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Ann Thorac Surg 1997;63:756-761
© 1997 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Results of Extracorporeal Membrane Oxygenation in Children With Sepsis

University of Texas Southwestern Medical Center, Dallas, Texas, and The University of Michigan, Ann Arbor, Michigan

Accepted for publication October 22, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Despite good results in neonates, extracorporeal membrane oxygenation (ECMO) is less well accepted in pediatric patients. Older children frequently undergo ECMO for severe bacterial, viral, or aspiration pneumonia and many have coexisting systemic sepsis. We reviewed data from a national registry to study the influence of sepsis on survival from ECMO.

Methods. Six hundred fifty-five patients (aged 2 weeks to 17 years) with respiratory failure treated with ECMO were divided into two groups by the presence (n = 76) or absence (n = 579) of sepsis. Groups were compared by univariate analysis and by multivariate logistic regression that considered 10 additional pre-ECMO variables (age, sex, weight, arterial blood gas results, ventilator parameters, and renal failure).

Results. By univariate analysis, survival was lower in septic children (36.8% versus 51.6%; p < 0.02). However, by multivariate analysis, sepsis was not an independent survival predictor (odds ratio, 0.578; 95% confidence interval, 0.288–1.162; p = 0.12). The ECMO complications predicted by the presence of sepsis included (1) seizures, (2) other neurologic complications, and (3) infection at other sites (all p < 0.05).

Conclusions. Systemic sepsis does not independently influence survival in pediatric ECMO. This therapy should not be withheld solely because of sepsis, although neurologic complications may occur more frequently.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Since its introduction in 1975, extracorporeal membrane oxygenation (ECMO) has evolved into a standard treatment for neonates with severe respiratory failure [1]. Much of the success of this modality was based on the transient nature of the neonatal disease processes for which ECMO was selected, such as persistent pulmonary hypertension of the newborn [2] or persistent fetal circulation [3]. However, the use of this technology in the pediatric population is less accepted. In pediatric patients, ECMO is often used in cases of severe bacterial, viral, or aspiration pneumonia. Many of these patients present with systemic sepsis and data supporting the use of ECMO in this setting is even more limited. Some investigators have suggested that the presence of systemic sepsis has a negative effect on outcome [4], whereas others have claimed that sepsis does not adversely affect results [5–7]. However, these studies restricted their analysis to the neonatal population (age, <14 days), an age group in which ECMO is infrequently applied for septic conditions. Data are lacking for the pediatric population.

This study used data from the Extracorporeal Life Support Organization (ELSO) registry to critically evaluate the effectiveness of ECMO in children aged 14 days to 18 years with respiratory failure when systemic sepsis was a concurrent condition. The study tested the hypothesis that coexisting systemic sepsis adversely affects (1) survival and (2) complication rates in children with respiratory failure treated with ECMO.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Patients
This study consisted of 655 children (aged 14 days to 17 years) placed on ECMO for respiratory failure between November 1987 and June 1993 and entered in the ELSO registry. The age distribution and specific indications for ECMO are presented in Figures 1 and 2. Patients with diagnoses labeled "Other" include patients placed on ECMO for respiratory failure for an uncommon or uncertain diagnosis. Coexisting systemic sepsis was present in 76 patients (11.6%) in this series, and these patients were identified as group 1. Group 2 included all patients on ECMO without systemic sepsis (n = 579). Sepsis, as defined by the ELSO registry, was the presence of pathogenic microorganisms or their toxins in the blood or other tissues. It may be diagnosed clinically by symptomatic evidence of infection, or by laboratory studies. It may also be diagnosed by a documented positive culture. The presence or absence of sepsis was determined by thereporting center. No patients placed on ECMO for cardiac support were included.

View larger version (26K): [in this window] [in a new window]   Fig 1. . Age distribution of 655 pediatric patients placed on extracorporeal membrane oxygenation. Both nonseptic or septic groups had similar frequency distributions over each age range.

View larger version (40K): [in this window] [in a new window]   Fig 2. . Primary diagnosis for 655 pediatric patients in nonseptic and septic children treated with extracorporeal membrane oxygenation. ( ASPIR = aspiration pneumonia; BPNEU = bacterial pneumonia; IPH/PNCYS = intrapulmonary hemorrhage/pneumocystis; OTHER = respiratory failure of uncommon or uncertain causes; VPNEU = viral pneumonia.)

Factors Before Extracorporeal Membrane Oxygenation
In addition to the presence of systemic sepsis, 10 variables were used in the evaluation as predictors of outcome. These variables included patient age at the time of ECMO, sex, weight, the results of the most recent arterial blood gas analysis before ECMO, the ventilator parameters of the patient immediately before initiation of ECMO, and the presence of renal failure before ECMO. The mode of ECMO was not included as 83% underwent ECMO through a venoarterial technique. The variables used before ECMO are listed in Appendix 2.

Statistical Analysis
Data were analyzed using commercially available statistical software (SAS Institute, Cary, NC). A univariate analysis of all outcome variables was performed initially to compare results between groups 1 and 2, with a p value of less than 0.05 by two-tailed Fisher's exact test considered significant.

To account for interactions between variables before ECMO, additional tests were performed. For each outcome variable, a multivariate stepwise logistic regression analysis was performed. All variables listed in Appendix 2 were candidates for entry into the model. For each resulting model, the "group" variable (ie, the presence or absence of systemic sepsis) was always included, whereas only those remaining variables that met the 0.05 significance level were entered. For each element in the model, a parameter estimate was calculated from which a p value and an odds ratio for the variable were derived.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Overall Results
For the entire group of 655 children, survival was 49.9%. When examined by age intervals, survival was 55.0% for children less than 24 months (n = 407), 47.4% for children 24 to 72 months (n = 133), 38.2% for those 72 to 156 months (n = 76), and 28.2% for those more than 156 months (n = 39). This trend of reduced survival with advancing age was statistically significant (p < 0.05).

Univariate Analysis
A univariate analysis of patient survival was undertaken to compare the 76 children with sepsis while on ECMO (group 1) with the remaining 579 patients (group 2). Survival was significantly better in group 2 (51.6%) than in group 1 (36.8%) (p < 0.02 by Fisher's two-tailed exact test).

Multivariate Analysis
To account for potential interactions between variables before ECMO, a stepwise regression was performed for each variable as described previously. Survival was not significantly different between groups when the variables before ECMO were accounted for by this analysis (odds ratio, 0.578; 95% confidence interval, 0.288–1.162; p = 0.12). Only older age, lower pH, and lower arterial oxygen tension in arterial blood gas levels before ECMO were predictors of increased mortality. The effect of sepsis was tested by this multivariate analysis for each of the age ranges defined. In no subset was sepsis a significant predictor of survival (all p > 0.10). Because the presence of before ECMO variables affected the analysis of survival, only the results of the multivariate analysis are reported for ECMO complications.

The ECMO complications that were found to be significantly different between the two groups at p < 0.05 are listed in Table 1. Not surprisingly, culture-proven infections at locations other than the site of primary infection were more common in the septic group. Neurologic sequelae (seizures and other neurologic complications) were also more frequent in group 1. The duration of ECMO did not differ significantly between groups (276 ± 192 hours versus 248 ± 195 hours for the nonseptic and septic patients, respectively, mean ± standard deviation).

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

Overall survival results with ECMO for the management of respiratory failure in the pediatric population have not matched the excellent statistics seen in neonates. Survival rates more than 90% have been recorded for neonatal respiratory failure attributable to meconium aspiration syndrome, and survival for all indications in the neonatal population averages 80% [8]. In the pediatric group, the use of ECMO for respiratory support has resulted in survival rates approaching only 60%. The best results in this group of patients have been those with aspiration pneumonia (64%), and the lowest survival rate has been noted for pediatric patients with pneumocystis (38%) [9].

Part of the reason for this difference in survival between the neonatal and pediatric patient groups may relate to differences in the underlying disease conditions. In the neonate, respiratory failure is often the result of physiologic perturbations such as persistent pulmonary hypertension of the newborn or persistent fetal circulation. These conditions are frequently reversible with the time provided by ECMO support. In the older patient, where respiratory failure is most commonly secondary to viral or bacterial pneumonia, pulmonary dysfunction is less likely to be a fully reversible process. Furthermore, survival rates with ECMO progressively decline with advancing age, even within the pediatric population. It is unknown whether this trend is explained by changing indications (including the infectious agents responsible for pneumonia) or by age-related differences in pulmonary susceptibility to injury or in propensity to develop adult respiratory distress syndrome or multisystem organ failure [10].

Other researchers have examined predictors of survival from ECMO in the pediatric population. O'Rourke and associates [11] reviewed ELSO data from 1982 to 1991 for 285 patients aged 14 days to 17 years and found an overall survival rate of 47%. The most common indications for this therapy were viral pneumonia and adult respiratory distress syndrome. Predictors of decreased survival were examined by univariate techniques and found to include higher mean airway pressure, lower arterial pH, and higher peak inspiratory pressure. However, multivariate analysis was not applied and the presence or absence of sepsis was not considered in this study. A retrospective, multivariate analysis of survival in 220 pediatric patients conducted by Moler and colleagues [10] found younger age, shorter duration of pre-ECMO mechanical ventilation, lower peak inspiratory pressure, lower alveolar–arterial oxygen tension difference, and more recent ECMO experience as predictors of improved survival. Again, sepsis was not included as a candidate variable in this model.

Information on ECMO for pediatric patients with systemic sepsis is available only from limited case studies. Farmer and colleagues [12] studied 8 patients where ECMO was used as salvage from surgical emergencies. In 3 pediatric patients where sepsis was present before ECMO, 2 survivors were reported. Ehren and associates [13] reported favorable results using ECMO in 12 patients treated primarily for aspiration or pneumonia of varied causes. Nine patients were weaned from ECMO and 8 survived long term. However, the incidence of systemic sepsis was not stated. Beca and Butt [14] reported the use of ECMO in 9 children with culture-proven refractory septic shock. A survival rate of 56% suggested that septic shock should not be a contraindication to ECMO.

Most other studies examining ECMO in septic patients have been restricted to neonates. Kornhauser and associates [4] reported no survivors treated with ECMO for neonatal Group B streptococcal pneumonia, whereas Hocker and colleagues [7] observed an 87% survival rate in hypotensive neonates with this same disease process. Recently, we examined sepsis as a predictor of survival in neonates using a multivariate analysis of ELSO data [5]. Neonates with sepsis placed on ECMO achieved a survival benefit equal to those patients without sepsis, although neurologic, renal, and metabolic complications were more frequent. Nevertheless, applying neonatal results to the pediatric population may not be valid.

Several studies have theorized that extracorporeal support might be deleterious in the presence of sepsis where an inflammatory response has been initiated. Prolonged circulatory support has been shown to cause elevated neutrophil CD11b levels [15, 16], decreased neutrophil counts [17], elevated neutrophil lactoferrin and elastase levels [15, 17], and increases in plasma C3a, C5b-9, and interleukin-8 [16, 18]. These changes suggest that activation of host inflammatory responses may be accelerated by ECMO and the body's ability to combat infection may be altered. In contrast, DePuydt and colleagues [19] demonstrated that neutrophil phagocytosis and killing were not significantly affected by 5 days of ECMO support. Thus, the overall balance of effects on the host response to infection is incompletely defined. In view of the similar survival found in the septic and nonseptic groups in this study, any adverse effect attributable to inflammatory factors does not appear to affect mortality. However, these factors may play a role in some of the complications arising in septic children.

ECMO Complications
Several complications were more common in the septic group. These included the development of seizures (p < 0.05), other neurologic complications (p < 0.05), and culture-proven infection at other sites (p < 0.05). The predominance of neurologic problems is likely not related to intracranial hemorrhage or infarction, as these events are coded separately on the ELSO data forms. However, some of these neurologic problems may relate to hypoperfusion or cerebral microemboli or microhemorrhages that are not detectable by standard imaging techniques. Trends toward increased complication rates in other organ systems (gastrointestinal hemorrhage, renal failure, cardiac arrhythmias) began to appear in analysis of some of the older age groups. Younger pediatric patients, who comprised the majority of this study, may be less susceptible to these problems, and their profile of complications more closely approximated those seen in neonates.

Study Limitations
Several important limitations of this study should be noted. The study is retrospective and spans a considerable time period during which both ECMO and conventional ventilatory techniques have evolved. For example, 83% of the children in this study were treated with venoarterial ECMO, whereas currently venovenous techniques have become more popular in hemodynamically stable patients.

Multivariate analysis was applied to control for the effects of other associated variables on survival. Nevertheless, these statistical techniques are limited and will not account for factors not included in the model, which may also affect survival. The analysis is further limited by the size of the study group, particularly when older subgroups are studied independently. Here, type II statistical errors (where actual differences are not found) remain a substantial risk. Moreover, the ELSO registry is a voluntary data base, and bias toward centers that are major contributors cannot be excluded.

The pediatric ECMO population is very heterogeneous in age distribution, indication for ECMO, and specific organisms identified (in cases of pneumonia). It remains possible that sepsis may influence outcome in some patient subsets. The definition of sepsis itself is problematic in this analysis. According to the ELSO registry, no formal documentation of sepsis, such as positive blood cultures, is required for a patient to be designated as septic. Many of the patients were classified as septic based purely on clinical data, as the designation of sepsis was at the discretion of the reporting institution. Moreover, identification of the actual target organism was rarely available. Also, the associated treatments for sepsis (antibiotics and steroids) are not provided in the data base, and the effects of these treatments cannot be evaluated. Finally, no long-term follow-up data are available from the registry and conclusions must be restricted to early outcomes only.

Clearly, although ECMO is very effective in neonatal respiratory failure, results are significantly worse in the pediatric population. Examination of the raw survival data suggests that children with sepsis have an even more dismal outlook. However, our analysis has demonstrated that the presence of systemic sepsis does not independently predict a lower survival from ECMO in children when factors such as age, arterial blood gas results before ECMO, and ventilator parameters before ECMO are considered. On the basis of these data, ECMO should not be withheld from children solely on the basis of sepsis.

This study demonstrates the value of large data registries in the analysis of complex questions where many variables need to be considered. Pooled data from multiple centers may allow adequate numbers to better examine issues that may not be less well studied by any individual center.

Appendix 1. Outcome Variables Used in Analysis
General outcome Survival

Hemorrhagic complications

Intracranial infarct by computed tomographic scan

Intracranial hemorrhage by computed tomographic scan

Significant gastrointestinal hemorrhage

Significant surgical site bleeding

Other hemorrhagic problem

Neurologic complications

Brain death

Probable or definite seizure

Excessive jitteriness

Other neurologic problem

Renal complications

Creatinine level more than 1.5 or less than 3.0 mg/dL

Creatinine level more than 3.0 mg/dL

Dialysis or hemofiltration

Other renal problem

Cardiovascular complications

Cardiopulmonary resuscitation required

Cardiac arrhythmias

Inotropes on ECMO Hypertension (systolic blood pressure >150 mm Hg; dia stolic blood pressure >90 mm Hg)

Other cardiovascular problem

Pulmonary complications

Pneumothorax requiring chest tube

Other pulmonary problem

Septic complications

Culture-proven infection

White blood cell count less than 1,500/µL

Other infectious problem

Metabolic complications

Serum potassium level less than 2.5 mEq/L

Serum potassium level more than 7.5 mEq/L

Serum sodium level less than 120 mEq/L

Serum sodium level more than 160 mEq/L

Serum calcium level less than 6 mEq/L

Serum calcium level more than 14 mEq/L

Blood glucose level less than 20 mg/dL

Blood glucose level more than 350 mg/dL

pH less than 7.05 pH more than 7.75

Other metabolic problem

Appendix 2. Variables Before ECMO Used in Evaluation
General

Patient age at time of ECMO

Patient sex

Weight

Most recent arterial blood gas before ECMO pH

Partial pressure of carbon dioxide

Partial pressure of oxygen

Most recent ventilator settings before ECMO

Ventilator rate

Fractional concentration of oxygen

Other factors

Systolic blood pressure

Renal failure before ECMO

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We are grateful to Thomas DeLosh and Charles J. H. Stolar, MD, of the Extracorporeal Life Support Organization for providing access to the ELSO Registry data base, and to Donald McIntire, PhD, for assisting in the statistical analysis.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Meyer, Division of Thoracic and Cardiovascular Surgery, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75235-8879.

This article has been selected for the open discussion forum on the STS Web site: http://www.sts.org/annals

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Dan M. Meyer Michael E. Jessen Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Meyer, D. M. Articles by Jessen, M. E. Search for Related Content PubMed PubMed Citation Articles by Meyer, D. M. Articles by Jessen, M. E.