Dynamic Trajectories of Pupillary Light Reflex Parameters and Prognosis in Critically Ill Patients: A Multicenter Prospective Cohort Study (PUPIL)

Critically ill patients admitted to emergency intensive care units often have complex underlying conditions, rapid changes in disease severity, fluctuating organ function, and multiple therapeutic influences. Conventional assessment tools, including vital signs, Glasgow Coma Scale, RASS, CPOT, APACHE II, laboratory tests, and imaging examinations, are important in clinical practice but may be limited by subjectivity, intermittent availability, or reduced reliability in patients receiving sedation, analgesia, mechanical ventilation, or organ support.

The pupillary light reflex is a classic component of neurological examination. Automated quantitative pupillometry provides objective and reproducible measurements of pupillary light reflex parameters, including pupil diameter, constriction velocity, dilation velocity, constriction percentage, maximum constriction velocity, and latency. These parameters may reflect brainstem reflex function, autonomic nervous system activity, medication effects, pain, circulatory status, and systemic stress responses in critically ill patients.

This study will enroll adult critically ill patients admitted to participating emergency intensive care units. After written informed consent is obtained from the participant or a legally authorized representative, baseline demographic data, primary diagnosis, disease severity scores, treatment information, organ support, sedation and analgesia status, vasoactive medication use, and vital signs will be collected. Pupillary light reflex parameters will be measured using a handheld automated quantitative pupillometer once daily during the first 7 days after EICU admission, or until EICU discharge or death, whichever occurs first. Additional measurements may be performed when clinically indicated.

The primary analysis will focus on the dynamic trajectory of constriction velocity during the early EICU period. Dilation velocity, pupil diameter, constriction percentage, maximum constriction velocity, and latency will be analyzed as supplementary pupillary light reflex parameters. Group-based trajectory modeling will be used to identify distinct longitudinal trajectory patterns of pupillary light reflex parameters.

The primary outcome is 90-day functional outcome assessed by the Glasgow Outcome Scale-Extended. Unfavorable functional outcome is defined as a GOS-E score of 4 or lower, and death during follow-up will be included in the GOS-E scoring system. The secondary outcome is discharge outcome, which will be analyzed primarily as a binary outcome. Favorable discharge outcome is defined as discharge home or transfer to a rehabilitation facility. Unfavorable discharge outcome is defined as in-hospital death, discharge to hospice or long-term care facility, or discharge against medical advice. Transfer to a higher-level hospital or another medical institution for continued treatment will be recorded as an indeterminate disposition and further followed when feasible.

This study will further evaluate whether dynamic trajectories of pupillary light reflex parameters provide additional prognostic value beyond conventional static measurements and clinical variables. No treatment assignment or intervention will be performed as part of this study. All clinical management decisions will be made by the treating physicians according to routine clinical practice.