Table 1 shows clinical characteristics of the group and compares clinical characteristics of survivors and nonsurvivors. Nonsurvivors weighed less, were more frequently placed on ECMO in the first 7 days of life, and required shorter median times from intubation to ECMO support. Among neonates requiring prolonged ECMO support, those with congenital diaphragmatic hernia (CDH) represented the predominant primary diagnosis. The survival of CDH group (22%) was lower than the non-CDH group (28%). Among the CDH subgroup (data not shown), survivors differed significantly from nonsurvivors only by weight (3.1 kg [2.9–3.4] vs. 3 kg [2.7–3.3]; p = 0.04) (median [interquartile range (IQR)]; p value) among the compared clinical characteristics.
Table 2 shows a comparison between survivors and nonsurvivors for worst gas exchange variables and therapies provided before ECMO deployment. There were no significant differences between survivors and nonsurvivors. Among the subgroup of neonates with CDH (data not shown), survivors differed significantly from nonsurvivors for the use of pre-ECMO high frequency ventilation (57% vs. 79%; p < 0.001), bicarbonate therapy (50% vs. 32%; p = 0.01), and time off ECMO to extubation (549 hr [403–952] vs. 30 hr [0–312]; p < 0.001) (median [IQR]; p value).
Figure 3 shows survival curves for four major diagnoses (bacterial pneumonia, CDH, viral pneumonia, and meconium aspiration syndrome [MAS]). Median time to death with 95% confidence intervals (CI) was 35.5 days (26.8–41.8 days) for bacterial pneumonia, 36.8 days (34.2–40.3 days) for CDH, and 31.5 days (29.7 days, upper bound could not be estimated) for viral pneumonia. Meconium aspiration syndrome had a significantly better survival compared with the other three diagnoses (p < 0.001).
Complications on ECMO
Table 3 depicts complications occurring while on ECMO. Nonsurvivors were more likely to have hemorrhage, CNS infarction, renal dysfunction, cardiac arrhythmias, and required hemofiltration and inotropic support. Overall, nonsurvivors had more aggregate complications compared with survivors (p ≤ 0.001). Multivariate analysis for complications showed that receiving inotropes while on ECMO support was independently associated with death before hospital discharge (odds ratio, 2.2; 95% CI, 1.3–3.7; p = 0.003). Among the subgroup of neonates with CDH (data not shown), survivors differed significantly from nonsurvivors for increased frequency of cardiac arrhythmias (1% vs. 12%; p = 0.01), receipt of inotropes 34% vs. 56%; p = 0.001), and total number of ECMO complications (4 [2.0–6.3] vs. 5.0 [3.0–8.0]; p = 0.03) on univariable comparison. We found no impact in utilization of inotropes while on ECMO support on mortality among those on venovenous (VV) and venoarterial ECMO for any of the diagnostic categories (see Figure, Supplemental Data Content 1, http://links.lww.com/ASAIO/A44).
In this retrospective review of the ELSO registry data set among neonates who required prolonged ECMO support (>21 days): 1) CDH accounted for almost two-third of all cases, 2) overall survival to hospital discharge was only 24%, 3) neonates with MAS had a significantly better survival to hospital discharge compared with the other diagnostic groups (CDH, bacterial and viral pneumonia), and 4) the need for inotropes while on ECMO support was independently associated with death before hospital discharge.
Our study revealed that neonates with CDH account for 69% of patients requiring prolonged ECMO support for respiratory failure. In comparison, review of the neonatal ELSO registry data for the same era shows that CDH is the most common indication for ECMO in the United States and accounts for 29% of all neonatal ECMO patients.1 The survival among infants with CDH requiring prolonged ECMO (22%) is significantly lower compared with the overall report of ~50% survival from the ELSO registry and other single-center experience.5–11 Furthermore, our analysis did not show significant change in survival over the study period. Previously, in a single-center study, Tiruvoipati et al.6 showed that the mortality of CDH patients receiving ECMO support for >2 weeks was 82% (n = 2/11 survived). It can be speculated that the prolonged duration of ECMO and poor outcomes among neonates with CDH requiring prolonged ECMO may be related to the presence of severe pulmonary hypoplasia and irreversible pulmonary hypertension for which unfortunately, the ELSO registry database does not carry any information. Other factors previously identified to impact survival in this population, including gestational age, 5 minute Apgar score, PaO2, and PaCO2,6,7,9,10 were characteristics that did not affect survival in our analysis. Thus, these variables appear less significant once an infant with CDH requires ECMO for >21 days.
Although the number of patients with MAS requiring prolonged ECMO was small (n = 27), the survival to hospital discharge was significantly better (71%) compared with the other study groups (26.3%). However, the survival among these neonates with MAS is lower than overall survival for MAS (94%) reported for the ELSO registry. Radhakrishnan et al.12 speculate that more patients with MAS receive VV ECMO than their no-MAS counterparts, leading to less morbidity and thus less mortality in those infants.5 Surprisingly, there were no cases of isolated persistent pulmonary hypertension noted in this study. All patients reported to have pulmonary hypertension was in the setting of other underlying disease (MAS, CDH with/without lung agenesis). Interestingly, neonates requiring prolonged ECMO also showed a much lower survival to discharge than those requiring prolonged ECMO support among older children (38% vs. 24%). These differences may be related to the functional immaturity of neonates compared with older children and with a different case mix with CDH being the predominant diagnosis among the neonatal population.
Similar to previous results from prolonged ECMO in older children,8,13 we found that complications commonly occurred during ECMO support, with a median of three complications in survivors and nonsurvivors. In our study, inotropic support while on ECMO was independently associated with mortality, suggesting that ongoing cardiopulmonary dysfunction despite ECMO support may impact outcomes. This is similar to the report by Brogan et al. 8 among older children with respiratory failure on prolonged ECMO support. However, in contrast to their report, metabolic acidosis was not independently associated with mortality in this study. Other reports on prolonged ECMO in children have shown that ECMO complications did not influence either outcome or duration of ECMO.13
This study is subject to several limitations as data are abstracted in a retrospective manner into the ELSO registry. As a retrospective study of registry data, it is subject to considerable bias, both in reporting and in selection. Overall, 13% (57/439) were categorized as “other” as they carried nonspecific primary diagnosis of acute respiratory failure and respiratory distress syndrome, and the registry data set does not provide additional information to allow more precise classification of this group of patients. Furthermore, there is lack of standardization in the application of ECMO, which lends to large variability between and within centers to accurately exact indications and threshold for offering ECMO support. Also, ELSO does not release data on individual centers the data set is limited so as to investigate institutional variations. Finally, data on quality of survival and residual respiratory function are lacking, which is important especially in those requiring prolonged ECMO and survived to hospital discharge. Furthermore, among nonneonates discharged from the hospital, 1 year post-ECMO survival of 14% is discouraging but represented 75% of patients who survived to discharge.13 The current database is limited in providing long-term follow-up data on the survivors.
Neonates receiving prolonged ECMO support (>21 days) for respiratory failure have a much poorer survival to discharge (24%) compared with overall results reported by the ELSO registry (75%). Furthermore, the need for prolonged ECMO appears to be related to the underlying diagnosis as CDH accounts for almost two-third of cases. The survival among this group was almost half of those reported for overall survival in the ELSO registry. Complications on ECMO are common, but only the receipt of inotropes while on ECMO support (suggestive of poor cardiorespiratory support) increased the odds of mortality.
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Keywords:Copyright © 2014 by the American Society for Artificial Internal Organs
prolonged; extracorporeal membrane oxygenation; acute respiratory failure; neonates; outcomes