Defining the 'Hypothermia Resistant' phenotype in neonatal HIE: persistent multi-organ dysfunction on day 3 is the...

Therapeutic hypothermia (TH) reduces mortality in neonatal hypoxic-ischemic encephalopathy (HIE), yet nearly half of treated infants suffer adverse outcomes. This study aimed to define the "Hypothermia Resistance" phenotype by characterizing the 4-day trajectories of multi-organ dysfunction and identifying the physiological signals associated with severe MRI injury.

This retrospective cohort study included 24 term neonates with moderate-to-severe HIE treated with whole-body hypothermia. Patients were stratified into "Responder" (n = 18) and "Resistant" (n = 6) phenotypes based on systemic recovery patterns. Serial biomarkers (Lactate, Creatinine, AST, Platelets) were analyzed daily from Day 1 to Day 4. The primary outcome was brain injury severity on MRI assessed by the Weeke score.

Admission characteristics and Day 1 biomarkers were comparable between groups. However, trajectories diverged significantly by Day 3 (72 h). The Resistant phenotype was characterized by a failure to clear systemic dysfunction, manifesting as persistent renal impairment (Median Creatinine: 1.39 vs 0.65 mg/dL; p < 0.01) and worsening thrombocytopenia (Median Platelets: 114 vs 190 × 10³/µL; p < 0.05) at 72 h. This "Day 3 Cliff" profile (Creatinine >1.0 mg/dL combined with Platelets <120 × 10³/µL) was strongly associated with severe MRI injury (diffusion restriction in basal ganglia/thalamus).

Physiological recovery during cooling is a dynamic process. Persistent multi-organ dysfunction on Day 3 constitutes a "Hypothermia Resistance" profile that serves as a robust surrogate marker for ineffective neuroprotection, distinct from early severity markers.