Role of extracorporeal membrane oxygenation in children with sepsis: a systematic review and meta-analysis

Background The benefits of extracorporeal membrane oxygenation (ECMO) in children with sepsis remain controversial. Current guidelines on management of septic shock in children recommend consideration of ECMO as salvage therapy. We sought to review peer-reviewed publications on effectiveness of ECMO in children with sepsis. Methods Studies reporting on mortality in children with sepsis supported with ECMO, published in PubMed, Scopus and Embase from 1972 till February 2020, were included in the review. This study was done in adherence to Preferred Reporting Items for Systematic Review and Meta-Analysis statement after registering the review protocol with PROSPERO. Study eligibility was independently assessed by two authors and disagreements resolved by a third author. Publications were reviewed for quality using Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Random-effects meta-analyses (DerSimonian and Laird) were conducted, and 95% confidence intervals were computed using the Clopper-Pearson method. Outliers were identified by the Baujat plot and leave-one-out analysis if there was considerable heterogeneity. The primary outcome measure was survival to discharge. Secondary outcome measures included hospital length of stay, subgroup analysis of neonatal and paediatric groups, types and duration of ECMO and complications . Results Of the 2054 articles screened, we identified 23 original articles for systematic review and meta-analysis. Cumulative estimate of survival (13 studies, 2559 patients) in the cohort was 59% (95%CI: 51–67%). Patients had a median length of hospital stay of 28.8 days, median intensive care unit stay of 13.5 days, and median ECMO duration of 129 h. Children needing venoarterial ECMO (9 studies, 208 patients) showed overall pooled survival of 65% (95%CI: 50–80%). Neonates (< 4 weeks of age) with sepsis needing ECMO (7 studies, 85 neonates) had pooled survival of 73% (95%CI: 56- 87%). Gram positive organisms were the most common pathogens (47%) in septic children supported with ECMO. Conclusion Survival rates of children with sepsis needing ECMO was 59%. Neonates had higher survival rates (73%); gram positive organisms accounted for most common infections in children needing ECMO. Despite limitations, pooled survival data from this review indicates consideration of ECMO in refractory septic shock for all pediatric age groups.

Care Units (ICUs) [1]. The World Health Assembly, the decision-making body of the World Health Organisation, adopted a recent resolution to reduce the global burden of sepsis through early identification, prevention and management [1][2][3][4][5]. The percentage of all global deaths in 2017 related to sepsis was highest in neonates and children compared to the adult population [5]. A recent systematic review revealed that nearly 1 in 4 children with sepsis die. Children most at risk of death are younger patients and those with septic shock; sepsis and infections account for 6.3 deaths of 1000 live births among children younger than 5 years [6].
While current best practice includes the early delivery of sepsis treatment bundles, therapeutic options for children refractory to initial resuscitation remain very limited [7]. The development of refractory shock is associated with a steep increase in mortality in pediatric sepsis [8][9][10][11]. Previous sepsis guidelines, including the American College of Critical Care Medicine, recommended consideration for Extracorporeal Membrane Oxygenation (ECMO) for persistent shock in spite of early fluid-and inotrope-based resuscitation [12,13]. Studies have reported an increase in use of ECMO for pediatric septic shock with improving outcomes over time [14][15][16][17]. Survival rates of septic patients supported with ECMO are above 70% for neonates [16,18,19] and approximately 40% for older children in both single centre and registry studies. Accordingly, the 2020 Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children recommended venoarterial ECMO as rescue therapy in children with septic shock only if refractory to all other treatments, with a low level of evidence and a weak recommendation [20].
These recommendations remain based on few, relatively small studies. Additional challenges relate to the difficulties in assessing outcomes in heterogeneous cohorts of critically ill children and the number of factors which may contribute to outcomes, including patient selection, time to ECMO initiation, cannulation strategies, different ECMO technology, and the experience of the treating team [17,21]. As a result, the outcome benefits of ECMO in pediatric sepsis remain controversial. We sought to systematically review the literature to examine survival rates of pediatric and neonatal patients with sepsis needing ECMO, and to describe etiologies of sepsis and the complication rates in published cohorts of neonates and children treated with ECMO for sepsis.

Methods
This study was done in adherence to the ethical guidelines stated in the Declaration of Helsinki following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. [22] The review protocol was registered with PROSPERO (Ref:CRD  42020161828).

Study selection
A comprehensive literature search was performed using MEDLINE, Embase and Scopus databases to retrieve published data from 1972 up to 15 th February 2020 on the use of ECMO in neonatal and pediatric septic patients. The search phrases for the three databases included Boolean terms ' AND' and 'OR' with the following keywords in various possible combinations: "ECMO", "extracorporeal membrane oxygenation", "ECLS", "Infant", "newborn", "neonatal", "pediatric", "sepsis", and "infection" [Additional file 1: eTable 1]. In addition, a hand search of all relevant studies and their citation lists was performed to identify additional articles for inclusion. Articles were selected for systematic review if they described neonatal and/or pediatric septic patients undergoing venoarterial and venovenous ECMO and the incidence of mortality was clearly stated. No restriction was placed on study type (prospective or retrospective). For studies that included overlapping patients (period of overlap > 1 year), the largest study was included in the meta-analysis while the rest of the studies were included in the review. We excluded studies with predominantly patients above 18 years old, articles with fewer than 5 patients, articles not written in English, conference abstracts, surveys and articles without full text, review articles and case reports. Publications from the Extracorporeal Life Support Organization (ELSO) International registry were excluded since data on patients reported to the ELSO Registry are likely also reported to national databases and present in single center reviews and thus potentially duplicated. Studies based on national registers were included provided there was no overlap with single-center studies. The eligibility of studies was independently assessed by two review authors (NY and KR) and disagreements were resolved by consensus or appeal to a third author (GM). Publications were reviewed for quality using the Joanna Briggs Institute (JBI) checklist for prevalence studies [23] as well as the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to the determine the overall rating confidence in the body of evidence [24]. Case reports and case series (< 5 patients) were excluded due to likelihood of positive outcome bias.

Study analysis
Data including study design, outcomes, patient characteristics, and interventions were extracted independently. Neonates were defined as children 28 days or less of age. Descriptive statistics, such as the medians and 25th to 75th percentiles were reported for continuous variables, and the counts and percentages were reported for categorical variables. Survival to discharge was the primary measure of outcome in our meta-analysis. Secondary outcome measures included hospital length of stay, types and duration of ECMO and complications. Subgroup analysis were also performed for the neonatal and pediatric age group.
We anticipated heterogeneity between studies. To account for the variability between studies in the metaanalysis, we used the random-effects model that was based on the inverse variance method where the DerSimonian and Laird method [25] was used to estimate the between-study variance. Briefly for the meta-analysis of proportions, exact confidence interval (CI) for each proportion was computed using the Clopper-Pearson method [26]. A variance-stabilizing transformation, called the Freeman-Tukey double arcsine transformation [27], was applied to all proportions and the meta-analysis was performed on the transformed proportions. The pooled transformed proportion and its 95%CI were back transformed to obtain pooled estimates on the original proportion scale. To obtain a pooled mean age of study participants across studies, studies that did not report the mean and/or its corresponding standard deviation (SD) had these quantities estimated from the reported medians, range, and IQR using the methods proposed by Wan et al. [28].
Statistical heterogeneity between studies was identified using I 2 statistics, where I 2 ≤ 40%, between 30-60%, between 50-75% and ≥ 75% indicated low, moderate, substantial, and considerable heterogeneity, respectively. P values for I 2 statistic were derived from the chi-square distribution of Cochran's Q test. Together with the visual inspection of the forest plot, additional diagnostics were carried out to identify outlying or/and influential studies. Firstly, studies with studentized deleted residuals greater than 1.96 or less than -1.96 were identified as potential outliers [29]. Next, a set of leave-one-out analysis was performed to identify potential influential studies that resulted in a large change in the pooled estimates after they were left out one at a time from all studies. Lastly, a Baujat plot was used to identify studies that had high contributions to the heterogeneity in the meta-analytic data [30]. With these diagnostics, an agreement was made between two investigators to identify and remove outlying/influential studies. A funnel plot and Egger's tests was conducted to assess for reporting publication bias. Univariate meta regression analysis was also conducted on pre-ECMO characteristics where at least 4 data points were available. The analyses were conducted using the R Studio (Version 3.6.1, R Studio, Inc. Boston) using the 'metafor' and 'meta' packages.

Primary outcome
Thirteen studies (Additional file 1: eTable 2) reported 2559 paediatric and neonatal patients with sepsis who needed ECMO support. The overall pooled estimate of survival in the cohort was 59% (95%CI: 51% to 67%, p < 0.01) (Fig. 1). There was considerable heterogeneity amongst the studies; we identified three studies [31,32,46] that were outliers or influential with the leave one out analysis and the Baujat plot. After excluding the three studies, the remaining 10 studies had 2486 patients with a cumulative pooled estimate survival of 55% (95% CI 49% to 62%, p < 0.01) (Additional file 1: Fig. 2).
Univariate meta regression analysis was also conducted on pre-ECMO characteristics where at least 4 data points were available: there was no significant association found between survival and pre-ECMO lactate levels, Cardiac Arrest (%), need for renal replacement therapy (%), ECMO duration, overall length of stay in hospital and overall length of stay in ICU. (Table 2

Risk of bias
All of the 13 studies that were assessed through the JBI checklist were good quality with minimum high score of 8/9 with no concerns on risk of bias. Egger's test and funnel plots showed some evidence of publication bias in the total ECMO group which was resolved after removal of influential studies (Additional file 1: Fig. 14). There was no evidence of publication bias in the VA-ECMO, pediatric ECMO and neonatal ECMO groups: Additional file 1: Figs. 15, 16, 17 respectively) (Additional file 1: eTable 5). The GRADE system showed high level of certainty in the use of ECMO in pediatric and neonatal and venoarterial ECMO groups and a moderate level of certainty in the overall use of ECMO in children with sepsis (Table 3).

Discussion
The use of ECMO in pediatric sepsis has increased over the past decade [49] with variable survival rates [49][50][51]. Our meta-analysis of observational studies showed that overall survival rates of children with sepsis treated with ECMO were 59%. Neonates had higher survival rates (73%). Gram positive organisms were the most common type of pathogen.
The hemodynamic manifestations of septic shock can vary between different age groups. While early-onset sepsis may present predominantly as right heart dysfunction from persistent pulmonary hypertension of the newborn (PPHN), older infants and young children often manifest severe left ventricular dysfunction. Older children and adults more commonly present with distributive shock [15]. The role of ECMO in the management of refractory septic shock in neonates and children stems by virtue of its ability to provide perfusion of oxygenated blood to tissues and maintain gas exchange even in refractory cardiopulmonary failure. However, the specific threshold as to when shock, or multi-organ dysfunction should be considered "refractory", remains poorly defined. Some data indicate that venoarterial ECMO is associated with better survival than conventional therapy in children with septic shock if high ECMO flows (> 150 mL/kg/min) can be provided [20,45]. While data on ECMO flows were not available in all the studies included in this metaanalysis, our analysis of neonatal and pediatric septic patients who needed venoarterial (VA) ECMO showed an overall pooled survival of 63%; subsequent removal of outlier studies yielded an overall pooled survival of 53%. Children who underwent central ECMO cannulation have been shown to have survival rates up to 73% in single centre studies [17]. In comparison, the ELSO registry reported survival rates for pediatric patients with sepsis supported on ECMO of 52% [49].
The American College of Critical Care Medicine guidelines for hemodynamic support of pediatric and neonatal septic shock recommends ECMO as the therapy of choice for newborn patients with refractory PPHN and sepsis with Level 1 C evidence; however the guidelines highlight an expected survival with ECMO for septic shock being no greater than 50% in children, with Level 2 C evidence for consideration of ECMO in this group [18]. The recently published Surviving Sepsis Campaign International Guidelines in children suggested venovenous ECMO for children with sepsis induced respiratory distress syndrome and refractory hypoxia as well as venoarterial ECMO as a rescue therapy in children with septic shock refractory to all other treatments. The recommendations for both above were weak based on very low quality of evidence [20]. Our meta-analysis supplement the above recommendations and showed survival rates above 50% in septic children and more than 70% in neonatal sepsis with moderate to high level of certainty in the level of evidence.
There are several limitations to the study. This review is based on non-randomized or non-propensity-matched studies, and the studies selected for analysis showed moderate heterogeneity. The challenges of interpreting the heterogeneity using I2 values has been highlighted when studies with large sample sizes result in very narrow confidence intervals. It has also been established that I2 for the pooled estimate can be high even in the presence of modest inconsistency and can be misleading [52]. Inter-center practice variability, patient selection,  [56] while some reported using the International Classification of Diseases (ICD-9) to define septic shock and most of the papers diagnosed septic shock based on their institutional guidelines. An international multicentre study based on a Delphi process followed by data-driven derivation and validation defined refractory septic shock in children as the combination of severe cardiovascular dysfunction (measured by poor cardiac function and/or preceding cardiac arrest), high lactate, and high vasopressor requirements (measured by vasopressor-inotrope score) [11]. Unfortunately, the data provided in the studies included in this metanalysis would not allow to verify if the proposed refractory septic shock criteria were met. The timing of ECMO initiation in children with sepsis could not be assessed with certainty from the literature, although one recent multicentre cohort study concluded that ECMO was only of benefit if the predicted risk of death was > 50% (48). The studies included in our analysis spanned from 1992 to 2020, where sepsis diagnosis, sepsis management, ECMO technology and ECMO practice have undergone substantial changes. Also, meta-regression analyses are inherently constrained by a lack of power, resulting in an increased risk of Type 2 errors suggesting that lack of significant association does not imply that a correlation does not exist [57]. However, this remains the largest available cohort of patients which has been analysed so far; there was no evidence of publication bias and the methodological quality of all the studies included in our analysis scored high (> 8/9), using the JBI critical appraisal tool (Additional file 1: Table 6). The GRADE analysis demonstrated moderate to high certainty in the evidence presented in this paper.

Conclusion
The use of ECMO to resuscitate and support children with sepsis and refractory shock is feasible and is associated with survival rates as high as 59%. Neonates had higher survival rates and central cannulation may be associated with better outcomes in children needing ECMO with sepsis. Despite the limitations of studies included in this metanalysis, the aggregate data indicate that survival for patients treated with septic shock overall justifies recommendation to consider ECMO in refractory septic shock for all pediatric age groups. Future studies should provide more evidence to inform on timing and thresholds for ECMO initiation, including dynamic assessment of response to therapy/deterioration.