The goal of this clinical trial is to explore whether different modes of mechanical ventilation affect pupillary constriction velocities in critically ill patients without brain injury. The study aims to determine whether the type of mechanical ventilation (volume control, pressure control, or pressure-regulated volume control) influences the maximum and mean constriction velocity measured by automated pupillometry. The trial also investigates whether changes in pupil dynamics reflect subtle alterations in brainstem-autonomic interaction induced by ventilation mode.

The comparison involves volume control, pressure control, and pressure-regulated volume control in a randomized crossover design to assess whether ventilation mode has a measurable effect on pupil response.

Eligible participants will be intubated ICU patients receiving assist control ventilation who are not yet ready for spontaneous breathing trials. Serial pupillometry measurements will be conducted while participants are ventilated with each mode for at least 15 minutes. Sedation and lighting conditions will remain consistent throughout the protocol. Participants with acute or chronic neurologic conditions or ventilator dyssynchrony will be excluded.

This is a prospective, randomized, crossover study designed to evaluate the effect of different modes of mechanical ventilation on pupillary constriction velocity in critically ill patients. Recent data suggest that even in the absence of direct pulmonary or neurologic injury, mechanical ventilation with positive pressure may impact brain function, possibly through vagal-brainstem-autonomic pathways. These effects may be subtle and difficult to detect with standard neurological examination but may be reflected in changes in the dynamic pupillary light reflex.

The pupillary light reflex (PLR), measured using automated infrared pupillometry, provides a quantitative, non-invasive assessment of brainstem and autonomic nervous system function. IThe investigators aim to determine whether the PLR, specifically, the mean and maximum constriction velocity, differs across three commonly used ventilation modes: Volume Control (VC), Pressure Control (PC), and Pressure-Regulated Volume Control (PRVC).

All included participants will be mechanically ventilated, sedated, and not yet candidates for spontaneous breathing trials. Exclusion criteria include any acute or chronic neurologic disorder or signs of ventilator dyssynchrony. Sedation regimens (e.g., propofol, remifentanil, dexmedetomidine) will be kept constant during the study, and ambient light will remain unchanged.

Each participant will undergo the three ventilation modes in a randomized order, with each mode applied for a minimum of 15 minutes to ensure washout before pupillometry measurements are performed. Physiological parameters such as respiratory rate, minute ventilation, FiO₂, heart rate, and mean arterial pressure will be recorded in parallel with pupil measurements. Blood gas analysis and full pupillometry data, including pupil size, constriction and dilation velocities, latency, and the Neurological Pupil Index (NPi), will also be collected.

The primary outcome is the difference in maximum pupillary constriction velocity between ventilation modes. Secondary outcomes include mean constriction velocity, NPi, and other pupillary metrics. Based on pilot data, a total of 36 participants are required to detect a significant difference in the primary outcome. Statistical analysis will include repeated measures ANOVA or the Friedman test, with post hoc Wilcoxon Signed-Rank testing as appropriate.

The findings of this study may provide support for the use of pupillometry as a tool to assess subtle CNS effects of mechanical ventilation and could support the theory of ventilation-brainstem interactions during mechanical ventilation.

Inclusion Criteria

• Adult patients (≥18 years old)
• Receiving positive-pressure mechanical ventilation
• Under light or no sedation (e.g., RASS score between -2 and 0)
• Clinically assessed by the treating physician as not yet ready for weaning from mechanical ventilation
• Hemodynamically stable at the time of measurement
• Presence of an arterial catheter in place for blood gas analysis
• Written informed consent obtained from the patient's legal representative Exclusion Criteria
• Acute or chronic neurological disease affecting brainstem function or pupillary responses
• Dyssynchrony with the ventilator or need for high ventilatory support adjustments
• Facial injuries, edema, or conditions precluding accurate pupillometry
• Use of neuromuscular blocking agents within the prior 6 hours
• Severe metabolic or acid-base imbalances that may influence autonomic regulation
• Concurrent participation in another interventional study that could affect neurological or autonomic outcomes

De-identified individual participant data (IPD) related to primary and secondary outcome measures will be made available to other researchers upon reasonable request, after publication of the main study results.

Beginning 6 months after publication of the primary manuscript and continuing for 3 years.

Access will be granted to qualified researchers for scientifically sound proposals. Requesters will need to submit a brief proposal outlining the purpose and methods of the secondary analysis.

The outcome assessor will be masked to the ventilation mode sequence applied during each pupillometry measurement. Pupillometry data will be anonymized and coded prior to statistical analysis to prevent bias in outcome evaluation.