Defining benefit threshold for extracorporeal membrane oxygenation in children with sepsis—a binational multicenter cohort study

Patients with age below 16 years that were non-electively admitted to a PICU or a general ICU in Australia and New Zealand between January 1, 2002, and December 31, 2016, with sepsis or septic shock at ICU admission were eligible. Patients were required to have sepsis or septic shock (including toxic shock) as the principal diagnosis, the underlying diagnosis of ICU admission, or as a high-risk diagnosis [23]. In addition, we included patients if they had any invasive infection (including meningitis, pneumonia/pneumonitis, peritonitis, necrotizing fasciitis, osteomyelitis, endocarditis, tracheitis, epiglottitis) as the principal or the underlying diagnosis and also had sepsis and/or septic shock (including toxic shock) in any other diagnostic field.

Controls were defined as patients < 16 years with sepsis and septic shock as defined above, which did not receive any ECMO.

We identified patients that underwent treatment with ECMO in the ANZPIC registry and manually checked these against the institutional ECMO databases of the six centers which provided ECMO during the study period. We checked the institutional ECMO databases and patient charts for the indications for ECMO and type of cannulation. Only veno-arterial (VA)-ECMO runs that were initiated to treat cardiovascular or combined cardiorespiratory failure in septic shock defined as per the 2005 International Pediatric Sepsis Consensus Conference [23] in patients who required inotropes prior to ECMO initiation and/or extracorporeal cardiopulmonary resuscitation (ECPR) were included as cases. Details on physiology upon initiation of ECMO, cannulation mode, and patient flow rates at 4 h post ECMO initiation were extracted from the institutional ECMO databases.

The primary outcome was defined as ICU mortality. ICU mortality and ICU length of stay were available for 100% of patients. Patient comorbidities were extracted from the diagnostic coding in the registry as described elsewhere [1, 21]. The Pediatric Index of Mortality 2 (PIM2) [24] was used to assess patient illness severity at ICU admission.

Data are presented as percentages and numbers or medians with interquartile range (IQR). Two-sample Wilcoxon rank-sum (Mann-Whitney) tests were used to compare subgroups.

We previously demonstrated the high performance of a set of easily available clinical variables to predict sepsis-related mortality in critically ill children within 1 h of ICU admission [1]. We optimized this sepsis-specific mortality prediction model using a stepwise logistic regression approach in the dataset restricted to septic patients which were not treated with VA-ECMO, including additional variables on treatment delivered during admission. The mortality prediction model included patient characteristics (age, interhospital transfer, immunosuppression), physiological parameters (arterial hypotension, PaO₂/FiO₂ ratio, lactate), clinical characteristics (presence of shock on admission, dilated unresponsive pupils, cardiac arrest prior to admission), and treatment interventions (ventilation during the first hour of admission; intubation; continuous renal replacement therapy; high-frequency oscillation ventilation (HFOV), and inhaled nitric oxide). We defined arterial hypotension as systolic blood pressure below the 5th percentile for age and sex as previously described [25]. We used all variables significantly associated with the primary outcome in univariable analyses to develop the multivariable models. This “naive” baseline risk adjustment model was built using only those patients who did not receive ECMO as part of their treatment. Reverse stepwise regression was used to select final covariates with exit criteria of p < 0.2. We applied the Hosmer-Lemeshow goodness of fit test to assess calibration of the model in septic patients not treated with ECMO and described the area under the curve of receiver-operating-characteristic (AUROC) curve analysis. This disease-specific prediction model was then used for every patient (both septic controls and ECMO cases) to calculate the predicted mortality based on patient characteristics, severity upon presentation to intensive care, and level of support. We then used the linear prediction of the baseline risk adjustment model as a covariate in a second-stage model, the “treatment model,” to evaluate the effect of ECMO on ICU mortality for children with sepsis and septic shock. We estimated this second-stage model using a bootstrap procedure with 1000 repetitions. The samples were the same size as the total dataset and drawn with replacement from the original data stratified by ECMO treatment. The coefficients from each model repetition were used to estimate a distribution for the benefit threshold. The median was used to estimate the estimated threshold in baseline risk for benefit, and the 2.5th and 97.5th percentiles were used to estimate uncertainty intervals. This second-stage model was then repeated as a sensitivity analysis in only those patients coded with septic shock.

All analyses were conducted using Stata (version 15.0, Stata Corp, College Station, TX, USA).

During the study period, 5062 children coded as sepsis and septic shock met the eligibility criteria, of which 80 (1.6%) were treated with ECMO for septic shock, which was confirmed using manual checking of patient records (Table 1). The crude mortality was 10.6% (483/4982) in controls and 45.0% (36/80) in ECMO cases (p < 0.001). The median time from ICU admission to death was 53.0 h (IQR 15.2–189.2, Additional file 2). In 61.3% (49/80) of ECMO cases and 45.2% (2250/4982) of controls, a bacterial pathogen was identified (Additional file 3). Patients treated with ECMO for septic shock were more likely to have undergone interhospital transfer and were sicker on admission to PICU as evidenced by lower systolic blood pressure, higher lactate, and higher PIM-2 scores. The proportion of children with sepsis treated with ECMO during the study period did not change substantially (14.2 ECMO-treated children per 1000 pediatric sepsis admissions in 2002–2009 compared with 17.0/1000 in 2010–2017, p = 0.425). In the ECMO group, 13 (16.3%) were diagnosed with ARDS, in comparison to 157 (3.2%) of patients in the control group (p < 0.001). Nine (11%) of the ECMO patients had undergone cannulation at a referring hospital.

The final multivariable model to predict ICU mortality in children with sepsis and septic shock admitted to ICU included severe respiratory failure (PaO2/FiO2 ratio, intubation, and treatment with HFOV); shock or cardiac arrest (arterial hypotension, shock on presentation, cardiac arrest pre ICU admission); metabolic (high lactate), central nervous system (dilated pupils), and renal (need for renal replacement) dysfunction; and underlying immunosuppression as significant predictors (Table 2). The model was well calibrated (Hosmer-Lemeshow goodness-of-fit test chi-square 9.83, p = 0.277) and predicted mortality with an AUROC of 0.879 (95% CI 0.864–0.895) which was significantly superior to mortality prediction using PIM-2 (AUROC 0.789; 0.765–0.813, p < 0.0001).

The benefit threshold, defined as the baseline mortality risk generated by our predictive model for which ECMO was associated with increased survival was calculated as 47.1% risk of mortality (95%CI 27.9–84.3%, Fig. 1 and Additional file 5). Of the children who received ECMO, 31.3% (25) had a baseline risk above the benefit threshold. The observed mortality for children treated with ECMO below the threshold was 41.8% (23 deaths), compared to a predicted mortality of 30.0% as per the baseline model (16.5 deaths; standardized mortality rate 1.40, 95% confidence interval 0.89–2.09). Among patients above the benefit threshold the observed mortality was 52.0% (13 deaths) compared to 68.2% as per the baseline model (16.5 deaths; standardized mortality rate 0.61, 95% confidence interval 0.39–0.92). Sensitivity analyses restricted to patients coded as septic shock in the ANZPICR resulted similarly (n = 80 cases, n = 2347 controls, benefit threshold of 47.7%; 95% CI 17.4–93.6%) (Additional file 6).

Based on these figures, we estimate that a future trial on ECMO in pediatric septic shock would require enrolment of at least 143 children treated with ECMO with baseline risk above the threshold to detect a mortality difference of 16.2% (52% versus 68.2%) with a power of 80% and a two-sided significance level of 0.05. Such a trial would need to screen approximatively 300,000 children admitted to ICU with sepsis and septic shock in our population.

Crude mortality in the 80 patients treated with VA-ECMO for septic shock was 45% (36/80) (Table 3 and Additional file 4). Thirty-two (40%) suffered a cardiac arrest prior to ECMO including 18 (23%) patients treated with ECPR for sepsis-related cardiac arrest. Fifty-seven out of 80 (71%) underwent primary open-chest cannulation in comparison to 23/80 (29%) who were initially cannulated peripherally. The median time from ICU admission to ECMO cannulation was 7 h in ECMO survivors compared to 2.8 h in ECMO deaths (p = 0.13). Children treated with ECMO who survived had lower admission lactate and PIM2 scores, higher pH and bicarbonate pre-ECMO, and a lower proportion with cardiac arrest prior to ECMO and were more often cannulated centrally. While the flow rates measured at 4 h were not significantly different between ECMO survivors and fatalities (Additional file 7), the mean flow rates of children cannulated centrally were 173 ml/kg/min in comparison to 129 ml/kg/min in children cannulated peripherally (p < 0.05). Multivariable analyses confirmed that higher lactate (odd’s ratio 1.21, 95%CI 1.04–1.40, p = 0.012), cardiac arrest prior to ECMO (OR 4.59, 1.58–13.10, p = 0.005) and central cannulation (OR 0.31, 0.10–0.98, p = 0.046) were significant independent predictors of mortality (Table 4, AUC 0.776).