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

Abstract

Background: The surviving sepsis campaign recommends consideration for extracorporeal membrane oxygenation (ECMO) in refractory septic shock. We aimed to define the benefit threshold of ECMO in pediatric septic shock.

Methods: Retrospective binational multicenter cohort study of all ICUs contributing to the Australian and New Zealand Paediatric Intensive Care Registry. We included patients < 16 years admitted to ICU with sepsis and septic shock between 2002 and 2016. Sepsis-specific risk-adjusted models to establish ECMO benefit thresholds with mortality as the primary outcome were performed. Models were based on clinical variables available early after admission to ICU. Multivariate analyses were performed to identify predictors of survival in children treated with ECMO.

Results: Five thousand sixty-two children with sepsis and septic shock met eligibility criteria, of which 80 (1.6%) were treated with veno-arterial ECMO. A model based on 12 clinical variables predicted mortality with an AUROC of 0.879 (95% CI 0.864-0.895). The benefit threshold was calculated as 47.1% predicted risk of mortality. 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% CI 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% CI 0.39-0.92). Multivariable analyses identified lower lactate, the absence of cardiac arrest prior to ECMO, and the central cannulation (OR 0.31, 95% CI 0.10-0.98, p = 0.046) as significant predictors of survival for those treated with VA-ECMO.

Conclusions: This binational study demonstrates that a rapidly available sepsis mortality prediction model can define thresholds for survival benefit in children with septic shock considered for ECMO. Survival on ECMO was associated with central cannulation. Our findings suggest that a fully powered RCT on ECMO in sepsis is unlikely to be feasible.

Keywords: Childhood; Extracorporeal life support; Extracorporeal membrane oxygenation; Infection; Mortality; Pediatric; Prediction; Sepsis; Septic shock.

Fig. 1

Estimating treatment benefit for children with sepsis and septic shock treated with extracorporeal life support (ECMO) versus controls. The marginal mean for estimated mortality is shown (y-scale) versus the baseline mortality score (x-scale) for children treated with ECMO (dark blue line) versus controls (light blue line). Full lines indicate the effect estimate, and dashed lines indicate 95% confidence intervals. The benefit threshold, defined as the baseline risk for which ECMO became beneficial, reflects the intersection of both lines at 47.1% predicted risk of mortality. The predicted mortality risk is adjusted for covariates on respiratory failure (PaO2/FiO2 ratio, intubation, treatment with HFOV); cardiovascular (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. The naïve baseline risk model is given by F1, where p_B is the baseline probability of mortality estimated among non-treated patients, BRS is the Baseline Risk Score, B₀ is the intercept, and B_n and X represent a matrix of coefficients and risk factors. F1: Logit(p_B) = BRS = B₀ + B_nX. The treatment model is given by F2, where p_D is the estimated mortality rate, BRS is the Baseline Risk Score (from F1), B₀ is the intercept, and ECMO is a binary treatment variable (1 = yes). The final term is an interaction term between treatment and the baseline risk score. F2: Logit(p_D) = B₀ + B₁ × BRS + B₂ × ECMO + B₃ × (ECMO ∗ BRS)