Sepsi e shock settico in Terapia Intensiva Pediatrica (TiPed): esplorazione dei fattori diagnostici, terapeutici e prognostici in pazienti pediatrici critici con infezione

Background: Sepsis and septic shock are leading cause of mortality and morbidity among children globally, thus requiring prompt diagnosis, intervention, and prognostication. From an interventional point of view, the choice of vasoactive agent for fluid-refractory septic shock (FRSS) in pediatric patients remains unclear. Similarly, from a diagnostic and prognostic point of view, the ideal organ-dysfunction score for risk assessment upon admission for pediatric sepsis requires further clarification. Objectives: To investigate extensively the diagnostic, therapeutic and prognostic factors of critically ill children admitted to the Pediatric Intensive Care Unit (PICU) with sepsis and septic shock. Methods: This is a sequence of three studies: 1. Systematic review and meta-analysis on vasoactive agents in FRSS 2. Single-center retrospective observational cohort study on patients with sepsis admitted to the PICU from January 2010 to December 2019. 3. Multi-center prospective observational cohort study on patients admitted to 8 Italian PICUs with a diagnosis of infection from February 2022 to January 2024 comparing prognostic accuracy of different organ dysfunction scores for sepsis. Results: 1. Systematic Review: Of 26,284 identified articles, 13 met inclusion criteria, including a total of 997 children. Twelve studies included 748 patients receiving a single vasoactive agent. Of these, 361 received dopamine, 271 epinephrine, and 116 norepinephrine. Pooled estimate of mortality was 11% (CI 3%-36%) for patients receiving dopamine, 17% (CI 6%-37%) for patients receiving epinephrine, 7% (CI 1%-48%) for patients receiving norepinephrine. Four studies (3 RCTs, 1 observational cohort studies) addressed the comparison between patients receiving first-line dopamine (176 patients) and patients receiving first-line epinephrine (142 patients). The prevalence ratio overall favored the administration of epinephrine (PR 1.38, CI 0.81-2.38), however not showing statistical significance. 2. Retrospective Cohort Study: Sixty patients with sepsis were identified, 4 (6.7%) died, 7 (11.7%) developed new disability, 26 (43.3%) experienced prolonged length of stay, 21 (35%) prolonged invasive MV. The prognostic ability in mortality discrimination was significantly higher for organ-dysfunction scores, with PELOD-2 showing the best performance (AUROC 0.924, 95% CI 0.837-1.000), significantly better than SIRS 3 criteria (0.924 vs 0.509, p=0.009), SIRS 4 criteria (0.924 vs 0.509, p<0.001) and severe sepsis (0.924 vs 0.527, p<0.001). 3. Prospective Cohort Study: Of 466 enrolled patients, 20 died (4.63%). Median duration of mechanical ventilation was 3 days, median PICU LOS was 5 days for the overall sample. Patients meeting the International Pediatric Sepsis Consensus Conference (IPSCC) sepsis criteria had higher mortality (6.61%, p=0.027), higher rate of oncologic/hematologic (13.79%, p<0.001) and transplantologic (3.45%, p=0.007) comorbidities, longer mechanical ventilation duration (4 days, IQR 2 – 9, p=0.003) and PICU LOS (5.5 days, IQR 3 – 11, p=0.002). Prediction power for the primary outcome was better than that of the IPSCC criteria (AUROC 0.5774) for pSOFA Sclapbach (AUROC 0.8789, p<0.001), pSOFA Matics (AUROC 0.8855, p<0.001), pSOFA Shime (AUROC 0.9211, p<0.001), P-MODS (AUROC 0.8168, p<0.001) calculated at Day 1, yielding similar results when calculated at Day 2. Conclusions: This project highlights and emphasize the need for high-quality data in both interventional and prognostic domains for sepsis. Our systematic review has contributed valuable insights regarding the primary vasoactive agent of choice for patients with FRSS, which presently stands as epinephrine. Regardind the prognostic domains, our retrospective and prospective studies have confirmed a recent body of pediatric and adult evidence supporting the use of organ dysfunction scores for prognostication in infections and sepsis.