Luregn Schlapbach

Background The Resuscitation in Paediatric Septic Shock using Vitamin C and Hydrocortisone (RESPOND) trial is a multicentre randomised controlled trial exploring whether the use of hydrocortisone alone, or in combination with vitamin C, increases time alive and free of vasopressors for critically ill children. Objective To present the prespecified statistical analysis plan (SAP) for the RESPOND trial prior to finalising recruitment and locking the trial dataset. Design, setting, and participants The RESPOND trial is a three-arm, parallel group, open-label, randomised controlled trial, recruiting in paediatric intensive care units in Australia, New Zealand, India, and Brazil. The planned sample size is 384 participants. Main outcome measures The primary outcome is time alive and free of inotropes/vasopressors, censored at 7 days post-randomisation. Secondary outcomes include clinical (e.g. alive and free of multi-organ dysfunction, length of stay), safety, health economics (e.g. incremental costs, quality-adjusted life years), and long-term outcomes (measured at 6 months post-randomisation; e.g. health-related quality of life). Results and conclusions The SAP was designed by the Chief Investigators and approved by the RESPOND Steering Committee. Statistical analyses are summarised. The primary outcome will be analysed using quantile regression adjusted for stratification variables. Appropriate statistical comparisons between groups were planned and described in a way that is transparent, available to the public, verifiable, and predetermined before completion of data collection. The trial statistician, RESPOND Steering Committee members, and SAP authors remain blind to treatment allocation throughout the study. Data Safety and Monitoring Board members were provided with safety data with masked group identifiers during interim analyses. The RESPOND trial commenced recruitment in December, 2021, and aims to complete recruitment by mid-2026. Trial registration ACTRN12621000247875.

Background: Critically ill children receiving continuous renal replacement therapy may experience sub-therapeutic concentrations for antimicrobials leading to treatment failure and antimicrobial resistant pathogens. The objective of this study was to determine whether antimicrobial concentrations are reduced by a paediatric continuous renal replacement therapy (CRRT). Method: An ex vivo closed continuous veno–venous haemodiafiltration was simulated for a 3 kg infant to assess antimicrobial clearance across three ultrafiltration rates (zero, low and high flux). Slow continuous ultrafiltration was used to assess antimicrobial adsorption and recovery over 240 minutes. Controls were included to account for spontaneous drug degradation. This study was conducted in a university research laboratory with no participants. Antimicrobial concentrations were measured using a validated HPLC-MS/MS method. Results: The antimicrobial filter clearance during high-flux filtration was significantly increased for fluconazole, piperacillin, tazobactam, vancomycin and voriconazole (P < 0.05). The antimicrobial recovery [mean (%)] at 240 minutes in the CRRT model was significantly different from baseline (time zero) for ampicillin 49%, fluconazole 76%, gentamicin (0%) meropenem 51%, piperacillin 54%, vancomycin 31% and voriconazole 47% (P < 0.05). A significant relationship was demonstrated between antimicrobial recovery and molecular charge (R2 = 0.58 P 70% of the study antimicrobials in the ex vivo paediatric CRRT model, as a result of an increase in filter clearance during high-flux filtration or from drug-circuit adsorption. These findings suggests that antimicrobial dosing in critically ill children receiving CRRT requires assessment to determine whether antimicrobial concentrations are therapeutic.

Objectives: – Evaluate the predictive and prognostic performance of the Phoenix Sepsis Criteria (PSC) and Phoenix Sepsis Score (PSS) compared with International Pediatric Sepsis Consensus Conference (IPSCC) criteria and other organ dysfunction scores in children admitted to the PICU with suspected infection. Design: – Multicenter, prospective cohort study. Setting: – Eight PICUs within the Italian Network of PICU Study Group (TIPNet). Patients: – Patients younger than 18 years admitted with suspected infection (from February 2022 to April 2024). Interventions: – None. Measurements and Main Results: – Vital signs, organ dysfunction markers, and organ support requirements were collected during day 1 and day 2 of PICU admission. Sepsis was assessed using IPSCC criteria and PSC. IPSCC Severe Sepsis, PSS, Phoenix-8, Pediatric Logistic Organ Dysfunction-2 (PELOD-2), pediatric Sequential Organ Failure Assessment, and Pediatric Multiple Organ Dysfunction Score were calculated as organ dysfunction scores. Sepsis criteria predictive performance was assessed using sensitivity and positive predictive value (PPV). Organ dysfunction scores prognostic performance was assessed using the area under the precision-recall curve (AUPRC). Primary outcome was PICU mortality. Among 687 patients, PSC showed higher predictive performance than IPSCC sepsis criteria, with improved sensitivity and PPV for mortality on day 1 (PSC: sensitivity, 96.4%; 95% CI, 95.0–97.8%; PPV, 7.6%; 95% CI, 5.6–9.6% and IPSCC: sensitivity, 82.1%; 95% CI, 79.3–85.0%; PPV, 6.2%; 95% CI, 4.4–8.0%) and day 2 (PSC: sensitivity, 100.0%; 95% CI, 100.0–100.0%; PPV, 10.0%; 95% CI, 7.6–12.5% and IPSCC: sensitivity, 75.0%; 95% CI, 71.5–78.5%; PPV, 9.0%; 95% CI, 6.7–11.3%). PELOD-2 exhibited the highest AUPRC for mortality (day 1, 0.45; 95% CI, 0.26–0.63 and day 2, 0.59; 95% CI, 0.38–0.77). IPSCC Severe Sepsis score was outperformed by all other organ dysfunction scores, including PSS and Phoenix-8. All prognostic performances improved from day 1 to day 2. Conclusions: – PSC and PSS performed superior to IPSCC criteria in diagnosing and prognosticating pediatric sepsis, with improved performance at day 2 of PICU admission. This study first validated PSC and PSS in a European cohort.