Extracorporeal Support in Children With Pediatric Acute Respiratory Distress Syndrome: Proceedings From the Pediatric Acute Lung Injury Consensus Conference Heidi J. Dalton, MD, MCCM1; Duncan J. Macrae, MB, ChB2; for the Pediatric Acute Lung Injury Consensus Conference Group
Department of Child Health, University of Arizona College of MedicinePhoenix, Phoenix, AZ. 2 Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom. The Pediatric Acute Lung Injury Consensus Conference Group is listed in Appendix 1. Supported, in part, by the Department of Pediatrics, Pennsylvania State University College of Medicine; Health Outcome Axis–Ste Justine Research Center, Montreal, Canada; Respiratory Research Network of Fonds de Recherche du Québec-Santé, Québec, Canada; Mother and Children French-Speaking Network; French-Speaking Group in Pediatric Emergency and Intensive Care (Groupe Francophone de Réanimation et Urgences Pédiatriques), Frenchspeaking intensive care society (Société de Réanimation de Langue Française); European Society for Pediatric and Neonatal Intensive Care Society for the travel support of European experts; Australian and New Zealand Intensive Care Society for the travel of Australian expert. Financial support for publication of the supplement in Pediatric Critical Care Medicine is from the Children’s Hospital Foundation of Children’s Hospital of Richmond at Virginia Commonwealth University, the Division of Pediatric Critical Care Medicine, C.S. Mott Children’s Hospital at the University of Michigan, and the Department of Anesthesia and Critical Care, Children’s Hospital of Philadelphia. Dr. Jouvet received grants from the respiratory research network of Fonds de Recherche du Québec-Santé, Réseau mère enfant de la francophonie, and Research Center of Ste-Justine Hospital related to the submitted work; and received equipment on loan from Philips and Maquet outside the submitted work. Dr. Thomas served on the Advisory Board for Discovery Laboratories and Ikaria outside the submitted work; received a grant from United States Food and Drug Administration Office of Orphan Product Development outside the submitted work. Dr. Willson served on the Advisory Board for Discovery Laboratories outside the submitted work. Drs. Khemani, Smith, Dahmer, and Watson received grants from the National Institutes of Health (NIH) outside the submitted work. Dr. Zimmerman received research grants from the NIH, Seattle Children's Research Institute, and ImmuneXpress outside the submitted work. Drs. Flori and Sapru received grants from the NIH related to the submitted work. Dr. Cheifetz served as a consultant with Philips and Hill-Rom outside the submitted work; and received grants from Philips, Care Fusion, Covidien, Teleflex, and Ikaria outside the submitted work. Drs. Rimensberger and Kneyber received travel support from the European Societiy of Pediatric and Neonatal Intensive Care related to this work. Dr. Tamburro received a grant from United States Food and Drug Administration Office of Orphan Product Development outside the submitted work. Dr. Emeriaud received a grant from Respiratory Health Network of the Fonds de la Recherche du Québec–Santé outside the submitted work. Dr. Newth 1
Copyright © 2015 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000439
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served as a consultant for Philips Medical outside the submitted work. Drs. Erickson, Quasney, Curley, Nadkarni, Valentine, Carroll, Essouri, Dalton, Macrae, Lopez-Cruces, Santschi, and Bembea have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: [email protected]
Objective: Extracorporeal life support has undergone a revolution in the past several years with the advent of new, miniaturized equipment and success in supporting patients with a variety of illnesses. Most experience has come with the use of extracorporeal membrane oxygenation, a modified form of cardiopulmonary bypass that can support the heart, lungs, and circulation for days to months at a time. To describe the recommendations for the use of extracorporeal membrane oxygenation in children with pediatric acute respiratory distress syndrome based on a review of the literature and expert opinion. Design: Consensus conference of experts in pediatric acute lung injury. Methods: A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. The extracorporeal support subgroup comprised two international experts. When published data were lacking, a modified Delphi approach emphasizing strong professional agreement was used. Results: The Pediatric Acute Lung Injury Consensus Conference experts developed and voted on a total of 151 recommendations addressing the topics related to pediatric acute respiratory distress syndrome, 11 of which related to extracorporeal support. All recommendations had agreement, with 10 recommendations (91%) achieving strong agreement. These recommendations included the utilization of extracorporeal support for reversible causes of pediatric acute respiratory distress syndrome, consideration of quality of life when making the decision to use extracorporeal support, and the use of the Extracorporeal Life Support Organization registry to report all extracorporeal support activity, among others. www.pccmjournal.org
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Dalton and Macrae Conclusions: Pediatric extracorporeal membrane oxygenation for pediatric acute respiratory distress syndrome could benefit from more specific data collection and collaboration of focused investigators to establish validated criteria for optimal application of extracorporeal membrane oxygenation and patient management protocols. Until that time, consensus opinion offers some insight into guidelines. (Pediatr Crit Care Med 2015; 16:S111–S117) Key Words: acute lung injury; acute respiratory distress syndrome; criteria; ECMO; extracorporeal support; pediatrics
E
xtracorporeal 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.
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INDICATIONS FOR ECMO IN CHILDREN WITH PARDS Recommendations 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 Rationale 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 ventilatorassociated 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; June 2015 • Volume 16 • Number 5 (Suppl.)
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Table 1. Outcome of Pediatric Patients Who Receive Extracorporeal Membrane Oxygenation: Pediatric Respiratory Runs by Diagnosis Total Runs
Average Run Time
Longest Run Time
1,371
320
2,968
884
64%
651
282
1,411
379
58%
33
359
1,144
17
52%
Aspiration pneumonia
293
247
2,437
201
69%
ARDS, postoperative/trauma
183
248
935
114
62%
ARDS, not postoperative/trauma
530
305
3,086
285
54%
Acute respiratory failure, not ARDS
1,101
255
2,429
594
54%
Other
2,108
217
2,465
1,073
51%
Diagnosis
Viral pneumonia Bacterial pneumonia Pneumocystis pneumonia
Survived
% Survived
ARDS = acute respiratory distress syndrome. Run time is represented in hours. Data adapted from the International Registry of Extracorporeal Life Support Organization, July 2013, with permission. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
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 Pediatric Critical Care Medicine
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 www.pccmjournal.org
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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
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: ●●
Recommendations 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 Rationale 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 Recommendations 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 Rationale 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), S114
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●●
Venovenous ECMO is capable of providing efficient respiratory gas exchange, partially or fully replacing the gasexchange 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.
CIRCUITRY 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 June 2015 • Volume 16 • Number 5 (Suppl.)
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PARDS Supplement
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 singlesite 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).
SEDATION 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 Pediatric Critical Care Medicine
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).
FOLLOW-UP 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 postECMO care, except in many neonatal ICU centers (41–43). Improving follow-up efforts and sharing knowledge on shortand long-term outcomes of ECMO survivors is vital to help determine overall risks and benefits of ECMO support.
OTHER MODES OF EXTRACORPOREAL LUNG SUPPORT Recommendations 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) Rationale 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). www.pccmjournal.org
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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.
CONCLUSIONS 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.
REFERENCES
1. O’Rourke PP, Crone RK, Vacanti JP, et al: Extracorporeal membrane oxygenation and conventional medical therapy in neonates with persistent pulmonary hypertension of the newborn: A prospective randomized study. Pediatrics 1989; 84:957–963 2. Bartlett RH, Roloff DW, Cornell RG, et al: Extracorporeal circulation in neonatal respiratory failure: A prospective randomized study. Pediatrics 1985; 76:479–487 3. Bifano EM, Hakanson DO, Hingre RV, et al: Prospective randomized controlled trial of conventional treatment or transport for ECMO in infants with persistent pulmonary hypertension (PPHN). Pediat Res 1992; 31:196A 4. UK Collaborative ECMO Trial Group: UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. UK Collaborative ECMO Trail Group. Lancet 1996; 348:75–82 5. Mugford M, Elbourne D, Field D: Extracorporeal membrane oxygenation for severe respiratory failure in newborn infants. Cochrane Database Syst Rev 2008; 3:CD001340 6. Paden ML, Conrad SA, Rycus PT, et al; ELSO Registry: Extracorporeal Life Support Organization Registry Report 2012. ASAIO J 2013; 59:202–210 7. Peek GJ, Elbourne D, Mugford M, et al: Randomised controlled trial and parallel economic evaluation of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR). Health Technol Assess 2010; 14:1–46 8. Peek GJ, Mugford M, Tiruvoipati R, et al; CESAR Trial Collaboration: Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): A multicentre randomised controlled trial. Lancet 2009; 374:1351–1363 9. Green TP, Timmons OD, Fackler JC, et al: The impact of extracorporeal membrane oxygenation on survival in pediatric patients with acute respiratory failure. Pediatric Critical Care Study Group. Crit Care Med 1996; 24:323–329 10. Spear RM, Fackler JC: Extracorporeal membrane oxygenation and pediatric acute respiratory distress syndrome: We can afford it, but we don’t need it. Crit Care Med 1998; 26:1486–1487 11. Dreyfuss D, Saumon G: Ventilator-induced lung injury: Lessons from experimental studies. Am J Respir Crit Care Med 1998; 157:294–323 12. Brochard L, Roudot-Thoraval F, Roupie E, et al: Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trail Group on Tidal Volume reduction in ARDS. Am J Respir Crit Care Med 1998; 158:1831–1838
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13. De Prost N, Dreyfuss D: How to prevent ventilator-induced lung injury? Minerva Anestesiol 2012; 78:1054–1066 14. Dalton HJ, Butt WW: Extracorporeal life support: An update of Rogers’ Textbook of Pediatric Intensive Care. Pediatr Crit Care Med 2012; 13:461–471 15. Zabrocki LA, Brogan TV, Statler KD, et al: Extracorporeal membrane oxygenation for pediatric respiratory failure: Survival and predictors of mortality. Crit Care Med 2011; 39:364–370 16. The collaborative UK ECMO (extracorporeal membrane oxygenation) trial: Follow-up to 1 year of age. Pediatrics 1998; 101:E1 17. Trachsel D, McCrindle BW, Nakagawa S, et al: Oxygenation index predicts outcome in children with acute hypoxemic respiratory failure. Am J Respir Crit Care Med 2005; 172:206–211 18. Flori HR, Glidden DV, Rutherford GW, et al: Pediatric acute lung injury: Prospective evaluation of risk factors associated with mortality. Am J Respir Crit Care Med 2005; 171:995–1001 19. Erickson S, Schibler A, Numa A, et al; Paediatric Study Group; Australian and New Zealand Intensive Care Society: Acute lung injury in pediatric intensive care in Australia and New Zealand: A prospective, multicenter, observational study. Pediatr Crit Care Med 2007; 8:317–323 20. Khemani RG, Conti D, Alonzo TA, et al: Effect of tidal volume in children with acute hypoxemic respiratory failure. Intensive Care Med 2009; 35:1428–1437 21. Arnold JH, Anas NG, Luckett P, et al: High frequency oscillatory ventilation in pediatric respiratory failure: A multi-center experience. Crit Care Med 2000; 28:3913–3919 22. Khemani RG, Smith LS, Zimmerman JJ, et al: for the Pediatric Acute Lung Injury Consensus Conference Group: Pediatric Acute Respiratory Distress Syndrome: Definition, Incidence, and Epidemiology: Proceedings From the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care Med 2015; 16:(Suppl): S23–S40 23. Costello JM, Cooper DS, Jacobs JP, et al: Intermediate-term outcomes after paediatric cardiac extracorporeal membrane oxygenation—What is known (and unknown). Cardiol Young 2011; 21(Suppl 2):118–123 24. Lequier L, Joffe AR, Robertson CM, et al; Western Canadian Complex Pediatric Therapies Program Follow-up Group: Two-year survival, mental, and motor outcomes after cardiac extracorporeal life support at less than five years of age. J Thorac Cardiovasc Surg 2008; 136:976–983.e3 25. ELSO: ElSO Guidelines for ECMO Centers in Version 1.7. Ann Arbor, MI, ELSO, 2010 26. Extracorporeal Life Support Organization: ELSO Guidelines for Cardiopulmonary Extracorporeal Life Support. Version 1:1. Ann Arbor, MI, Extracorporeal Life Support Organization, 2009 27. Extracorporeal Life Support Organization: Patient Specific Supplements to the ELSO General Guidelines (Version 1.1). Ann Arbor, MI, Extracorporeal Life Support Organisation, 2009 28. Extracorporeal Life Support Organization: ELSO Guidelines for Training and Continuing Education of ECMO Specialists (Version 1.5). Ann Arbor, MI, Extracorporeal Life Support Organization, 2010 29. Annich G, Lynch W, MacLaren G (Eds), et al: ECMO: Extracorporeal Cardiopulmonary Support in Critical Care. Fourth Edition. Ann Arbor, MI, Extracorporeal Life Support Organisation, 2012 30. Dalton HJ: Extracorporeal membrane oxygenation in the 21st century: A decade of change. Pediatr Crit Care Med 2011; 12:692–693 31. McMullan DM, Emmert JA, Permut LC, et al: Minimizing bleeding associated with mechanical circulatory support following pediatric heart surgery. Eur J Cardiothorac Surg 2011; 39:392–397 32. Barrett CS, Jaggers JJ, Cook EF, et al: Pediatric ECMO outcomes: Comparison of centrifugal versus roller blood pumps using propensity score matching. ASAIO J 2013; 59:145–151 33. Barrett CS, Thiagarajan RR: Centrifugal pump circuits for neonatal extracorporeal membrane oxygenation. Pediatr Crit Care Med 2012; 13:492–493 34. Agati S, Ciccarello G, Salvo D, et al: Use of a novel anticoagulation strategy during ECMO in a pediatric population: Single-center experience. ASAIO J 2006; 52:513–516 35. Baird CW, Zurakowski D, Robinson B, et al: Anticoagulation and pediatric extracorporeal membrane oxygenation: Impact of activated clotting time and heparin dose on survival. Ann Thorac Surg 2007; 83:912–919 June 2015 • Volume 16 • Number 5 (Suppl.)
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PARDS Supplement 36. Niebler RA, Christensen M, Berens R, et al: Antithrombin replacement during extracorporeal membrane oxygenation. Artif Organs 2011; 35:1024–1028 37. Bembea MM, Annich G, Rycus P, et al: Variability in anticoagulation management of patients on extracorporeal membrane oxygenation: An international survey. Pediatr Crit Care Med 2013; 14:e77–e84 38. Garcia JP, Iacono A, Kon ZN, et al: Ambulatory extracorporeal membrane oxygenation: A new approach for bridge-to-lung transplantation. J Thorac Cardiovasc Surg 2010; 139:e137–e139 39. Hayes D Jr, Galantowicz M, Preston TJ, et al: Cross-country transfer between two children’s hospitals of a child using ambulatory extracorporeal membrane oxygenation for bridge to lung transplant. Pediatr Transplant 2013; 17:E117–E118 40. Curley MA, Fackler JC: Weaning from mechanical ventilation: Patterns in young children recovering from acute hypoxemic respiratory failure. Am J Crit Care 1998; 7:335–345 41. Amigoni A, Pettenazzo A, Biban P, et al: Neurologic outcome in children after extracorporeal membrane oxygenation: Prognostic value of diagnostic tests. Pediatr Neurol 2005; 32:173–179
42. Hamrick SE, Gremmels DB, Keet CA, et al: Neurodevelopmental outcome of infants supported with extracorporeal membrane oxygenation after cardiac surgery. Pediatrics 2003; 111:e671–e675 43. Jen HC, Shew SB: Hospital readmissions and survival after nonneonatal pediatric ECMO. Pediatrics 2010; 125:1217–1223 44. Mallick A, Elliot S, McKinlay J, et al: Extracorporeal carbon dioxide removal using the Novalung in a patient with intracranial bleeding. Anaesthesia 2007; 62:72–74 45. McKinlay J, Chapman G, Elliot S, et al: Pre-emptive Novalung-assisted carbon dioxide removal in a patient with chest, head and abdominal injury. Anaesthesia 2008; 63:767–770 46. Kopp R, Bensberg R, Wardeh M, et al: Pumpless arterio-venous extracorporeal lung assist compared with veno-venous extracorporeal membrane oxygenation during experimental lung injury. Br J Anaesth 2012; 108:745–753 47. Gazit AZ, Sweet SC, Grady RM, et al: First experience with a paracorporeal artificial lung in a small child with pulmonary hypertension. J Thorac Cardiovasc Surg 2011; 141:e48–e50
APPENDIX 1. Pediatric Acute Lung Injury Consensus Conference Group
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
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
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Department of Child Health, University of Arizona College of MedicinePhoenix, Phoenix, AZ. 2 Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom. The Pediatric Acute Lung Injury Consensus Conference Group is listed in Appendix 1. Supported, in part, by the Department of Pediatrics, Pennsylvania State University College of Medicine; Health Outcome Axis–Ste Justine Research Center, Montreal, Canada; Respiratory Research Network of Fonds de Recherche du Québec-Santé, Québec, Canada; Mother and Children French-Speaking Network; French-Speaking Group in Pediatric Emergency and Intensive Care (Groupe Francophone de Réanimation et Urgences Pédiatriques), Frenchspeaking intensive care society (Société de Réanimation de Langue Française); European Society for Pediatric and Neonatal Intensive Care Society for the travel support of European experts; Australian and New Zealand Intensive Care Society for the travel of Australian expert. Financial support for publication of the supplement in Pediatric Critical Care Medicine is from the Children’s Hospital Foundation of Children’s Hospital of Richmond at Virginia Commonwealth University, the Division of Pediatric Critical Care Medicine, C.S. Mott Children’s Hospital at the University of Michigan, and the Department of Anesthesia and Critical Care, Children’s Hospital of Philadelphia. Dr. Jouvet received grants from the respiratory research network of Fonds de Recherche du Québec-Santé, Réseau mère enfant de la francophonie, and Research Center of Ste-Justine Hospital related to the submitted work; and received equipment on loan from Philips and Maquet outside the submitted work. Dr. Thomas served on the Advisory Board for Discovery Laboratories and Ikaria outside the submitted work; received a grant from United States Food and Drug Administration Office of Orphan Product Development outside the submitted work. Dr. Willson served on the Advisory Board for Discovery Laboratories outside the submitted work. Drs. Khemani, Smith, Dahmer, and Watson received grants from the National Institutes of Health (NIH) outside the submitted work. Dr. Zimmerman received research grants from the NIH, Seattle Children's Research Institute, and ImmuneXpress outside the submitted work. Drs. Flori and Sapru received grants from the NIH related to the submitted work. Dr. Cheifetz served as a consultant with Philips and Hill-Rom outside the submitted work; and received grants from Philips, Care Fusion, Covidien, Teleflex, and Ikaria outside the submitted work. Drs. Rimensberger and Kneyber received travel support from the European Societiy of Pediatric and Neonatal Intensive Care related to this work. Dr. Tamburro received a grant from United States Food and Drug Administration Office of Orphan Product Development outside the submitted work. Dr. Emeriaud received a grant from Respiratory Health Network of the Fonds de la Recherche du Québec–Santé outside the submitted work. Dr. Newth 1
Copyright © 2015 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0000000000000439
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served as a consultant for Philips Medical outside the submitted work. Drs. Erickson, Quasney, Curley, Nadkarni, Valentine, Carroll, Essouri, Dalton, Macrae, Lopez-Cruces, Santschi, and Bembea have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: [email protected]
Objective: Extracorporeal life support has undergone a revolution in the past several years with the advent of new, miniaturized equipment and success in supporting patients with a variety of illnesses. Most experience has come with the use of extracorporeal membrane oxygenation, a modified form of cardiopulmonary bypass that can support the heart, lungs, and circulation for days to months at a time. To describe the recommendations for the use of extracorporeal membrane oxygenation in children with pediatric acute respiratory distress syndrome based on a review of the literature and expert opinion. Design: Consensus conference of experts in pediatric acute lung injury. Methods: A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. The extracorporeal support subgroup comprised two international experts. When published data were lacking, a modified Delphi approach emphasizing strong professional agreement was used. Results: The Pediatric Acute Lung Injury Consensus Conference experts developed and voted on a total of 151 recommendations addressing the topics related to pediatric acute respiratory distress syndrome, 11 of which related to extracorporeal support. All recommendations had agreement, with 10 recommendations (91%) achieving strong agreement. These recommendations included the utilization of extracorporeal support for reversible causes of pediatric acute respiratory distress syndrome, consideration of quality of life when making the decision to use extracorporeal support, and the use of the Extracorporeal Life Support Organization registry to report all extracorporeal support activity, among others. www.pccmjournal.org
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Dalton and Macrae Conclusions: Pediatric extracorporeal membrane oxygenation for pediatric acute respiratory distress syndrome could benefit from more specific data collection and collaboration of focused investigators to establish validated criteria for optimal application of extracorporeal membrane oxygenation and patient management protocols. Until that time, consensus opinion offers some insight into guidelines. (Pediatr Crit Care Med 2015; 16:S111–S117) Key Words: acute lung injury; acute respiratory distress syndrome; criteria; ECMO; extracorporeal support; pediatrics
E
xtracorporeal 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.
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INDICATIONS FOR ECMO IN CHILDREN WITH PARDS Recommendations 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 Rationale 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 ventilatorassociated 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; June 2015 • Volume 16 • Number 5 (Suppl.)
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Table 1. Outcome of Pediatric Patients Who Receive Extracorporeal Membrane Oxygenation: Pediatric Respiratory Runs by Diagnosis Total Runs
Average Run Time
Longest Run Time
1,371
320
2,968
884
64%
651
282
1,411
379
58%
33
359
1,144
17
52%
Aspiration pneumonia
293
247
2,437
201
69%
ARDS, postoperative/trauma
183
248
935
114
62%
ARDS, not postoperative/trauma
530
305
3,086
285
54%
Acute respiratory failure, not ARDS
1,101
255
2,429
594
54%
Other
2,108
217
2,465
1,073
51%
Diagnosis
Viral pneumonia Bacterial pneumonia Pneumocystis pneumonia
Survived
% Survived
ARDS = acute respiratory distress syndrome. Run time is represented in hours. Data adapted from the International Registry of Extracorporeal Life Support Organization, July 2013, with permission. Adaptations are themselves works protected by copyright. So in order to publish this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation.
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 Pediatric Critical Care Medicine
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 www.pccmjournal.org
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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
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: ●●
Recommendations 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 Rationale 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 Recommendations 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 Rationale 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), S114
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Venovenous ECMO is capable of providing efficient respiratory gas exchange, partially or fully replacing the gasexchange 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.
CIRCUITRY 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 June 2015 • Volume 16 • Number 5 (Suppl.)
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PARDS Supplement
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 singlesite 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).
SEDATION 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 Pediatric Critical Care Medicine
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).
FOLLOW-UP 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 postECMO care, except in many neonatal ICU centers (41–43). Improving follow-up efforts and sharing knowledge on shortand long-term outcomes of ECMO survivors is vital to help determine overall risks and benefits of ECMO support.
OTHER MODES OF EXTRACORPOREAL LUNG SUPPORT Recommendations 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) Rationale 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). www.pccmjournal.org
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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.
CONCLUSIONS 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.
REFERENCES
1. O’Rourke PP, Crone RK, Vacanti JP, et al: Extracorporeal membrane oxygenation and conventional medical therapy in neonates with persistent pulmonary hypertension of the newborn: A prospective randomized study. Pediatrics 1989; 84:957–963 2. Bartlett RH, Roloff DW, Cornell RG, et al: Extracorporeal circulation in neonatal respiratory failure: A prospective randomized study. Pediatrics 1985; 76:479–487 3. Bifano EM, Hakanson DO, Hingre RV, et al: Prospective randomized controlled trial of conventional treatment or transport for ECMO in infants with persistent pulmonary hypertension (PPHN). Pediat Res 1992; 31:196A 4. UK Collaborative ECMO Trial Group: UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. UK Collaborative ECMO Trail Group. Lancet 1996; 348:75–82 5. Mugford M, Elbourne D, Field D: Extracorporeal membrane oxygenation for severe respiratory failure in newborn infants. Cochrane Database Syst Rev 2008; 3:CD001340 6. Paden ML, Conrad SA, Rycus PT, et al; ELSO Registry: Extracorporeal Life Support Organization Registry Report 2012. ASAIO J 2013; 59:202–210 7. Peek GJ, Elbourne D, Mugford M, et al: Randomised controlled trial and parallel economic evaluation of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR). Health Technol Assess 2010; 14:1–46 8. Peek GJ, Mugford M, Tiruvoipati R, et al; CESAR Trial Collaboration: Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): A multicentre randomised controlled trial. Lancet 2009; 374:1351–1363 9. Green TP, Timmons OD, Fackler JC, et al: The impact of extracorporeal membrane oxygenation on survival in pediatric patients with acute respiratory failure. Pediatric Critical Care Study Group. Crit Care Med 1996; 24:323–329 10. Spear RM, Fackler JC: Extracorporeal membrane oxygenation and pediatric acute respiratory distress syndrome: We can afford it, but we don’t need it. Crit Care Med 1998; 26:1486–1487 11. Dreyfuss D, Saumon G: Ventilator-induced lung injury: Lessons from experimental studies. Am J Respir Crit Care Med 1998; 157:294–323 12. Brochard L, Roudot-Thoraval F, Roupie E, et al: Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trail Group on Tidal Volume reduction in ARDS. Am J Respir Crit Care Med 1998; 158:1831–1838
S116
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13. De Prost N, Dreyfuss D: How to prevent ventilator-induced lung injury? Minerva Anestesiol 2012; 78:1054–1066 14. Dalton HJ, Butt WW: Extracorporeal life support: An update of Rogers’ Textbook of Pediatric Intensive Care. Pediatr Crit Care Med 2012; 13:461–471 15. Zabrocki LA, Brogan TV, Statler KD, et al: Extracorporeal membrane oxygenation for pediatric respiratory failure: Survival and predictors of mortality. Crit Care Med 2011; 39:364–370 16. The collaborative UK ECMO (extracorporeal membrane oxygenation) trial: Follow-up to 1 year of age. Pediatrics 1998; 101:E1 17. Trachsel D, McCrindle BW, Nakagawa S, et al: Oxygenation index predicts outcome in children with acute hypoxemic respiratory failure. Am J Respir Crit Care Med 2005; 172:206–211 18. Flori HR, Glidden DV, Rutherford GW, et al: Pediatric acute lung injury: Prospective evaluation of risk factors associated with mortality. Am J Respir Crit Care Med 2005; 171:995–1001 19. Erickson S, Schibler A, Numa A, et al; Paediatric Study Group; Australian and New Zealand Intensive Care Society: Acute lung injury in pediatric intensive care in Australia and New Zealand: A prospective, multicenter, observational study. Pediatr Crit Care Med 2007; 8:317–323 20. Khemani RG, Conti D, Alonzo TA, et al: Effect of tidal volume in children with acute hypoxemic respiratory failure. Intensive Care Med 2009; 35:1428–1437 21. Arnold JH, Anas NG, Luckett P, et al: High frequency oscillatory ventilation in pediatric respiratory failure: A multi-center experience. Crit Care Med 2000; 28:3913–3919 22. Khemani RG, Smith LS, Zimmerman JJ, et al: for the Pediatric Acute Lung Injury Consensus Conference Group: Pediatric Acute Respiratory Distress Syndrome: Definition, Incidence, and Epidemiology: Proceedings From the Pediatric Acute Lung Injury Consensus Conference. Pediatr Crit Care Med 2015; 16:(Suppl): S23–S40 23. Costello JM, Cooper DS, Jacobs JP, et al: Intermediate-term outcomes after paediatric cardiac extracorporeal membrane oxygenation—What is known (and unknown). Cardiol Young 2011; 21(Suppl 2):118–123 24. Lequier L, Joffe AR, Robertson CM, et al; Western Canadian Complex Pediatric Therapies Program Follow-up Group: Two-year survival, mental, and motor outcomes after cardiac extracorporeal life support at less than five years of age. J Thorac Cardiovasc Surg 2008; 136:976–983.e3 25. ELSO: ElSO Guidelines for ECMO Centers in Version 1.7. Ann Arbor, MI, ELSO, 2010 26. Extracorporeal Life Support Organization: ELSO Guidelines for Cardiopulmonary Extracorporeal Life Support. Version 1:1. Ann Arbor, MI, Extracorporeal Life Support Organization, 2009 27. Extracorporeal Life Support Organization: Patient Specific Supplements to the ELSO General Guidelines (Version 1.1). Ann Arbor, MI, Extracorporeal Life Support Organisation, 2009 28. Extracorporeal Life Support Organization: ELSO Guidelines for Training and Continuing Education of ECMO Specialists (Version 1.5). Ann Arbor, MI, Extracorporeal Life Support Organization, 2010 29. Annich G, Lynch W, MacLaren G (Eds), et al: ECMO: Extracorporeal Cardiopulmonary Support in Critical Care. Fourth Edition. Ann Arbor, MI, Extracorporeal Life Support Organisation, 2012 30. Dalton HJ: Extracorporeal membrane oxygenation in the 21st century: A decade of change. Pediatr Crit Care Med 2011; 12:692–693 31. McMullan DM, Emmert JA, Permut LC, et al: Minimizing bleeding associated with mechanical circulatory support following pediatric heart surgery. Eur J Cardiothorac Surg 2011; 39:392–397 32. Barrett CS, Jaggers JJ, Cook EF, et al: Pediatric ECMO outcomes: Comparison of centrifugal versus roller blood pumps using propensity score matching. ASAIO J 2013; 59:145–151 33. Barrett CS, Thiagarajan RR: Centrifugal pump circuits for neonatal extracorporeal membrane oxygenation. Pediatr Crit Care Med 2012; 13:492–493 34. Agati S, Ciccarello G, Salvo D, et al: Use of a novel anticoagulation strategy during ECMO in a pediatric population: Single-center experience. ASAIO J 2006; 52:513–516 35. Baird CW, Zurakowski D, Robinson B, et al: Anticoagulation and pediatric extracorporeal membrane oxygenation: Impact of activated clotting time and heparin dose on survival. Ann Thorac Surg 2007; 83:912–919 June 2015 • Volume 16 • Number 5 (Suppl.)
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PARDS Supplement 36. Niebler RA, Christensen M, Berens R, et al: Antithrombin replacement during extracorporeal membrane oxygenation. Artif Organs 2011; 35:1024–1028 37. Bembea MM, Annich G, Rycus P, et al: Variability in anticoagulation management of patients on extracorporeal membrane oxygenation: An international survey. Pediatr Crit Care Med 2013; 14:e77–e84 38. Garcia JP, Iacono A, Kon ZN, et al: Ambulatory extracorporeal membrane oxygenation: A new approach for bridge-to-lung transplantation. J Thorac Cardiovasc Surg 2010; 139:e137–e139 39. Hayes D Jr, Galantowicz M, Preston TJ, et al: Cross-country transfer between two children’s hospitals of a child using ambulatory extracorporeal membrane oxygenation for bridge to lung transplant. Pediatr Transplant 2013; 17:E117–E118 40. Curley MA, Fackler JC: Weaning from mechanical ventilation: Patterns in young children recovering from acute hypoxemic respiratory failure. Am J Crit Care 1998; 7:335–345 41. Amigoni A, Pettenazzo A, Biban P, et al: Neurologic outcome in children after extracorporeal membrane oxygenation: Prognostic value of diagnostic tests. Pediatr Neurol 2005; 32:173–179
42. Hamrick SE, Gremmels DB, Keet CA, et al: Neurodevelopmental outcome of infants supported with extracorporeal membrane oxygenation after cardiac surgery. Pediatrics 2003; 111:e671–e675 43. Jen HC, Shew SB: Hospital readmissions and survival after nonneonatal pediatric ECMO. Pediatrics 2010; 125:1217–1223 44. Mallick A, Elliot S, McKinlay J, et al: Extracorporeal carbon dioxide removal using the Novalung in a patient with intracranial bleeding. Anaesthesia 2007; 62:72–74 45. McKinlay J, Chapman G, Elliot S, et al: Pre-emptive Novalung-assisted carbon dioxide removal in a patient with chest, head and abdominal injury. Anaesthesia 2008; 63:767–770 46. Kopp R, Bensberg R, Wardeh M, et al: Pumpless arterio-venous extracorporeal lung assist compared with veno-venous extracorporeal membrane oxygenation during experimental lung injury. Br J Anaesth 2012; 108:745–753 47. Gazit AZ, Sweet SC, Grady RM, et al: First experience with a paracorporeal artificial lung in a small child with pulmonary hypertension. J Thorac Cardiovasc Surg 2011; 141:e48–e50
APPENDIX 1. Pediatric Acute Lung Injury Consensus Conference Group
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
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
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