmonary hypertension of the newborn, meconium aspiration syndrome, persistent fetal circulation, and congenital diaphragmatic hernia, yielding survival rates of >80% (10). From the success in neonates, and supported by good evidence-based medicine for treatment of respiratory failure, the technology was adapted to pediatrics in the early 1980s. In 1989, the Extracorporeal Life Support Organization registry was founded. This registry has been able to track pediatric patients treated with ECMO and was able to document a cumulative survival rate of 53% in 982 cases of pediatric respiratory failure from 1990 to 1995 (11). The use of ECMO has continued to undergo multiple refinements and technical improvements, allowing for expansion of the patient selection criteria and an evolution from a rescue therapy to use as early intervention therapy and use in the ED. The ECMO Circuit ECMO is a complex therapy modality with two standard modes, venoarterial (VA) and venovenous (VV). Each mode uses the same basic circuit components, with placement of the cannulas determining the mode. The basic ECMO circuit is composed of vascular cannulas for access and blood return, circuit tubing, a pump, a gas-exchange device, a heat exchanger, and systemic anticoagulation with heparin to keep the system patent (Figures 1 and 2) (2,5,13). In VA ECMO, the circuit requires accessing a major vein and a major artery, whereas VV ECMO requires only access to either two major veins or a single major vein using a double-lumen catheter.

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Figure 2. Patient on VA ECMO circuit (photo courtesy of R Fortuna).

Vascular access is the first step in the initiation of ECMO. The technique of cannulation occurs either peripherally via the neck or femoral vessels, or centrally via the right atrium and aorta. The cannulae can be placed using various methods, including: percutaneously by a Seldinger technique, open surgical exposure of the vessels, or by direct central cannulation via sternotomy or thoracotomy (14). The site of cannulation is determined by the size of the patient and the size of the catheters needed to maintain projected ECMO flow rates. In newborns and infants, this usually requires surgical access

to the right internal jugular vein and right common carotid artery for cannulation under direct vision. The small vessels become occluded by the large catheters, so it is critical that flow through the left internal jugular vein and left common carotid artery is not compromised. Teenagers and adolescents may be cannulated in the femoral vessels, most commonly by percutaneous methods using the Seldinger technique. Usually this can be accomplished without occluding the vessels, but the femoral artery is at greatest risk. If distal perfusion of the leg with arterial cannulation is compromised, a second, smaller arterial catheter may need to be placed in the distal femoral artery to separately perfuse the leg. Cannulation of the patient is usually initiated by a cardiovascular surgeon, but has also been initiated by the emergency physicians percutaneously placing cannulas using the Seldinger technique (15–18). Once vascular access has been obtained, the patient can be connected to the ECMO circuit. Blood is drawn by gravity through the venous cannula into the circuit and a pump is used to move blood through the circuit. There are two main types of pumps: a roller type and a centrifugal type, each with its own advantages and disadvantages. It is the rate of rotation of the pump that determines nonpulsatile flow rate of the blood. Within the system there is a pressure transducer that will slow or stop to ensure the pump rate does not exceed the rate that the blood exits the patient. The patient’s hemoglobin is saturated with oxygen as the blood is passed through the membrane oxygenator, and CO2 is removed by diffusion. The oxygenated blood then passes through a heat exchanger to ensure that the blood returning to the patient is a safe temperature (19). The type of ECMO cannulation utilized depends primarily upon the clinical condition being treated. VA ECMO helps support cardiac output and delivers higher levels of oxygenation support than VV ECMO (Table 1). VA ECMO is indicated for situations of primary cardiac dysfunction. In hypotensive patients requiring inotropic support for which ECMO is being considered, clinicians must determine if the hypotension is of a primary cardiac etiology or secondary to the effect

Table 1. Characteristic Differences between VV and VA ECMO VA ECMO

VV ECMO

Cannulation site

Right internal jugular vein or femoral vein and right carotid artery

Oxygenation Removal of CO2 Circulatory support Use in patients with primary heart failure Use in patients with primary renal failure

High High Partial to complete Yes Yes

Internal jugular vein and femoral vein; femoral vein and femoral vein; dual-lumen single cannula right internal jugular vein Moderate High None No Yes

VV = venovenous; VA = venoarterial; ECMO = extracorporeal membrane oxygenation.

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of primary respiratory failure on the circulation. Improvements in acid-base balance, myocardial oxygen delivery, and pulmonary hypertension with VV ECMO can have dramatic effects on cardiac function and overall patient hemodynamics. For VA ECMO, one cannula is placed in the venous system (right internal jugular or femoral vein) and the other is placed in the arterial system (carotid artery for newborns and smaller children or femoral artery for older children and teenagers) (20). Venovenous (VV) ECMO is the newer of the two modalities. The deoxygenated blood is removed from the venous system; then, after it has been oxygenated, it is returned to circulation through the venous system. In pediatric patients the cannulas are placed either jugular–femoral or femoral–femoral (5,12,13). VV ECMO is the modality best suited for reversible severe acute respiratory failure (21–23). The advantages of VV include avoiding repair or ligation of the carotid artery, decreasing the potential for ischemic lung injury, and decreasing the risk of systemic or cerebral thromboembolic complications. However, the main disadvantage of VV ECMO is the modality does not provide direct circulatory support, so it cannot be used in patients with refractory hypotension or primary cardiac failure (21). It should also be noted that the oxygenation provided by VV ECMO might also be lower because the returning circuit blood enters the right atrium, and is mixed with unsaturated venous blood. At times, the maximum SaO2 achievable may be as low as 80–85% (3,5,24). Indications In general, ECMO for pediatric patients should be considered as a last option when standard medical management has failed to correct severe cardiorespiratory failure that has a reversible etiology or for which the patient is amenable for organ transplantation (bridge for transplantation). As ECMO represents a highly invasive procedure associated with potentially life-threatening complications, proper patient selection for ECMO is important. Guidelines for the initiation or exclusion of ECMO are not universal, but often determined by each institution, depending on resources and expertise. Some common, but not all-inclusive, pediatric patient selection criteria can be seen in Table 2 (3,21,25). When determining which patients are appropriate for ECMO, it needs to be remembered that the primary goal of ECMO is to provide tissue perfusion and oxygenation, allowing time for pulmonary and cardiac ‘‘rest.’’ As such, ECMO in itself is not a therapy; therefore, the success of the modality is not a diagnosis-dependent intervention. The most common diagnoses in newborns and infants requiring ECMO support include sepsis, viral bronchiolitis (respiratory syncytial virus), and congenital heart

L. P. Gehrmann et al. Table 2. Possible ECMO Indications Inclusion factors

Exclusion factors

1. PaO2/FiO2 10 days

ECMO = extracorporeal membrane oxygenation; AIDS = acquired immune deficiency syndrome.

disease (either known or undiagnosed). Adolescents and teenagers present with a larger variety of diagnoses necessitating ECMO treatment. These include respiratory causes including pneumonia, status asthmaticus, ARDS, near drowning, acute chest syndrome, and posttraumatic lung injury. Cardiac diagnoses include myocarditis, intractable dysrhythmias, beta blocker/calcium channelblocker poisoning, and cardiac arrest. Respiratory failure. ECMO has become a vital tool in the management of severe pediatric acute respiratory failure. Some of the common diagnoses leading to respiratory failure that have been treated successfully with ECMO are pneumonia (viral and bacterial), status asthmaticus, aspiration syndromes, ARDS, and burn injuries. Multiple retrospective cohort studies have reported survival rates based on pulmonary diagnosis, ranging from 83% for status asthmaticus to 39% for severe pertussis (22,26–28). The use of ECMO in status asthmaticus has also been a successful option when the mechanical ventilation becomes unmanageable due to lung hyperinflation and auto-positive end-expiratory pressure (auto-PEEP). Pediatric patients in status asthmaticus placed on ECMO have had a reversal of hypercapnia and acidosis in as little as 2–4 h of treatment (29,30). At present, there are no evidence-based guidelines on when to initiate ECMO for status asthmaticus, but a study by Kukita et al. has suggested use in the setting of persistent hypoxemia, pH < 7.2, PCO2 > 100 mm Hg, or in the face of life-threatening complications due to ventilation, such as hypotension or barotrauma (31). Sepsis. Septicemia was once a contraindication to ECMO because there were concerns that the infecting organism would seed the ECMO circuit leading to intractable bacteremia and death (32–34). Although this is still a controversial topic, ECMO use as a rescue therapy in

ECMO: Introduction for EM Physicians

patients with severe sepsis has reported success in stabilizing those who would have otherwise died of hypoxemia or inadequate cardiac output. In 2007, MacLaren et al. described a series of 45 children with profound septic shock refractory to conventional treatment who were placed on ECMO (35). Twenty-one children (47%) were discharged and survived with no serious disability. A study of the Extracorporeal Life Support Organization registry of noncardiac sepsis pediatric patients aged 0 to 18 years from 1990 to 2008 documented an overall survival of 68% for septic patients placed on ECMO. Data analysis revealed a decreased survival with increasing age (73% in newborns #1 month, 40% in children 1 month to 12 years, and 32% in adolescents > 12 years), use of vasoactive drugs, and advanced respiratory support (36). Cardiac arrest. Pediatric survival to discharge after an in-hospital cardiac arrest with standard cardiopulmonary resuscitation (CPR) has been reported to be 25–33%, and even lower for out-of-hospital arrests (37–39). Survival drops exponentially as the length of resuscitation efforts are prolonged, even with the implementation of the Pediatric Advanced Life Support guidelines (38–41). In 1992, del Nido et al. were the first to report the use of ECMO as a rescue therapy for cardiac arrest in children; this utilization has been deemed E-CPR (extracorporeal cardiopulmonary resuscitation) (42). Recent series have reported survival to hospital discharge for patients supported with E-CPR ranging from 33–55% (43–46). The success of these studies resulted in the first major change to the traditional technique of CPR, prompting the current American Heart Association Pediatric Advanced Life Support recommendations to consider E-CPR for in-hospital pediatric cardiac arrest patients ‘‘if the conditions leading to arrest are reversible, or amenable to heart transplantation’’ (47). With the survival rates for pediatric out-of-hospital arrest being reported as low as 2% (and most suffering neurologic sequel), it is difficult to report survival statistics on the use of ECMO in these patients because no large case series or trials have been reported and only case reports exist (48,49). Although E-CPR has the potential to save lives, it also represents a highly invasive and complicated process; therefore, proper patient selection is warranted. The upper limit of hospital or bystander CPR duration prior to initiating E-CPR, and potentially allowing for a viable neurologic outcome, is unknown. Values reported from retrospective data revealed no statistical difference between survivors and nonsurvivors regarding the length of CPR prior to initiating E-CPR. Viable neurologic outcomes have been reported in patients with E-CPR initiated as long as 176 min post arrest, with the median intact survivor initi-

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ation time at approximately 50 min (44,45,49,50). Factors that improve the chance of survival include cardiac arrests due primarily to cardiac etiology (medical or surgical) as well as a witnessed arrest. Factors that have an associated increased mortality are a pre-ECMO pH < 7.0 and renal insufficiency (38). Hypothermia. Hypothermic cardiac arrest in the pediatric patient is a rare event, usually associated with a cold water drowning. It is important to note that some patients with profound hypothermia will have experienced a lethal event before hypothermia has occurred, whereas others may be protected for substantial periods of anoxia by the mammalian diving reflex. The mechanism for this reflex involves the sensory stimulus of cold water touching the face, inhibiting the respiratory center and inducing bradycardia and vasoconstriction. It is the combination of these responses that preserve the circulation to the heart and brain and reduces oxygen consumption, prolonging survival (51). There are many ways to rewarm the hypothermic patient, both passive and active, with ECMO being one of the more effective active methods. One of the advantages of active rewarming with ECMO is the rate of temperature rise (reported as fast as 0.4 C per minute), as ECMO rewarms the core first and immediately supplies circulatory support (52,53). ECMO used for rewarming the hypothermic patient has been criticized for being too time consuming and interfering with other rapid rewarming methods. Scaife et al. published their protocol for ECMO rewarming to limit the time to activate the initiation of ECMO for the hypothermic patient (54). Survival rate for the patients in their study was 50%, with the negative prognostic indicator being potassium > 10 mmol/L (52,54,55). Complications The complications of ECMO can be divided into two categories: mechanical and clinical. The mechanical category can be further grouped into equipment failure or malfunction, cannula problems, and blood clots or air in the circuit. The most common mechanical complication is blood clots developing in the circuit, which occurs in 19% of patients. The consequence of the blood clot formation within the circuit is increased hemolysis, and necessitates a change in circuit tubing or individual components (25). The two major life-threatening mechanical complications are air embolism or blood loss from a disruption of the circuit (5). These mechanical complications are monitored by trained ECMO technicians, but the emergency physician should be aware that these mechanical complications can occur. Hematological clinical complications are secondary to changes in the blood flow pattern and the blood surface

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interactions. This blood–surface interaction activates the coagulation cascade, resulting in thrombus formation and platelet consumption. Most ECMO centers counteract this complication through anticoagulation using heparin. Systemic heparinization and altered platelet activity increase the risk of bleeding complications. Disseminated intravascular coagulation may also occur, but this is often present prior to initiating EMCO from the illness itself (3,56). The neurological complications of ECMO include central nervous system (CNS) hemorrhage, CNS infarction, and seizure. Intracranial hemorrhage occurs in 7.4% of the ECMO-treated patients and is more likely to occur in patients younger than 30 days. Cerebral infarction occurs in 5.7% of all ECMO-treated patients, and 8.4% of the patients develop seizures (57). During the first 24–48 h of ECMO use, oliguric renal failure and acute tubular necrosis is common, and is more common among pediatric cardiac patients and those patients requiring ECMO for increased duration (5,58). Acute renal failure and the consequences of this organ dysfunction, such as hypervolemia, hyperkalemia, or azotemia, are indications for continuous hemofiltration placed in-line with the ECMO circuit (59). Cardiopulmonary complications occur in approximately 26% of patients. Specific complications include myocardial stun (7%), hypertension (13%), and pneumothorax (6%) (3). Cardiac stun occurs only when patients are on VA ECMO, and is defined as a decrease in the left ventricular shortening fraction by more than 25% with initiation of ECMO. Cardiac stun is transient, with return to pre-ECMO cardiac activity after 48 h (60,61). Patient Management The perfusionist and ECMO physician will address most, if not all, of the ECMO circuit complications and patient management issues. The emergency physician can help facilitate the care of these critical patients by having available all specific patient data and stabilizing the patient as much as possible prior to cannulation. Baseline patient laboratory data should include, but is not limited to, coagulation panels, a complete metabolic panel, a complete blood count, and blood type and cross. The resuscitation of the patient should be the same as any other critical patient, with intubation if necessary for respiratory distress, and intravenous fluids, blood products, and vasopressors as needed to maintain adequate blood pressure. If patients will require initiation of an ECMO circuit in the ED, blood products, as well as heparin, at the bedside will be essential. There are facilities where emergency physicians are placing the ECMO catheters in patients during E-CPR. There have been case series and reports of successful cannulation and resuscitation

L. P. Gehrmann et al.

of adults with cardiac arrest by emergency physicians in the ED (62). This has not been studied or practiced in the pediatric population, but the emergency physician may have a larger role in pediatric ECMO catheterization in the future. Once the patient is on full support ECMO, ventilator settings are set to minimize barotrauma, oxygen toxicity, and to maintain functional residual capacity. Basic settings include an FiO2 weaned to 17 s (3,5,25). Sedation can be difficult to maintain in children. Paralysis should be avoided except during the cannulation and decannulation procedures, but may be necessary when trying to achieve appropriate sedation level. Most patients are placed on a continuous infusion of a combination of benzodiazepine and opioid for sedation. It is important to note that the membrane oxygenator continuously binds fentanyl, and increasing the amount is often necessary (3,5). Transport For most community emergency medicine physicians, the facility that they are practicing at will not be an ECMO center, and the patient will need to be transferred for this therapy. In the United States there are three ECMO centers that have a mobile ECMO team that can be deployed to the referring facility (62). For the emergency physician, the decision to transfer a potential ECMO candidate can be difficult. The best resource is to contact the closest ECMO center for consultation with an ECMO team physician. Early consultation can allow transfer before the

ECMO: Introduction for EM Physicians

patient is unstable for safe transport. If the facility has the option of an ECMO or cardiovascular surgery team team being deployed to the ED, the cannulation procedures can be initiated and then the patient transported via ground or air. Texas Children’s Hospital has successfully transported ECMO candidate patients by both land and ground. From 1990 to 2005, 38 patients were successfully transferred to Texas Children’s Hospital without major complication or death (64). Emergency medicine physicians have a unique opportunity to not only facilitate these transfers, but to be a part of the initiation of ECMO, which could ultimately be lifesaving. Because emergency medicine physicians are at the forefront of out-of-hospital cardiac arrests, E-CPR is an ED-based therapy that has the potential to change the landscape of pediatric resuscitation; but further studies of efficacy and efficiency are necessary. The key to having successful and safe ECMO candidate transfers is to have a transfer plan in place prior to their presentation. It is recommended that contact with the ECMO team physician be initiated to verify eligibility, formulate a specific transfer plan, and ensure safe transport of these critically ill patients.

7

6.

7. 8.

9. 10. 11. 12.

13. 14. 15.

CONCLUSIONS 16.

The utilization and success of ECMO in the medical management of pediatric patients with respiratory or cardiac failure has been well documented in the inpatient setting; however, its use in the ED is limited but expanding, and continued research is necessary. Although this article has been focused on pediatric ECMO, it should be noted that there is also a resurgence and increased use of adult ECMO in recent years (65–67). It is important for the emergency medicine physician to understand the fundamentals of ECMO to properly weigh the risks and benefits when deciding which pediatric patients are appropriate to refer to an ECMO center or place on ECMO. Early consultation with an ECMO center, cardiovascular surgeon, and the pediatric critical care team is essential, and can result in appropriate and safe transfer of the potential ECMO pediatric patient.

17. 18. 19.

20. 21. 22. 23. 24.

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ECMO: Introduction for EM Physicians

ARTICLE SUMMARY Why is this topic important? Extracorporeal Membrane Oxygenation (ECMO) therapy is an accepted rescue option in the pediatric critical care environment, is now becoming a possible treatment modality for critically ill ED pediatric patients failing conventional therapy. Emergency physicians caring for these patients need to understand the basic concepts of ECMO. What does this review attempt to show? This review describes the fundamentals of ECMO and familiarizes the emergency medicine physician with its use in critically ill pediatric patients. What are the key findings? ECMO can be utilized as either a venoarterial (VA) or venovenous (VV) system, to support oxygenation and perfusion for pediatric patients in a variety of clinical scenarios. ECMO represents a highly invasive procedure associated with potential life-threatening complications, proper patient selection for ECMO is important. How is patient care impacted? ECMO in the ED setting allows for pulmonary and cardiac support in critically ill pediatric patients that have failed less invasive life support measures. Emergency physicians familiar with this option may facilitate ECMO initiation or transport of the patient to an ECMO center.

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