Survival of Newborn Infants With Severe Respiratory Failure
The establishment of an ECMO program was associated with a significant improvement in the survival of newborns with severe respiratory failure. Although this improvement was especially important in infants with CDH, survival of non-CDH infants with severe HRF also improved significantly, despite the documentation of a sicker cohort of infants during the ECMO period. Treatment with ECMO was successful in most patients with refractory respiratory failure.
After adjustments using multivariate analyses, severity of the pretreatment OI, late admission/referral to a tertiary center, presence of a previous pneumothorax, and the diagnosis of CDH were all significantly associated with the need for ECMO or death. The presence of a previous pneumothorax was one of the most significant factors associated with an adverse respiratory outcome. Similarly, delayed admission to the tertiary center was strongly associated with adverse outcomes including respiratory and neurologic complications and the need for ECMO, in agreement with Brown et al. We believe that adverse outcomes can be ameliorated and/or decreased through better coordination between centers as well as a more efficient patient referral leading to a more timely initiation of ECMO treatment.
ECMO therapy is lifesaving for infants with reversible respiratory and/or cardiac failure. Our home discharge survival rate of 85% is similar to reports from other centers and slightly better than the mean of ELSO centers. It is likely that careful selection of patients and strict guidelines for their care made this possible.
The CDH group had the greatest benefit in terms of increased survival; this might be due to the low survival rate in the pre-ECMO period and/or because worldwide this disease characteristically has the lowest response rate to iNO and HFOV. Although we admitted critically ill CDH patients to our ECMO program, many of them had lung injuries in addition to lung hypoplasia (pneumothorax, infection, and lung inflammation secondary to mechanical ventilation and oxygen), very often reversible with lung rest on ECMO. ECMO is more effective in such reversible lung injuries compared to a hypoplastic lung, and ECMO may rescue the lung from suboptimal perinatal care (lack of prenatal diagnoses, delivery in a non level III NICU) and/or suboptimal neonatal care in the immediate hours following delivery.
The U.K. Collaborative ECMO Trial demonstrated significantly improved short-term survival for CDH patients with ECMO; however, this significance disappeared in the follow-up report a year later. The U.K. trial enrolled neonatal patients with respiratory failure 20 years ago in the United Kingdom, including only a small subgroup of CDH patients (19%), who had a very low short-term survival after ECMO (28%). This survival rate is much lower than the survival seen today throughout the world (ELSO, 51%; United States, 46–71%; United Kingdom, 58%; Germany, 62%). An ECMO RCT, like the U.K. trial, exclusively for CDH is not possible today because of the evidence of better short- and long-term survival with ECMO.
The most important question today may focus on whether it is possible to achieve good long-term survival without severe disability, implicating the need for mandatory long-term follow-up in CDH patients. Our CDH survival rate was maintained relatively constant over time. In the long-term follow-up, 8% of our post-ECMO CDH infants died in the first 2 years of life, demonstrating a significant difference in survival.
Based on our findings, we recommend that all infants with prenatal diagnosis of CDH be born in a specialized center that offers advanced neonatal care following the highest standards of evidence-based practices. This includes gentle ventilation strategies and use of HFOV, iNO, and ECMO as needed. Patients with CDH born in centers without ECMO availability should be transferred to ECMO centers using coordinated referral protocols to prevent high-risk or delayed transfers that could negatively impact their respiratory and neurological prognosis.
This study has several limitations. It is a retrospective analysis over a 13-year period, during which global PPHN management has changed and improved over time including the availability of iNOi and HFOV. Survival may also be influenced by the enhanced, specialized training of the ECMO and NICU teams and the establishment of better protocols to manage infants with severe HRF. This benefitted both the ECMO patients and all infants hospitalized with severe HRF.
Our NICU at the Pontificia Universidad Católica de Chile, the only neonatal ECMO referral center in Chile, has progressively concentrated the sickest HRF patients. Thus, the number of admissions with HRF increased from 12 per year in the pre-ECMO period to 23 per year during the ECMO period, especially CDH infants, who accounted for the principal diagnosis in the ECMO period (36%). This change in demographics is similar to observations at other comparable ECMO centers in the last decade. This increase in newborn admissions provided us more clinical experience, which may also explain the improved CDH survival rate in the ECMO period (81% survival), which is higher compared to some centers, but similar to high-volume CDH centers (85% survival).
The higher number of transferred patients could also partially explain the better outcome due to the potential effect of improvements in care and transport. Also, the case-mix shift between the two periods could have potential effect on outcome. However, even though it is difficult to precisely compare both periods studied, it is unlikely that the increased survival rate is due only to selection bias. Separate analysis of inborn and outborn survival did not reveal any difference in these two groups (Table 3). We still appreciated a significant increase in survival rate between the pre-ECMO and ECMO period, especially in CDH infants. Based on our results, it does not seem likely that outborn selection bias affects survival.
The "hidden mortality" effect is less likely to explain the higher survival in the CDH group, because in Chile newborns with HRF and CDH are followed very closely by the public health system, and very few newborns died in the referral hospital before transfer to our ECMO center. Additionally, analyzing CDH survival rate in two of the most prominent referral centers to our ECMO program revealed that they also reach high survival rate, at the same magnitude, as compared to our results (nearly 80%). This increased percentage in CDH survival at these two referral centers matches very closely with the percentage of newborns with CDH transported from these NICUs to our ECMO center (30–40%).
Our ECMO program has contributed to the development of new ECMO programs in Latin America where no ECMO programs were available until recent years and hundreds of infants die due to severe but reversible HRF. We recommend that each country in Latin America have at least one ECMO referral center with a regionalized transfer program, well coordinated with the national health system. We believe that this technology offers an opportunity to save the lives of many infants while preventing long-term morbidity in Latin America and other developing regions of the world.
Discussion
The establishment of an ECMO program was associated with a significant improvement in the survival of newborns with severe respiratory failure. Although this improvement was especially important in infants with CDH, survival of non-CDH infants with severe HRF also improved significantly, despite the documentation of a sicker cohort of infants during the ECMO period. Treatment with ECMO was successful in most patients with refractory respiratory failure.
After adjustments using multivariate analyses, severity of the pretreatment OI, late admission/referral to a tertiary center, presence of a previous pneumothorax, and the diagnosis of CDH were all significantly associated with the need for ECMO or death. The presence of a previous pneumothorax was one of the most significant factors associated with an adverse respiratory outcome. Similarly, delayed admission to the tertiary center was strongly associated with adverse outcomes including respiratory and neurologic complications and the need for ECMO, in agreement with Brown et al. We believe that adverse outcomes can be ameliorated and/or decreased through better coordination between centers as well as a more efficient patient referral leading to a more timely initiation of ECMO treatment.
ECMO therapy is lifesaving for infants with reversible respiratory and/or cardiac failure. Our home discharge survival rate of 85% is similar to reports from other centers and slightly better than the mean of ELSO centers. It is likely that careful selection of patients and strict guidelines for their care made this possible.
The CDH group had the greatest benefit in terms of increased survival; this might be due to the low survival rate in the pre-ECMO period and/or because worldwide this disease characteristically has the lowest response rate to iNO and HFOV. Although we admitted critically ill CDH patients to our ECMO program, many of them had lung injuries in addition to lung hypoplasia (pneumothorax, infection, and lung inflammation secondary to mechanical ventilation and oxygen), very often reversible with lung rest on ECMO. ECMO is more effective in such reversible lung injuries compared to a hypoplastic lung, and ECMO may rescue the lung from suboptimal perinatal care (lack of prenatal diagnoses, delivery in a non level III NICU) and/or suboptimal neonatal care in the immediate hours following delivery.
The U.K. Collaborative ECMO Trial demonstrated significantly improved short-term survival for CDH patients with ECMO; however, this significance disappeared in the follow-up report a year later. The U.K. trial enrolled neonatal patients with respiratory failure 20 years ago in the United Kingdom, including only a small subgroup of CDH patients (19%), who had a very low short-term survival after ECMO (28%). This survival rate is much lower than the survival seen today throughout the world (ELSO, 51%; United States, 46–71%; United Kingdom, 58%; Germany, 62%). An ECMO RCT, like the U.K. trial, exclusively for CDH is not possible today because of the evidence of better short- and long-term survival with ECMO.
The most important question today may focus on whether it is possible to achieve good long-term survival without severe disability, implicating the need for mandatory long-term follow-up in CDH patients. Our CDH survival rate was maintained relatively constant over time. In the long-term follow-up, 8% of our post-ECMO CDH infants died in the first 2 years of life, demonstrating a significant difference in survival.
Based on our findings, we recommend that all infants with prenatal diagnosis of CDH be born in a specialized center that offers advanced neonatal care following the highest standards of evidence-based practices. This includes gentle ventilation strategies and use of HFOV, iNO, and ECMO as needed. Patients with CDH born in centers without ECMO availability should be transferred to ECMO centers using coordinated referral protocols to prevent high-risk or delayed transfers that could negatively impact their respiratory and neurological prognosis.
This study has several limitations. It is a retrospective analysis over a 13-year period, during which global PPHN management has changed and improved over time including the availability of iNOi and HFOV. Survival may also be influenced by the enhanced, specialized training of the ECMO and NICU teams and the establishment of better protocols to manage infants with severe HRF. This benefitted both the ECMO patients and all infants hospitalized with severe HRF.
Our NICU at the Pontificia Universidad Católica de Chile, the only neonatal ECMO referral center in Chile, has progressively concentrated the sickest HRF patients. Thus, the number of admissions with HRF increased from 12 per year in the pre-ECMO period to 23 per year during the ECMO period, especially CDH infants, who accounted for the principal diagnosis in the ECMO period (36%). This change in demographics is similar to observations at other comparable ECMO centers in the last decade. This increase in newborn admissions provided us more clinical experience, which may also explain the improved CDH survival rate in the ECMO period (81% survival), which is higher compared to some centers, but similar to high-volume CDH centers (85% survival).
The higher number of transferred patients could also partially explain the better outcome due to the potential effect of improvements in care and transport. Also, the case-mix shift between the two periods could have potential effect on outcome. However, even though it is difficult to precisely compare both periods studied, it is unlikely that the increased survival rate is due only to selection bias. Separate analysis of inborn and outborn survival did not reveal any difference in these two groups (Table 3). We still appreciated a significant increase in survival rate between the pre-ECMO and ECMO period, especially in CDH infants. Based on our results, it does not seem likely that outborn selection bias affects survival.
The "hidden mortality" effect is less likely to explain the higher survival in the CDH group, because in Chile newborns with HRF and CDH are followed very closely by the public health system, and very few newborns died in the referral hospital before transfer to our ECMO center. Additionally, analyzing CDH survival rate in two of the most prominent referral centers to our ECMO program revealed that they also reach high survival rate, at the same magnitude, as compared to our results (nearly 80%). This increased percentage in CDH survival at these two referral centers matches very closely with the percentage of newborns with CDH transported from these NICUs to our ECMO center (30–40%).
Our ECMO program has contributed to the development of new ECMO programs in Latin America where no ECMO programs were available until recent years and hundreds of infants die due to severe but reversible HRF. We recommend that each country in Latin America have at least one ECMO referral center with a regionalized transfer program, well coordinated with the national health system. We believe that this technology offers an opportunity to save the lives of many infants while preventing long-term morbidity in Latin America and other developing regions of the world.
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