Study design and study population
This was a prospective, observational study following the Helsinki Declaration and approved by the institutional review board. Patients older than 18 years who were admitted to the ICU of the Hospital de Clínicas, Montevideo, Uruguay, from October 1, 2018 to March 1, 2019 were included. Exclusion criteria were patients with ophthalmologic or periorbital pathology, including abnormal pupillary anatomy or neurologic assessment at baseline, or with facial or periorbital soft tissue edema that precluded eye opening, and therefore adequate IPA.
Upon admission to the ICU, consent was obtained from patients’ family members. Disease severity was determined following the Glasgow Coma Scale, and electronic medical records were reviewed to obtain demographics (age, gender, race), vital signs (heart rate, respiratory rate, blood pressure, temperature), and hemodynamic parameters (if any).
Non-invasive (minimal risk) ultrasonographic and infrared pupillary assessments were performed during same visit to the patient. Lights in patients’ room were turned off and windows and curtains were closed, thereby ensuring homogeny in rooms’ illumination regardless of time of the day.
Because UPA required manual measurement of pupillary diameter, we performed UPA first and then IPA, thereby reducing potential source of observer bias. The time frame between UPA and IPA was less than 3 min, during which there was no administration of new medications or physical maneuvers or activities on the patient. The examinations, both UPA and IPA, were performed at any time during ICU stay, by three authors (C.Y, S.P and M.L) who were experienced in UPA and IPA. On some patients, two or more pupillary examinations (UPA and IPA) were performed, each on different days while still in the ICU. The ultrasound and infrared devices and the information they yielded were used as standard of care; however, the devices themselves were not investigated.
Ultrasonographic pupillary assessment (UPA)
The ultrasonographic pupillary assessment included evaluation of bilateral pupillary diameter and pupillary light reflex. With the ultrasound machine on “small parts” preset and the patient in a supine, semi-recumbent position, a linear 7.5–15 MHz transducer was gently placed over the lower edge of the closed eye for a trans-palpebral tangential view, with the probe marker pointed toward the right side of the patient (Fig. 1).
Following FDA regulations for mechanical index and thermal index for ophthalmic ultrasound, we used values less than 0.23 for the mechanical index and less than 1.0 for the thermal index. Although we use the preset small parts, we lowered the mechanical index below 0.23 by changing the acoustic power.
Subsequent tilting movement of the probe was applied until the pupil is visualized. Then, on each eye at a time, over the closed eye and across the eyelid, a light stimulus was shown first ipsilateral to assess for direct pupillary light reflex. Only motion-mode (M-mode) ultrasonographic modality was used for the measurements (Fig. 2). The overall time for UPA per patient, including right and left eye, was never more than 3 min. Although the ultrasound machine is designed to produce minimal risk to the user and the patient, adverse events, such as eye discomfort, irritation, redness or pain, due to superficial pressure exerted by the transducer or due to eyelid and/or eye contact with the sonographic gel, if any, were documented.
Infrared pupillary assessment (IPA)
The infrared pupillary assessment included evaluation of bilateral pupillary diameter and pupillary light reflex. The infrared pupillometer is a monocular, stand-alone, hand-held, battery-operated instrument, which captures and analyzes the images in less than 3 s. When placed over the eye, the infrared pupillometer shows a light stimulus over the open eye in order to assess for the pupillary light reflex (Fig. 3). The overall time for IPA per patient, including right and left eye, was never more than 1 min. The infrared pupillometer machine is designed to produce minimal risk to the user and the patient. The only designated mechanical contact point with the patient is the headrest. All levels of radiation fall below threshold values recommended by the International Commission on Non-Ionizing Radiation Protection.
For both UPA and IPA, normal values of pupillary diameter were 2 to 4 mm. A pupillary diameter less than 2 mm was documented as miosis, whereas a pupillary diameter greater than 4 mm was documented as mydriasis. The pupillary light reflex was determined by the percentage of reduction in size of pupil diameter immediately after light stimuli. Such a light stimuli was given by the flashlight of a mobile phone model iPhone 6, iPhone 7, iPhone 8 or iPhone X, at an approximate distance of 8 to 12 cm from the eye, and at an angle of 90 degrees (i.e., perpendicular) to the coronal plane of the pupil, all of which have the same documented luminosity, regardless of remaining battery, according to Apple Inc. and were available to the research staff.
The reduction in pupillary diameter was calculated as follows: (maximum resting aperture − minimum aperture)/maximum resting aperture; where maximum resting aperture was the maximal pupillary diameter recorded before light stimuli was shown, minimum aperture was the minimal pupillary diameter recorded after light stimuli was shown. A normal pupillary light reflex was considered as percentage of reduction in size of pupil diameter after light stimuli of 10% or more according to a large study by Taylor et al. [7].
Statistical analysis
For the comparison between UPA and IPA, Bland–Altman and dispersion plots, simple linear regression models, and the Chi-square test were used. The Shapiro–Wilk test and Q–Q plots were used to corroborate normal distribution of the data. All calculations were done using the R programming language and statistical software (version 3.5.1).
