Propofol-associated Hypertriglyceridemia: a mechanistic and causal inference analysis - PROJECT SUMMARY/ABSTRACT Propofol-associated hypertriglyceridemia (P-HTG), defined as triglycerides ≥400 mg/dL, affects over 150,000 critically ill patients annually receiving first-line propofol sedation during mechanical ventilation. Recent work highlights that P-HTG is not merely a laboratory abnormality but a multi-system clinical syndrome: patients experience 49% increased mortality risk, 36% increased venous thromboembolism rates, and timing-dependent outcomes where early P-HTG (≤48h) doubles mortality risk. Despite this clinical impact, fundamental uncertainty pervades current practice – triglyceride monitoring occurs in only 25% of patients through ad-hoc testing, yet 70% of clinicians reflexively modify sedation within hours of P-HTG detection, predominantly switching to second-line agents with well-documented adverse effects including increased delirium and prolonged mechanical ventilation. No evidence-based guidance exists to inform critical decisions about how to monitor for or manage P-HTG, creating an urgent knowledge gap affecting thousands of patients daily. This comprehensive investigation will transform P-HTG from an inconsistently monitored laboratory value to a well-characterized clinical syndrome with evidence-based approaches to prediction, monitoring, and management through three synergistic specific aims. Specific Aim 1 establishes a prospective observational cohort with systematic triglyceride monitoring and comprehensive lipoprotein phenotyping to define P-HTG epidemiology, distinguish clearance-defect from production-excess mechanisms, and determine causal pathways linking propofol exposure to adverse outcomes. Specific Aim 2 develops a dynamic risk stratification system incorporating baseline triglycerides and time-varying features (cumulative propofol exposure, evolving clinical status) to achieve clinically actionable performance (AUC >0.85, sensitivity >0.80, specificity >0.70), enabling rational triglyceride monitoring and predictive enrichment for future intervention trials. Specific Aim 3 conducts comparative effectiveness analysis using target trial emulation in over 1,000 P-HTG patients, comparing propofol continuation versus sedation modification strategies on patient-centered outcomes (ventilator-free days, mortality, delirium), complemented by regression discontinuity analysis. This research addresses critical clinical decision-making gaps through rigorous epidemiologic investigation with systematic baseline triglyceride assessment, mechanistic phenotyping enabling precision therapeutic approaches, state-of-the-art causal inference methodology, and interdisciplinary collaboration combining critical care clinician-scientists, causal inference methodologists, and lipid metabolism experts. Findings will establish whether P-HTG is causally related to adverse outcomes, and whether reflexive sedation switching creates greater harm than continued propofol. This work will provide evidence-based guidance that transforms current inconsistent practice, improving the care for 600,000 mechanically ventilated patients annually.
