Extracorporeal Membrane Oxygenation in Resource-Limited Countries*

In the late 1960s, a membrane lung was developed that allowed for effective separation of the air and blood interface and created the possibility of prolonged cardiopulmonary bypass. A few years later, a young woman in labor arrived at Orange County Medical Center to deliver. The baby was term gestation but developed refractory, life-threatening respiratory failure shortly after birth. Instead of allowing her to die, her neonatologists consulted Robert Bartlett (1), a pioneering assistant professor of surgery, who was involved in developing the membrane lung and the technique of extracorporeal support. Bartlett assembled a membrane lung and extracorporeal circuit and provided venoarterial bypass support to the infant for 3 days, which completely reversed her pulmonary hypertension. The infant, named “Esperanza” (Spanish for hope), was discharged a few weeks later and grew to become a healthy adult who is now married and is with children (1). Bartlett and coworkers (2, 3) went on to publish groundbreaking studies that demonstrated the efficacy of extracorporeal membrane oxygenation (ECMO) for reversing neonatal respiratory failure and pulmonary hypertension. The therapy spread worldwide through the 1980s, and the prospective randomized U.K. ECMO trial published in 1996 was viewed as a definitive confirmation of the positive short- and long-term benefits of ECMO (4). As of January 2013, more than 26,000 neonates worldwide with respiratory failure have been reported to the Registry maintained by the Extracorporeal Life Support Organization (ELSO), with 75% overall survival (5). In the face of remarkable progress in refining techniques of ECMO support for critically ill infants and children, simultaneous progress was made in developing novel modes of mechanical ventilation (high-frequency oscillatory ventilation and high-frequency jet ventilation), innovative use of exogenous surfactant, and a dramatic increase in our understanding of the mechanisms of pulmonary vascular tone control, the role of inhaled nitric oxide in treating respiratory failure in young children, and the role of pulmonary vascular development in cases where ECMO cannot provide a bridge to cure (6). These successes have led to the decreased utilization of ECMO over the last 10 years for infants with otherwise uncomplicated pulmonary hypertension secondary to persistent pulmonary hypertension of the newborn (PPHN), meconium aspiration, or other acquired pulmonary diseases of the newborn period (7). In this issue of Pediatric Critical Care Medicine, Kattan et al (8) describe their experience of incorporating ECMO into a tertiary care referral neonatal ICU in Santiago, Chile, with ready availability of nitric oxide and other advanced respiratory support modalities. The Chilean experience is notable for a number of reasons. Chile is a resource-limited country, and ECMO is notoriously expensive and resource intensive because of the need for sophisticated equipment and well-trained nurses and technicians for constant monitoring. After beginning the ECMO program, nearly one out of every 10,000 neonates born in Chile was transferred to Universidad Católica de Chile for advanced respiratory care. Establishing the program and facilitating complex transports of critically ill infants across a large country is truly a remarkable achievement. In an era when the expenditure of economic resources on pediatric healthcare is being scrutinized, it is encouraging to see Chile’s commitment to enhancing the survival of infants in their community, knowing that good quality survival of infants with ECMO is likely to return more over the years than the initial expenditure of resources. The efficacy of ECMO in reducing neonatal mortality from respiratory failure was largely established prior to the widespread adoption of inhaled nitric oxide. In Chile, ECMO was used in 23% of infants referred for meconium aspiration syndrome, respiratory distress syndrome/pneumonia, and idiopathic PPHN, and their ECMO survival of 85% compared favorably to the ELSO International Registry database. Overall survival for the three conditions in the ECMO period was also modestly higher than in the pre-ECMO era (94% vs 89%), despite treatment of more outborn babies with worse disease. Although constrained by the limitations of a “before and after” analysis, report by Kattan demonstrates that even with availability of other modalities, ECMO continues to play an important role in improving outcomes for severe neonatal hypoxemic respiratory failure. Interestingly, most of the survival benefit in the Chilean post-ECMO cohort accrued because of reduced mortality for infants with congenital diaphragmatic hernia (CDH). The International ELSO Registry indicates that CDH is now the most common diagnosis leading to ECMO support for neonatal respiratory failure (5, 9), and more than half of the ECMO performed in Chile was for CDH. However, data demonstrating the efficacy of ECMO for CDH remain sparse and controversial, with only 35 infants with CDH enrolled in the randomized U.K. Collaborative ECMO Trial (4). ECMO support will reliably reverse hypoxemia and provide time for resolution of severe airspace disease and/or pulmonary hypertension underlying neonatal respiratory failure. Recognizing that infants with CDH may also have severe or lethal lung hypoplasia with an uncertain prognosis for reversibility, some referral centers identify subsets of infants who are not offered ECMO based on specific physiological variables (10). We and others have reported that suprasystemic pulmonary hypertension (PPHN physiology) is common early in the neonatal course in CDH and may persist for weeks (11, 12). Others have demonstrated that even after successful decannulation from ECMO, severe pulmonary hypertension can recur and vascular abnormalities remain at autopsy (13, 14). Given this background, the initiation of the Chilean ECMO program provided an impressive survival benefit to a group of Chilean infants who would have otherwise died. In the Chilean cohort, ECMO was used in 53% of the CDH infants, which is high compared to reports from major U.S. centers (15). On the other hand, the Chilean program’s survival for infants with CDH on ECMO was 83%, whereas survival for CDH from the most recent single-year data from the ELSO registry was only 40%. The overall survival for CDH was 81%, comparable to what is reported by major U.S. and Canadian centers (9, 12, 16). It will be interesting to follow survival trends over time in Chile to determine if survival without a need for ECMO increases over the next decade as the program gains more cumulative experience with CDH. Finally, the average number of infants referred with CDH tripled from three per year in the pre-ECMO period to nine per year in the ECMO period. These data point to changes in referral patterns within Chile following availability of ECMO and to important differences in referral patterns between Chile and U.S. centers. The “hidden mortality” of CDH was originally described by Harrison et al (17) in Norway and refers to the need to include deaths that occur prior to transport when reporting survival estimates. A recent Canadian study showed that despite universal access to healthcare, the hidden mortality due to CDH averaged three deaths per year in the province of Ontario (18). Thus, the introduction of an ECMO program may change referral patterns as well as the hidden mortality, and both could influence the volume and acuity of patients cared for in the ECMO center. Furthermore, Grushka et al (16) examined the impact of high- (> 6 infants/yr) and low-volume (≤ 6 infants/yr) referral centers on outcome and found survival of 85% in high-volume centers versus 66% in low-volume centers. Therefore, the Chilean approach to consolidate experience into a single ECMO center may have benefited survival in this challenging subset of patients. The development and rapid expansion of neonatal extracorporeal support programs is one of the greatest achievements of contemporary neonatology. The overall improvements in survival following the initiation of an ECMO program in Chile are likely multifactorial but should result in meaningful reductions in neonatal mortality for the country. The expected prevalence of PPHN (0.5–6/1,000 infants) also indicates that the program may not yet be fully serving all infants with severe lung disease (19), and the authors note opportunities to reduce the numbers of infants transferred with evidence for irreversible lung injury. The lessons from this report will also be valuable to other resource-limited countries planning to increase their level of available care. The Chilean experience highlights the advantages of regionalization of specialized medical therapies such as ECMO, which accelerates the accumulation of experience of surgeons, neonatologists, and other professionals who are best positioned to treat these infants.

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