PEDIATRICS Vol. 120 No. 4 October 2007, pp. e762-e768 (doi:10.1542/peds.2006-1955)
ARTICLE |
How Does the Changing Profile of Infants Who Are Referred for Extracorporeal Membrane Oxygenation Affect Their Overall Respiratory Outcome?
a Department of Infection, Immunity and Inflammation, University of Leicester and Institute of Lung Health, Leicester, United Kingdom
b Department of Respiratory Medicine, Glenfield Hospital, Leicester, United Kingdom
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. Extracorporeal membrane oxygenation has been shown to be effective in term neonates with severe but reversible lung disease within the context of randomized, controlled trials. Extracorporeal membrane oxygenation now has been open to a wider population of infants in the United Kingdom, and other treatments have become available. The population referred for extracorporeal membrane oxygenation, therefore, has changed. The aims of this study were to (1) compare respiratory outcomes of infants who received extracorporeal membrane oxygenation in recent years with those from 10 years ago and (2) determine whether respiratory outcome varied with diagnostic group.
METHODS. All infants who were referred to a single extracorporeal membrane oxygenation center and were <12 months old during a 7-year period were eligible. One year after extracorporeal membrane oxygenation, lung volume, airway conductance, maximum expiratory flow, and indices of tidal breathing were measured.
RESULTS. A total of 106 infants (77% of those eligible) were tested, and results were compared with those of 51 infants referred for extracorporeal membrane oxygenation as part of the original United Kingdom extracorporeal membrane oxygenation trial. Lung volume was not different, but there was a strong trend for the infants who were seen in more recent years to have better forced expiratory flow and specific airway conductance. Restricting analysis to the major subgroup (meconium aspiration) confirmed these findings. When divided into diagnostic subgroups, infants who required extracorporeal membrane oxygenation for respiratory distress syndrome or who were >2 weeks old when extracorporeal membrane oxygenation was commenced had a poorer respiratory outcome than others.
CONCLUSIONS. The respiratory outcome of infants who were treated beyond the tightly regulated criteria of the United Kingdom trial remains good and even shows a trend toward improvement. Certain subgroups require extracorporeal membrane oxygenation for longer and have poorer pulmonary function when followed up.
Key Words: lung function • meconium aspiration • diagnosis
Abbreviations: ECMO—extracorporeal membrane oxygenation • iNO—inhaled nitric oxide • FRCpleth—functional residual capacity measured by plethysmography • VmaxFRC—maximum expiratory flow at functional residual capacity • SGaw—specific airway conductance • SGawII—specific airway conductance during initial inspiration • RV-RTC—raised-volume rapid thoracic compression • FEVn—forced expiratory volume in n seconds • FVCp—forced vital capacity with applied pressure • tPTEF—time to peak tidal expiratory flow • tPTEF/te—ratio of tPTEF to expiratory time • CI—confidence interval • MAS—meconium aspiration • RDS—respiratory distress syndrome
Extracorporeal membrane oxygenation (ECMO) has been in use for >20 years and has been shown to reduce mortality in pediatric patients with acute respiratory failure1 and in mature newborns with potentially reversible respiratory disease.2 In addition to improving survival, a randomized, controlled trial of ECMO in the treatment of sick newborns resulted in improved respiratory function at 1 year.3 The beneficial influence of an ECMO policy has been shown to extend to these children when studied at 7 years.4
During the time in which ECMO has been available, other treatments (eg, surfactant therapy, inhaled nitric oxide [iNO], high-frequency oscillatory ventilation) have become available. In some centers, ECMO is now used in a smaller proportion of patients in particular diagnostic subgroups than was previously the case.5 There has been an overall fall in the number of neonatal patients who are treated with ECMO and a fall in the average number treated at each ECMO center since the early 1990s.6 Trials of iNO in neonates with hypoxemic respiratory failure have shown that it results in a decreased need for ECMO7,8 and is cost-effective.9,10 Despite the increasing use of iNO, ECMO still remains an essential back-up treatment for some patients, such as those with pneumothorax.11 There is less evidence for the effectiveness of iNO specifically for the treatment of infants who are born at or near term,12 but it seems to reduce the need for ECMO and be cost-effective.13 The benefits of iNO have been shown in both North America and Europe, but differences in survival rates between the continents suggests that approaches to treatment are not the same and highlights the need for caution when extrapolating findings.13
Against the background of changes in the population of patients who are referred for ECMO with regard to their diagnosis, treatment before referral, and possible clinical status at the time of initiating ECMO, there is the likelihood of changes in outcome. Diagnosis-specific mortality rates for infants with congenital diaphragmatic hernia, meconium aspiration, respiratory distress syndrome, and sepsis did not change significantly between 1988 and 1998,6 but there have been few reports of respiratory morbidity or lung function tests. As the ECMO center treating the largest number of patients in the United Kingdom, we are able to report respiratory outcomes in >100 infants who were treated after April 1997. Information on almost all infants who received ECMO in the United Kingdom between January 1993 and November 1995 is also available to us, because all such infants were enrolled in a nationwide trial of ECMO2 and almost 80% of these participated in respiratory follow-up at the age of 1 year.3 The first aim of this study, therefore, was to compare respiratory outcomes of infants who received ECMO in recent years with those from 10 years ago. The second aim was to determine whether the respiratory outcome varied with diagnostic group, and this was pursued with the more recent data exclusively from our own center. This could be important when counseling parents of infants who receive ECMO and have implications for workload planning of respiratory centers.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patients
Between April 1, 1997, and March 31, 2003, 186 infants who were younger than 12 months received ECMO at our center in Leicester, 137 of whom survived for follow-up 1 year later. A total of 108 infants came for general and developmental follow-up (data not shown), and 106 of them had assessment of their lung function, which was routine in our center. The percentage of eligible infants in the current study group who received respiratory follow-up was 77%.
The lung function from this group was compared with that of 51 infants who were studied previously as part of the United Kingdom ECMO trial.2 This national trial randomly assigned 185 infants to either referral for ECMO at 1 of 5 centers or conventional treatment. A total of 103 survived to discharge, and 99 (62 ECMO) were alive and potentially available for respiratory function testing at 1 year of age. Seventy-eight infants (51 ECMO) were studied at 1 of 2 centers (including the facility testing all the later cohort) involved in the respiratory follow-up.3 The percentage of eligible infants who were from the United Kingdom ECMO study and received respiratory follow-up was 78%.
The criteria for offering ECMO differed between the 2 populations. Infants who entered the United Kingdom ECMO trial were term infants of 
2 kg birth weight. An entry requirement was an oxygenation index of >40, or PaCO2 >12 kPa, and <10 days' high-pressure ventilation and age <28 days at trial entry.2 The criteria for offering ECMO in the time frame for treating the current population were relaxed, and 8 (7.5%) of the 106 infants were older than 28 days when ECMO was commenced. Twelve (11%) infants were born preterm (before 37 weeks' gestational age). The procedure for respiratory function tests common to infants in the United Kingdom ECMO trial and those studied later (lung volume, specific conductance, and maximum expiratory flow) were identical.3
Procedure
Infants attended the laboratory as outpatients. A questionnaire was administered to collect information on symptoms, medication, and health care consultations and the infant was given a clinical examination. Parents gave written consent for respiratory function testing; baseline oxygen saturation was recorded from a pulse oximeter (Nellcor, Pleasanton, CA); and infants were weighed, measured, and sedated with chloral hydrate (100 mg/kg body weight, up to a maximum dosage of 1 g). Once the infant was asleep, the pulse oximeter was reattached to the foot for safety monitoring.
Measurements of Lung Volume and Specific Conductance
The infant was placed within the Jaeger (VIASYS Healthcare, Warwick, United Kingdom) whole-body plethysmograph for measurement of functional residual capacity (FRCpleth) and specific airway conductance during initial inspiration (SGawII) by previously reported methods.3,14 Briefly, the infant breathed through a face mask (Rendell Baker [Intersurgical Ltd, Warwick, United Kingdom] size 2) and pneumotachograph (Jaeger infant model), which were connected to a valve block that permitted the infant to breathe heated, humidified air for measurement of SGawII or transient occlusion of the external airway. Signals of mask pressure, flow, and plethysmograph pressure were recorded onto a personal computer (Elonex, Watford, United Kingdom) with specialist software (RASP; Physiologic, Newbury, United Kingdom). After a period of quiet breathing of heated, humidified air, the valves were closed and the infant made 2 or 3 respiratory efforts against the occlusion to permit calculation of FRCpleth. Approximately 5 separate measurements of FRCpleth were made. All recordings were visually inspected, and any that the operator judged to be not technically acceptable were discarded. SGawII was calculated as the mean of the best 7 individual breaths (selected by the operator on the basis of graphical appearance). The mean of all technically acceptable recordings of FRCpleth was reported.
Measurements of Maximum Expiratory Flow
The infant was wrapped in an inflatable "squeeze" jacket for measurements of maximum expiratory flow (VmaxFRC). A period of regular breathing of 
20 seconds was observed before the jacket was inflated at the end of a tidal inspiration.15 Measurements of VmaxFRC were repeated over a range of jacket pressures up to a maximum of 6.5 kPa to obtain the highest values of VmaxFRC, and the pressure at which this was achieved (the optimal pressure) was noted for each infant. Several measurements were obtained at optimal pressure. The highest value of VmaxFRC was reported, provided that the next highest value was within 10% of this.
Measurements of Forced Expired Volumes by the Raised-Volume Technique (Raised-Volume Rapid Thoracic Compression)
A bias flow of air was attached to the pneumotachograph using a T-piece attached to an adjustable blow-off valve set at 2.0 kPa. Augmented breaths were delivered through the face mask by manually occluding the bias flow at the onset of inspiration so that air was directed into the lungs. At the end of inspiration (when the applied pressure and volume reached plateau), the occlusion was removed and the infant breathed out passively. A series of 4 successive augmented inspirations were delivered with passive exhalations, followed by a fifth augmented inspiration, which was accompanied by jacket inflation at end inspiration using the previously determined optimal jacket pressure. Up to 6 measurements of raised-volume rapid thoracic compression (RV-RTC) were made in each infant.
Measurements of RV-RTC were analyzed using specialist software (Squeeze 2.04; Dixon and Stocks, Imperial College, London, United Kingdom), using a published technique.16 The largest forced expired volume breathed out in the RV-RTC maneuver (forced vital capacity with applied pressure [FVCp]) was recorded. The forced expired volume in the first 0.4 seconds and 0.5 seconds of expiration (FEV0.4 and FEV0.5) was measured from the RV-RTC, and the highest individual values were reported.
Tidal Breathing Analysis
The time to peak tidal expiratory flow (tPTEF) and the ratio of tPTEF to expiratory time (tPTEF/te) were measured from periods of quiet breathing recorded before VmaxFRC using specialist software (Squeeze 2.04). The 5 breaths immediately before jacket inflation were taken from each of the first 5 recordings of VmaxFRC, and mean values of tPTEF/te were calculated.
Analysis of Data
In the first stage of the analysis, the demographic data from infants in this follow-up study were compared with those who were assigned to the ECMO limb of the United Kingdom ECMO trial using unpaired t tests or 
2 tests. To take account of gender- and length-related differences in lung function, measurements of FRCpleth and VmaxFRC were expressed as SD scores.17,18 The differences of the mean SD scores were calculated, and the 95% confidence intervals (CIs) of the differences of the means were used to compare the 2 study populations. Measurements of SGawII can be compared directly, so the 95% CI of the difference of the means was used to determine whether there was any difference between the groups.
In the second stage of the analysis, infants in the current study were divided into subgroups on the basis of underlying diagnosis. Because all infants in the current study received ECMO at a single center, discharge summaries were readily available. The diagnostic subgroup was based on the discharge summary of each infant, which was reviewed by 1 of the clinical staff from the ECMO unit. Demographic data and lung function were compared between subgroups using analysis of variance.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Comparison of Current Population With Those Assigned to ECMO in the Original Trial
A total of 186 infants received ECMO between April 1997 and April 2003, 137 of whom survived beyond 1 year and 106 of whom attended for respiratory function testing. The main underlying reason for ECMO in the infants who were tested was meconium aspiration (MAS), which accounted for 67 (63%) of the infants studied. Neonatal sepsis accounted for the next largest subgroup (11 infants). Ten infants started ECMO when they were older than 2 weeks ("older") because of severe bronchiolitis (9 infants) or pertussis. The median age of commencing ECMO in this group was 42 days (range: 17–188), and 6 of them had been born preterm. Smaller subgroups received ECMO for persistent pulmonary hypertension of the newborn (7 infants) or respiratory distress syndrome (RDS; 5 infants). The remaining 6 infants were treated for congenital diaphragmatic hernia, pulmonary hemorrhage, or aspiration of blood after maternal antepartum hemorrhage. The infants who attended for respiratory function tests were not different from those who did not attend with respect to gestational age, birth weight, underlying diagnosis, or duration of ECMO (data not shown).
This study group was initially compared with the 51 infants who were assigned to ECMO in the original trial (Table 1). There were no overall differences in weight or length, but the current population was slightly older. This was mainly because the current population included the subgroup of 10 infants who received ECMO outside the first 2 weeks of life and were therefore older than the other infants when they were referred to the laboratory 1 year after ECMO. There were no differences in the proportions of infants who were on respiratory medications at the time of testing or the frequency of reported symptoms of upper respiratory tract infection since discharge from hospital, but the current population was more likely to come from a smoking household (P < .05). The measurements of FRCpleth were not different in the 2 populations and were very close to the predicted value. The mean VmaxFRC for both populations was within predicted limits but tended to be lower than predicted.18 The mean VmaxFRC from the current population (seen outside the trial setting) showed a strong trend toward improvement when compared with the infants in the original trial, although this did not reach conventional levels of statistical significance (Table 1). SGaw showed a marked trend toward improvement in this population (Table 1).
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Although there were no statistically significant differences in lung function, there were differences in diagnostic profile that could have confounded the results. The largest subgroup in both populations comprised those with MAS, so we compared these infants directly to determine whether any potential differences in the practice of ECMO might have had an impact on the outcome (Table 2). There were no differences in age, weight, or length of these 2 subgroups. The SD scores for FRCpleth and VmaxFRC were not different from each other, but there was a strong trend for SGaw to be better in the infants who were treated more recently than in those who were part of the ECMO trial.
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Comparison of Diagnostic Subgroups
Data from the current population of infants were divided into diagnostic subgroups, and demographic data and lung function were compared (Table 3). There were no differences between the groups with respect to weight or length, but the "older" group had a shorter mean gestational age and tended to be older at the time of testing than the other subgroups. The duration of ECMO varied between the subgroups, with those who were treated for RDS or who started ECMO beyond the first 2 weeks of life needing ECMO for longer. The median duration of ECMO in the older group was 7.5 days (range: 4–24 days), and for the RDS group, the median was 8 days (range: 4–12 days).
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Resting lung volume was similar in all subgroups, as shown by the lack of differences in FRCpleth. There were strong trends toward significant variation in airway function, seen in both VmaxFRC (P = .057) and SGaw (P = .076). This was because the older infants and those who were treated for RDS had worse values than the other subgroups. A similar pattern was seen with data from RV-RTC. There were no differences between the groups in FVCp, which may be considered as a surrogate for lung volume. The infants who were treated for RDS had the lowest values of FEV0.4 and FEV0.5 of the whole population, although differences between groups failed to reach statistical significance. When these timed volumes were expressed as percentages of FVCp, most subgroups had very similar values (Table 3), but the infants who were treated for RDS had much poorer function. Infants who were older when treated had intermediate values. Analysis of tidal breathing (tPTEF/te) did not demonstrate any differences between the subgroups.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We have shown that the respiratory outcomes of infants who received ECMO in more recent years are not statistically different from those who were seen at the time of the United Kingdom ECMO trial. There is a trend for improved outcome, seen in the measurements of airway function (VmaxFRC, SGaw, FEV0.4, and FEV0.5). When analysis was restricted to infants who were treated for MAS, this pattern was retained. When infants in this cohort were categorized according to the underlying reason for ECMO, the older group and (more particular) those who were treated for RDS had similar lung volumes but poorer airway function than the other groups. The comparison of respiratory function in the 2 populations may be biased by several factors, including the inclusion/exclusion criteria for ECMO, differences in treatment between the 2 populations (including differences in the delivery of ECMO), the survival rates of the 2 populations, and whether the infants tested were representative of the survivors.
The 1-year survival for infants in the original United Kingdom trial who were assigned to ECMO was 68%, and in the more recent cohort this had increased to 73%. Although this will reflect changes both in the criteria for offering ECMO and in treatment modalities between the 2 populations, the net effect of improved survival might have been an overall worsening of respiratory morbidity as a result of increased survival of infants with severely compromised lung function. Our finding of a trend toward improvement in lung function shows that this is not the case. By repeating the analysis and restricting it to infants with a primary diagnosis of MAS, we have shown that there is a marked trend toward improvement in airway function, which strongly suggests ongoing refinement of eligibility criteria and/or treatment of infants in our ECMO unit. The reported frequency of upper respiratory tract infections and the use of respiratory medications, however, were unchanged.
Although the respiratory function 1 year after treatment is similar in infants who were treated recently and those who received ECMO as part of the United Kingdom ECMO trial and shows a trend to improvement in airway function, the heterogeneous nature of the population could mask important differences related to underlying reason for ECMO treatment. Our second aim was to examine respiratory outcome with respect to diagnostic subgroup. With the exception of the MAS subgroup, the small size of the subgroups is a limitation of our study. In addressing our second aim, however, we have shown that infants with RDS or those whose treatment started beyond the first 2 weeks of life had poorer airway function than other subgroups. These 2 subgroups had required ECMO for longer than the others, suggesting that their underlying condition was worse at the outset and took longer to improve to the point at which the lungs could adequately perform their function of oxygenation. Previous reports of the use of ECMO to treat infants with bronchiolitis also demonstrated a need for relatively long duration of treatment.19–21 Our older group included 1 infant with pertussis, and our group previously reported the poor outcome in terms of survival for such infants when referred for ECMO.22 The remaining 9 infants in the older group all had respiratory syncytial virus bronchiolitis, and 6 of them had been born at 
32 weeks' gestational age. Only 2 of the 10 older infants would have met the eligibility criteria for the United Kingdom trial in terms of their gestation and age at onset of ECMO, so the requirement of this group for extended time on ECMO is particularly relevant for planning of health care provision in the future. The cost-effectiveness of ECMO in the context of the United Kingdom trial has been reported, and most of the additional costs of ECMO relate mainly to care in the neonatal period.23 The cost-effectiveness of ECMO for other groups of infants should be the basis of future economic research.23
Our largest subgroup comprised infants with MAS, who had normal values of FRCpleth, SGaw, and VmaxFRC. Predicted values of the other indices of lung function are less well established, but the infants with MAS had the highest measurements of FEV0.4 and FEV0.5 of any subgroup. Reports of lung function from children who survived MAS indicate airway obstruction, hyperinflation, and an increase in bronchial reactivity, although these groups did not include patients who were treated with ECMO.24,25 A report of lung function in children of school age who received ECMO in the neonatal period found that they were hyperinflated, as shown by an increase in residual volume.26 This study did not report measurements of FRC. In contrast, data from the children in the United Kingdom trial who received ECMO had normal values of FRC when compared with healthy matched control subjects, whereas the infants who were randomly assigned to conventional treatment had elevated FRC.27 The role of ECMO in preventing lung injury in infants with MAS needs additional research.
The 3 remaining subgroups in our recent cohort (persistent pulmonary hypertension of the newborn, sepsis, and other) were similar to infants with MAS in that the mean measurements of FRCpleth and VmaxFRC were within the predicted ranges. The measurements from RV-RTC and tidal breathing from these subgroups were indistinguishable from those in the infants with MAS.
This study provides the opportunity to examine which indices of respiratory function best identify any differences between groups, although this is limited by the small sizes of some subgroups. Measurements of lung volume, whether direct (FRCpleth) or indirect (FVCp), were not indicative of major differences, either between infants in the original United Kingdom trial and this cohort or between various diagnostic subgroups. Predicted ranges are available for FRCpleth,18 and it seems as though all groups of infants have volumes close to prediction. In contrast, airway function as assessed by VmaxFRC shows that the infants who were treated for RDS have mean values below the predicted range, and the older infants are on the lower limits of prediction. Other indices of airway function that are derived from RV-RTC (FEV0.4, FEV0.5, FEV0.4/FVCp, and FEV0.5/FVCp) also indicate poorer function in these groups. The measurement derived from tidal breathing (tPTEF/te) failed to discriminate between the subgroups. Low values of tPTEF/te have been shown to be associated with low forced expiratory flows in infants,28 and this, coupled with the attractiveness of a simple index that could potentially be measured without the need for sedation or complex equipment, was our reason to apply it in this study.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This study represents the largest respiratory follow-up of infants who have received ECMO to date. It shows that the respiratory outcome of infants who were treated subsequent to the United Kingdom trial remains good at 1 year after ECMO and even shows a trend toward improvement. Certain subgroups of infants, namely those who are treated for RDS or those who are treated beyond the first 3 weeks for bronchiolitis or pneumonia, require ECMO for longer and have poorer pulmonary function when followed up 12 months later. The modest size of the subgroups, however, indicates a need for caution in the interpretation of the data. Ongoing respiratory follow-up to include larger numbers of patients with findings extending to later childhood and beyond would be important when providing information to parents of infants being treated and may have implications for workload planning of ECMO units.
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ACKNOWLEDGMENTS |
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The follow-up reported in this study was funded by the Department of Health (United Kingdom).
We thank all staff in the ECMO office at Glenfield Hospital, UHL-NHS Trust, for assistance, and Sarah Clarke for help with data analysis. We acknowledge the consent of Prof Janet Stocks (Institute of Child Health, University of London) to include data from infants who were seen there during the 1-year respiratory follow-up in the United Kingdom ECMO Trial. We particularly thank all infants and their families for participation.
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FOOTNOTES |
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Accepted Mar 3, 2007.
Address correspondence to Caroline S. Beardsmore, PhD, Department of Infection, Immunity and Inflammation (Child Health), University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, PO Box 65, Leicester LE2 7LX, United Kingdom. E-mail: csb{at}le.ac.uk
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
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