Extracorporeal life support (ECLS), more commonly referred to as extracorporeal membrane oxygenation (ECMO), is a modified form of cardiopulmonary bypass. During ECMO, blood is pumped through an extracorporeal circuit containing an artificial lung (membrane oxygenator) in which oxygen is added and carbon dioxide removed from blood, which is then returned to the patient.
ECMO was pioneered as a technique to support term or near-term neonates with severe respiratory failure unresponsive to maximal conventional management, an indication supported by evidence from one large randomized controlled trial, several smaller trials (1–5), and a large body of data accumulated by the international Extracorporeal Life Support Organization (ELSO) registry (6). One review from the Cochrane database also confirmed the benefit of ECMO in neonates with respiratory failure. Infants with congenital diaphragmatic hernia remain a high-risk group in whom the benefit of ECMO in improving morbidity and mortality is less clear (5). Importantly, the successful use of ECMO in infants established ECMO as a technical success, which led to expansion in other critical care populations.
Much of the data regarding ECMO use comes from the International ELSO data registry. Now in its 25th year, ELSO contains data on over 55,000 patients who have received ECMO support (http://www.ELSO.org). Guidelines for use and texts are also available via ELSO. Data show that ECMO has been deployed for respiratory, cardiac, and multiple organ system failure in neonates (0–30 d of life), children (> 30 d to 18 yr), and adults (> 18 yr). Of these indications, high-quality clinical trial evidence exists only in support of the use of ECMO in neonates and adult severe respiratory failure (7, 8). Although attempts to perform similar trials in children outside the neonatal period have been performed, no study has reached recruitment conclusion and the benefit of ECMO in this age range is unproven (9, 10). The only attempt at a randomized, controlled trial in pediatric respiratory failure was discontinued due to futility in achieving enrollment goals and a much higher survival rate in the control population than predicted. As this trial occurred during the same period as when experience in high-frequency oscillation was gaining, the liquid ventilation trial was occurring, and lung protective ventilation was becoming more understood, it had many obstacles to prevent its successful conclusion. Despite lack of evidence for superiority, however, ECMO in pediatric acute respiratory distress syndrome (PARDS) is used in critically ill children throughout the world.
INDICATIONS FOR ECMO IN CHILDREN WITH PARDS
8.1.1 We recommend that ECMO should be considered to support children with severe PARDS where the cause of the respiratory failure is believed to be reversible or the child is likely to be suitable for consideration for lung transplantation. Strong agreement
8.1.2 It is not possible to apply strict criteria for the selection of children who will benefit from ECMO in PARDS. We recommend that children with severe PARDS should be considered for ECMO when lung protective strategies result in inadequate gas exchange. Strong agreement
8.1.3 We recommend that decisions to institute ECMO should be based on a structured evaluation of case history and clinical status. Strong agreement
8.1.4 We recommend that serial evaluation of ECMO eligibility is more useful than single-point assessment. Strong agreement
8.1.5 We recommend that careful consideration of quality of life and likelihood of benefit should be assessed. Strong agreement
Mechanical ventilation is a cornerstone in the management of patients with PARDS. Mechanical ventilation is, however, known to be associated with the development of further injury to the ventilated lung through overdistension and cyclic opening and closing of alveoli (11). While the occurrence of ventilator-associated lung injury may be minimized by adopting protective ventilatory strategies (12, 13), in severe lung disease, protective thresholds are often exceeded to maintain adequate gas exchange and it is in these situations that lung rest through the use of ECMO may be beneficial. Mortality in the sickest cohort of children with PARDS is extremely high and may exceed 90% without ECMO support. Survival of a similar population of children with severe respiratory failure who received ECMO was more favorable with 56% survival to discharge or transfer (ELSO International Summary 2011) (14). Zabrocki et al (15) recently reported on the use of ECMO for pediatric respiratory failure using data available through the ELSO registry. Survival for children categorized as “acute respiratory distress syndrome (ARDS)—sepsis” (n = 235) was 40%; for those categorized as “ARDS postoperative or trauma” (n = 159), it was 59%. Younger age and higher weight were associated with better survival. These descriptive data should be interpreted with caution, however, as the report focuses for the most part on “pediatric respiratory failure” and not specifically on PARDS. The International Registry of the ELSO notes an average of 57% survival among the 3,500 respiratory failure children reported to the registry. Summary statistics are shown in Table 1.
The apparent favorable impact of ECMO on survival in PARDS is of a similar order of magnitude to the improvements associated with the use of ECMO in the large U.K. neonatal and adult randomized ECMO trials. In the neonatal trial, 68% of infants allocated to ECMO survived to hospital discharge compared with 41% allocated conventional care (relative risk of death without ECMO was 0.55; 95% CI, 0.39–0.77; p = 0.0005) (4, 16). In the adult trial, Conventional Ventilation or ECMO for Severe Adult Respiratory Failure, analysis on an intention to treat basis showed survival at 6 months to be 63% in the ECMO group versus 47% in the conventional group (relative risk 0.69; 95% CI, 0.05–0.97; p = 0.03) (7, 8).
There are no agreed criteria for the provision of ECMO support for children with PARDS. Two physiological abnormalities are characteristic of PARDS: low lung compliance and impaired oxygenation. Of the available indices, two stand out as potentially useful as a guide to clinical decision making: oxygenation index (OI) (17), a composite measure reflects both oxygenation and level of ventilatory support (a surrogate for compliance), and PaO2/FIO2 (P/F) ratio (a measure of the lungs ability to oxygenate) (18) have been validated as descriptors of the severity of PARDS in relatively recent populations (19, 20). A multicenter review has also shown that OI is a predictor of mortality in pediatric respiratory failure (21). Post hoc data from the randomized trial of pediatric ECMO versus conventional therapy noted that the OI was an independent predictor of mortality. In 53 diagnosis and risk-matched pairs, patients who received ECMO had significantly lower mortality compared with non-ECMO-treated patients (26.4% vs 47.2%; p < 0.001). In the 50–75% stratified mortality risk from this same data registry, mortality for ECMO patients was 27% compared with 71% in the non-ECMO group (p < 0.05) (9). More recent data suggest that lower quartiles of OI than those reported in the past are associated with increased mortality. Although these measures are easily calculated from available data at the bedside and appear to reflect, consistently, risk in populations of patients not only at presentation but also through the first days of intensive care when applied to populations, their ability to predict death or poor outcomes in individual patients is poor. In the Australian and New Zealand Intensive Care Society (ANZICS) study (19), although P/F ratio and OI could predict those groups of patients at highest risk of mortality, less than 40% of total deaths were predicted by P/F or OI as sensitivity was low. More detailed discussion on the risk stratification of children with PARDS can be found in other sections of this ARSD supplement (22). One thing that remains logical is to follow such measures serially during the course of respiratory failure. Despite low sensitivity, when data from the ANZICs and Children's Hospital of Los Angeles studies were combined, an OI increase from 13 to more than 16 was associated with increased mortality to more than 40%. Thus, the OI at which ECMO might be considered may be much lower than the historical levels (usually > 40), which have been previously reported. With the advent of the electronic record, it seems a simple task to serially collect values for scores such as the P/F and OI on a larger, multicenter scale and correlate them to outcome. Collaboration between centers for this purpose seems a logical and timely project to undertake.
Given the lack of clear criteria applicable to individual patients, there is a strong consensus that decisions to use ECMO support in children with PARDS should be based on serial structured evaluations of clinical data, including evidence of improving or deteriorating trends. A failure to maintain clinical stability within the recommended limits for “safe” mechanical ventilation is a strong indication for consideration of ECMO support in the absence of any absolute or relative contraindication. ECMO is only supportive and is a complex therapy associated with specific additional risks. Its use and potential benefits should be carefully balanced against the risk of harm and the likely future quality of life of the child. All patients should be entered into an ECMO registry to facilitate on-going evaluation of success or failure and provide data for future prognostication and areas where research should be focused. The largest ECMO registry, the International Registry of the ELSO, is currently undergoing some revision to provide more specific data on patient diagnosis, pre-ECMO severity of illness, and other details, which may further inform the field in the future. Other efforts to design, implement, and complete research studies focused on specific variables of interest related to ECMO are also occurring. Development of a research network focused on answering questions such as “optimal” entry criteria, anticoagulation monitoring, and other aspects of patient management is a timely project. Collaboration between centers to standardize ECMO equipment and patient management schemes may also improve the ability to obtain scientifically valid results to answer specific questions.
CONTRAINDICATIONS TO ECMO IN CHILDREN WITH SEVERE PARDS
8.2.1 We recommend that ECMO should not be deployed in patients in whom life-sustaining measures are likely to be limited. Strong agreement
There are few absolute contraindications to ECMO support in children with PARDS. Long-term outcomes from underlying comorbidities are often the most important factors to consider when deciding whether to implement ECLS or not. Patient with neurologic injury prior to ECMO or developing injury during ECMO support may require long-term rehabilitation and care and the financial, family, and societal burden should be considered as part of ECMO decision making (23, 24).
TEAM TRAINING AND ORGANIZATION
8.3.1 We recommend that ECMO programs should have clearly defined leadership structure, including administrative support. Strong agreement
8.3.2 We recommend that all personnel directly caring for the patient should have an understanding of the ECMO circuit and the physiologic interactions between it and the patient. Competencies for physicians with primary patient care duties and ECMO specialists should be required. Strong agreement
8.3.3 We recommend that all centers providing ECMO support should belong to and report all patient activity to ELSO or similar organization. Strong agreement
8.3.4 We recommend that ECMO programs should benchmark themselves against other programs via the ELSO registry or similar. Strong agreement
ECMO is technically complex to deliver, and in order to maximize benefit and minimize risks, it is widely recognized that ECMO should be delivered in the context of a formally structured service by staff trained in its use who follow guidelines appropriate to the patient group concerned. While there will be interinstitutional and regional variations in the delivery of ECMO services, use of the guidelines published by the ELSO are recommended as a benchmark of current practice. ELSO publishes guidelines for the establishment of ECMO centers (25), general guidelines for the management of patients who receive ECMO support (26), pediatric-specific guidelines (27), and guidelines for the training of ECMO specialists (28). Additional resources from ELSO available to support practitioners and promote good practice include a comprehensive textbook (29) and their international database, which permits centers to compare their outcomes with those of the wider community of ECMO practitioners.
VENOVENOUS VERSUS VENOARTERIAL ECMO
ECMO is provided by two forms of support:
- Venovenous ECMO is capable of providing efficient respiratory gas exchange, partially or fully replacing the gas-exchange functions of the native lung during the period of ECMO support. Blood is both withdrawn and returned to the patient’s venous circulation. It requires adequate pumping of the native heart.
- Venoarterial ECMO is capable of providing efficient respiratory gas exchange and circulatory support by partially or fully replacing the gas-exchange functions of the native lung and of the cardiac pump functions of the heart during the period of ECMO support. In this mode, blood is withdrawn from the venous circulation and returned to the arterial circulation of the patient. Of note, venoarterial ECMO increases afterload on the left heart, and care must be taken to recognize and treat acute left ventricular failure during venoarterial ECMO support, as pulmonary venous hypertension leading to pulmonary hemorrhage is possible.
ELSO data show a trend toward a preference for venovenous ECMO for respiratory support in children. However, the choice of whether to use venovenous or venoarterial ECMO cannulation must be based on an assessment of the individual child, in particular whether or not there is circulatory compromise which would favor the choice of venoarterial support. In the absence of cardiac or circulatory dysfunction, expert opinion favors the choice of venovenous ECMO.
For more detailed descriptions of the physiology and practice of the various modes of ECMO support, there are numerous review articles and book chapters available within the critical care literature (29, 30). The ELSO organization also publishes a thorough text covering these issues.
At the current writing, the use of low-resistance, hollow-fiber oxygenators has almost completely replaced solid silicone membrane lungs during ECMO support. Many centers have also switched from semiocclusive roller pumps to newer versions of centrifugal technology. Although centrifugal pumps have some theoretical advantages, their superiority over roller devices is not yet well proven (31–33). They are sensitive to preload and afterload and can entrain air or produce microemboli. They do not, however, require gravity drainage for venous blood supply and do not run the risk of high pressure on the postpump head side of the circuit. These characteristics make them easier to use both at the bedside and during patient transport. Use of these devices at low flow rates such as needed in infants remains a concern at some sites, as risk for hemolysis or microemboli may be greater at lower flow rates. Other centers have noted less bleeding complications and improved outcomes when using a combination of hollow-fiber oxygenators and centrifugal setups. Further research into the advantages and disadvantages of various types of ECMO circuitry is needed. Newer cannulas for vessel access also have improved flow characteristics and single-site access for venovenous support.
OTHER ASPECTS OF ECMO CARE
Anticoagulation to prevent clotting in the ECMO circuit while limiting bleeding complications remains the major unsolved problem during ECMO support. Heparin remains the mainstay of anticoagulation, but debate continues as to the most appropriate means of monitoring and adjusting anticoagulation goals. The use of the activated clotting time has been the predominant bedside test for anticoagulation. More recent tests such as the anti-Xa level to monitor heparin effect, factor-specific assays, thromboelastography, and others are also being incorporated into ECMO anticoagulation algorithms. Use of direct thrombin inhibitors such as argatroban or bivalirudin may also offer alternatives to heparin. The optimal anticoagulation regimen has yet to be defined (34–36). Recent reports indicate the variable practices present throughout the world and add further credence to the lack of consensus on this important area of ECMO and mechanical support (37). Research efforts continue in this area. The ELSO organization has recently published general anticoagulation guidelines based on query of common clinical practice (http://www.ELSO.org).
As ECMO equipment has become more efficient and more easily applied due to new percutaneous double-lumen cannulas and circuits, there has been a shift to maintaining patients in a more awake state to improve overall physical rehabilitation function while on ECMO support and limit adverse effects of prolonged sedation. Although awake ECMO seems most successful in the patient with single-organ failure awaiting lung transplant, it is becoming more common even in cases of severe ARDS. The ability for patients to maintain muscle strength and tone during prolonged ECMO support may infer some survival benefit, and scattered reports of active rehabilitation on ECMO now appear. Whether such an approach can be successful in patients with severe dyspnea during ECMO support requires more study (37, 38), as does determination of factors involved in dyspnea in patients who seem well supported with ECMO from a gas-exchange perspective.
DURATION OF ECMO AND WEANING
Although the shortest period of ECMO support required to allow native restoration of adequate gas exchange and organ function is the goal, prolonged ECMO support up to weeks or months can also be successful. Determination of futility of ECMO support is difficult. Development of complications such as neurologic damage or unremitting multiple organ failure are most often the reasons for ECMO withdrawal. Failure of lung recovery after multiple weeks of ECMO support may also lead to consideration for lung transplant in some patients. Although complications increase with prolonged duration of ECMO, overall survival of patients supported for more than 7 weeks is not statistically different than those supported for less than 2 weeks from data within the ECMO registry, although the number of long duration patients is small (H.J. Dalton, ELSO Registry Review, unpublished data, 2014). Weaning from ECMO in venovenous patients only requires cessation of gas-exchange support across the membrane oxygenator while monitoring the patient’s ability to support adequate ventilation and oxygenation with native lung function.
Venoarterial ECMO requires a trial at low flow or no flow to determine if adequate ventilation, oxygenation, and hemodynamic stability can be attained prior to final separation from the ECMO circuit (14, 40).
All patients should have minimal neurologic evaluation by CT or MRI (preferred) prior to discharge if possible. Routine follow-up for quality of life, ongoing medical issues, and organ recovery is optimal but is not yet a common practice in post-ECMO care, except in many neonatal ICU centers (41–43). Improving follow-up efforts and sharing knowledge on short- and long-term outcomes of ECMO survivors is vital to help determine overall risks and benefits of ECMO support.
OTHER MODES OF EXTRACORPOREAL LUNG SUPPORT
8.4.1 We recommend that patients suffering from extreme hypercarbia and mild-to-moderate hypoxia may benefit from new extracorporeal devices that provide partial respiratory support. Such devices may be effective in removing all carbon dioxide and may not require a pump to provide blood flow but may instead use the patient’s own generated systemic blood pressure to drive blood through a low-resistance oxygenator. Weak agreement (63% agreement)
Extreme hypercarbia can lead to neurologic and cardiac dysfunction and respiratory failure. ECMO or adapted devices can allow almost total removal of native carbon dioxide while providing variable oxygenation as well. In some patients, placement of a low-resistance oxygenator between an arterial and venous blood source (often using femoral artery and vein) and allowing the patient’s native systemic blood pressure to drive blood through the oxygenator provides adequate control of carbon dioxide (44–46). A recent adaptation of this method in children with severe pulmonary hypertension is to interpose the oxygenator between the pulmonary artery and left atrium to alleviate hypoxemia and improve right heart function (47). Such patients may require bridge to heart/lung transplant or recover to the point where such intervention can be avoided. In other patients, a low-resistance oxygenator using an integrated pump (which is very similar to venovenous ECMO but requires a low blood flow) is also effective in control of hypercarbia while providing some oxygenation support. Use of other membrane devices such as those used for renal replacement therapy can also provide small amounts of carbon dioxide removal and oxygenation.
Although well-defined criteria and clinical practice parameters for ECMO do not exist, it is used as a rescue therapy in many ICUs for children with respiratory failure. Collaborations to perform scientifically valid studies would provide needed data on optimal initiation criteria, patient management, and outcome measures (both short and long term). Developing consensus on these important areas is a strategic and vital need. This project is another step in this process.
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APPENDIX 1. Pediatric Acute Lung Injury Consensus Conference Group
Organizing Committee: Philippe Jouvet, University of Montreal, Canada; Neal J. Thomas, Pennsylvania State University; Douglas F. Willson, Medical College of Virginia
Section 1, Definition, incidence, and epidemiology: Simon Erickson, Princess Margaret Hospital for Children, Australia; Robinder Khemani, University of Southern California; Lincoln Smith, University of Washington; Jerry Zimmerman, University of Washington
Section 2, Pathophysiology, comorbidities, and severity: Mary Dahmer, University of Michigan; Heidi Flori, Children’s Hospital & Research Center Oakland; Michael Quasney, University of Michigan; Anil Sapru, University of California San Francisco
Section 3, Ventilatory support: Ira M. Cheifetz, Duke University; Peter C. Rimensberger, University Hospital of Geneva, Switzerland
Section 4, Pulmonary-specific ancillary treatment: Martin Kneyber, University Medical Center Groningen, The Netherlands; Robert F. Tamburro, Pennsylvania State University
Section 5, Nonpulmonary treatment: Martha A. Q. Curley, University of Pennsylvania; Vinay Nadkarni, University of Pennsylvania; Stacey Valentine, Harvard University
Section 6, Monitoring: Guillaume Emeriaud, University of Montreal, Canada; Christopher Newth, University of Southern California
Section 7, Noninvasive support and ventilation: Christopher L. Carroll, University of Connecticut; Sandrine Essouri, Université Pierre et Marie Curie, France
Section 8, Extracorporeal support: Heidi Dalton, University of Arizona; Duncan Macrae, Royal Brompton Hospital, United Kingdom
Section 9, Morbidity and long-term outcomes: Yolanda Lopez, Cruces University Hospital, Spain; Michael Quasney, University of Michigan; Miriam Santschi, Université de Sherbrooke, Canada; R. Scott Watson, University of Pittsburgh
Literature Search Methodology: Melania Bembea, Johns Hopkins University