Biological basis of critical illness subclasses: from the bedside to the bench and back again.

Critical illness syndromes including sepsis, acute respiratory distress syndrome, and acute kidney injury (AKI) are associated with high in-hospital mortality and long-term adverse health outcomes among survivors. Despite advancements in care, clinical and biological heterogeneity among patients continues to hamper identification of efficacious therapies. Precision medicine offers hope by identifying patient subclasses based on clinical, laboratory, biomarker and 'omic' data and potentially facilitating better alignment of interventions. Within the previous two decades, numerous studies have made strides in identifying gene-expression based endotypes and clinico-biomarker based phenotypes among critically ill patients associated with differential outcomes and responses to treatment. In this state-of-the-art review, we summarize the biological similarities and differences across the various subclassification schemes among critically ill patients. In addition, we highlight current translational gaps, the need for advanced scientific tools, human-relevant disease models, to gain a comprehensive understanding of the molecular mechanisms underlying critical illness subclasses.

Inflammatory and Hematologic Liver and Platelet (HALP) Scores in Hypothermia-Treated Hypoxic-Ischemic Encephalopathy (HIE).

OBJECTIVE: This study examined systemic inflammatory indices and "Hemoglobin, Albumin, Lymphocyte, Platelet (HALP) scores" in neonates with hypoxic-ischemic encephalopathy (HIE). METHODS: A total of 43 neonates with moderate-to-severe HIE at 36 weeks' gestation were assessed. Systemic inflammatory markers were measured before HT commenced within 0-6 h after birth and between 60 and 72 h during and after therapy or before adjusting for hypothermia. RESULTS: Platelet counts, hemoglobin levels, and platelet indices in the HIE group were significantly lower at both time points (p = 0.001). Both the neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) decreased in the HIE group after hypothermia therapy (p = 0.001). Seizures, PVL, and kidney injuries were associated with higher HALP scores. The AUCs of NLR, PLR, MLR, SII, SIRI, and platelet, neutrophil, monocyte, and lymphocyte Index (PIV) showed significant sensitivity and specified HIE, with area under the curve (AUC) values of 0.654, 0.751, 0.766, 0.700, 0.722, and 0.749, respectively. CONCLUSIONS: A significant difference in systemic inflammatory markers was found between the HIE and control groups after hypothermia treatment, with significant reductions in the MLR and NLR. These markers, particularly MLR, were significant predictors of adverse clinical outcomes including seizures, PVL, and kidney damage.

Utilization of Synthetic Human Angiotensin II for Catecholamine-Resistant Vasodilatory Shock in Critically Ill Children: A Single-Center Retrospective Case Series.

OBJECTIVES: To describe our institutional experience utilizing adjunctive synthetic angiotensin II in critically ill children with catecholamine-resistant vasodilatory shock (CRVS). DESIGN: Single-center, retrospective case series. SETTING: PICU and cardiac ICU (CICU) at a large, quaternary children's hospital in the United States. PATIENTS: Twenty-three pediatric patients with CRVS who were prescribed synthetic angiotensin II at the discretion of bedside clinicians from January 2018 to April 2023. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twenty-three patients (20 in PICU, 3 in CICU) with a median age of 10.4 years (interquartile range [IQR] 1.5-18.5) received angiotensin II over the study period, 70% of whom died. At the time of angiotensin II initiation, 17 patients (74%) were receiving one or more forms of extracorporeal therapy, and median Pediatric Logistic Organ Dysfunction-2 Score-2 in the prior 24 hours was 9 (IQR 7-11). The median time between initiation of the first vasoactive agent and angiotensin II was 127 hours (IQR 13-289), and the median total norepinephrine equivalent (NED) at initiation was 0.65 µg/kg/min (IQR 0.36-0.78). The median duration of therapy was 27 hours (IQR 4-68), and at each timepoint assessed, patients had median improvement in NED and mean arterial pressure (MAP) with treatment. Survivors initiated angiotensin II nearly 3 days earlier in vasoactive course (91.5 hr vs 161 hr, p = 0.23), and had both greater reduction in NED (-75% [IQR -96 to -50] vs +2.1% [IQR -55 to 33], p = 0.008) and greater increase in MAP (+15 mm Hg [IQR 10-27] vs -1.5 mm Hg [IQR -27 to 18], p = 0.052) at angiotensin II discontinuation. CONCLUSIONS: We demonstrate reduction in NED and improved MAP following initiation of angiotensin II in critically ill children with CRVS. Further prospective work is needed to examine optimal timing of angiotensin II initiation, appropriate patient selection, and safety in this population.