State-dependent pupil dilation rapidly shifts visual feature selectivity.

To increase computational flexibility, the processing of sensory inputs changes with behavioural context. In the visual system, active behavioural states characterized by motor activity and pupil dilation1,2 enhance sensory responses, but typically leave the preferred stimuli of neurons unchanged2-9. Here we find that behavioural state also modulates stimulus selectivity in the mouse visual cortex in the context of coloured natural scenes. Using population imaging in behaving mice, pharmacology and deep neural network modelling, we identified a rapid shift in colour selectivity towards ultraviolet stimuli during an active behavioural state. This was exclusively caused by state-dependent pupil dilation, which resulted in a dynamic switch from rod to cone photoreceptors, thereby extending their role beyond night and day vision. The change in tuning facilitated the decoding of ethological stimuli, such as aerial predators against the twilight sky10. For decades, studies in neuroscience and cognitive science have used pupil dilation as an indirect measure of brain state. Our data suggest that, in addition, state-dependent pupil dilation itself tunes visual representations to behavioural demands by differentially recruiting rods and cones on fast timescales.

Pupillary Responses Reflect Dynamic Changes in Multiple Cognitive Factors During Associative Learning in Primates.

Associative learning involves complex interactions of multiple cognitive factors. While adult subjects can articulate these factors verbally, for model animals such as macaques, we rely on behavioral outputs. In our study, we used pupillary responses as an alternative measure to capture these underlying cognitive changes. We recorded the dynamic changes in the pupils of three male macaques when they learned the associations between visual stimuli and reward sizes under the classical Pavlovian experimental paradigm. We found that during the long-term learning process, the gradual changes in the pupillary response reflect the changes in the cognitive state of the animals. The pupillary response can be explained by a linear combination of components corresponding to multiple cognitive factors. These components reflect the impact of visual stimuli on the pupils, the prediction of reward values associated with the visual stimuli, and the macaques' understanding of the current experimental reward rules. The changing patterns of these factors during interday and intraday learning clearly demonstrate the enhancement of current reward-stimulus association and the weakening of previous reward-stimulus association. Our study shows that the dynamic response of pupils can serve as an objective indicator to characterize the psychological changes of animals, understand their learning process, and provide important tools for exploring animal behavior during the learning process.

Failed remyelination of the nonhuman primate optic nerve leads to axon degeneration, retinal damages, and visual dysfunction.

White matter disorders of the central nervous system (CNS), such as multiple sclerosis (MS), lead to failure of nerve conduction and long-lasting neurological disabilities affecting a variety of sensory and motor systems, including vision. While most disease-modifying therapies target the immune and inflammatory response, the promotion of remyelination has become a new therapeutic avenue to prevent neuronal degeneration and promote recovery. Most of these strategies have been developed in short-lived rodent models of demyelination, which spontaneously repair and do not reflect the size, organization, and biology of the human CNS. Thus, well-defined nonhuman primate models are required to efficiently advance therapeutic approaches for patients. Here, we followed the consequence of long-term toxin-induced demyelination of the macaque optic nerve on remyelination and axon preservation, as well as its impact on visual functions. Findings from oculomotor behavior, ophthalmic examination, electrophysiology, and retinal imaging indicate visual impairment involving the optic nerve and retina. These visual dysfunctions fully correlated at the anatomical level, with sustained optic nerve demyelination, axonal degeneration, and alterations of the inner retinal layers. This nonhuman primate model of chronic optic nerve demyelination associated with axonal degeneration and visual dysfunction, recapitulates several key features of MS lesions and should be instrumental in providing the missing link to translate emerging repair promyelinating/neuroprotective therapies to the clinic for myelin disorders, such as MS.

Evidence of the protective role of Carvacrol in a retinal degeneration animal model.

Neurodegenerative pathologies affecting the posterior segment of the eye, are characterized by being devastating and responsible for the majority of visual dysfunctions worldwide. These diseases are primarily degenerative, progressing chronically, and can inflict gradual harm to the optic nerve, retinal ganglion cells (RGC), photoreceptors, and other retinal cells. This retinal damage leads to a progressive loss of vision, marking these conditions as a significant health concern worldwide. The intravitreal administration of the phytochemical Carvacrol (CAR) is expected to demonstrate a neuroprotective and antiapoptotic effect on retinal cells, with a specific focus on RGC. This effect will be observed in a retinal degeneration model (RDM) in rabbits induced by cytotoxic and oxidative agents, namely glutamate (GLUT) and L-buthionine-S, R-sulfoximine (BSO). An in vivo study was conducted using New Zealand rabbits in which retinal damage was created to evaluate the effectiveness of CAR. The effectiveness of CAR on the functionality of retinal neuronal cells in RDM was evaluated using pupillary light reflection (PLR). Furthermore, the phytotherapeutic's influence on cell viability was determined through flow cytometry analysis. Finally, the neuroprotective and antiapoptotic capabilities of CAR were specifically scrutinized in RGC through histological studies, quantifying cell survival, and employing immunohistochemical assays to detect the apoptotic index (%) using the TUNEL technique. Our results demonstrated that CAR promoted the recovery of the pupillary contraction profile over time, maintaining the functionality of retinal cells as healthy controls. Additionally, it showed increased cell viability under oxidative and cytotoxic conditions given by GLUT-BSO agents. Finally, we found that CAR protects the survival of RGC and decreases the percentage of apoptotic cells when compared to RDM. CAR demonstrated to have positive effects on the functionality of photoreceptive nerve cells by restoring pupillary contraction. Likewise, it was shown to have neuroprotective and antiapoptotic effects when evaluated in a general and specific way on retinal nerve cells.

Changes in Listening Effort Through Pupil Response After Atresioplasty in Children With Congenital Aural Atresia.

OBJECTIVES: This study aimed to determine whether the improvement of hearing by surgical treatment alleviates cognitive demands through pupil response in patients with unilateral congenital aural atresia (CAA). DESIGN: A prospective study was performed on patients with unilateral CAA who were scheduled to undergo primary atresioplasty between November 2017 and May 2020. Pure-tone audiometry, auditory digit span test, Korean Speech Perception in Noise test, pupil measurement during speech tests, and questionnaires (Sound-Spatial-Qualities of Hearing Scale; subjective listening effort rating) were performed before and 6 months after surgery. RESULTS: Of 30 consecutive patients who initially enrolled, only 18 patients (12 males and 6 females) were included in the analysis. When the improvement of the air-bone gap and interaural difference of air conduction within 30 dB was defined as a successful hearing outcome, successful hearing improvement was achieved in 50% of the 18 patients. In pupil measurement, the success group had a significantly smaller mean pupil dilation response than the nonsuccess group at 0 and -3 dB signal to noise ratio (SNR) (all p < 0.01). In addition, significant differences were identified between the two groups for peak dilation and peak latency at all noise levels (all p < 0.01). When analyzing the change in pupil response before and after surgery, the difference in relative mean pupil dilation in the success group was significantly greater than that in the nonsuccess group at -3 dB SNR ( p = 0.02). In addition, the success group showed a significantly greater change in peak latency than the nonsuccess group at the -3 dB SNR ( p < 0.01). The difference in peak dilation tended to be greater in the success group than in the nonsuccess group, but the difference was not statistically significant. CONCLUSIONS: Patients with unilateral CAA who achieved surgically improved hearing had a smaller pupil dilation response than those who did not. These results suggest that successful hearing outcomes after surgery in patients with unilateral CAA may reduce the cognitive effort required to understand speech under difficult listening conditions.

The use of quantitative pupillometry in brain death determination: preliminary findings.

PURPOSE: Quantitative pupillometry (QP) has been increasingly applied in neurocritical care as an easy-to-use and reliable technique for evaluating the pupillary light reflex (PLR). Here, we report our preliminary findings on using QP for clinical brain death (BD) determination. MATERIALS: This retrospective study included 17 patients ≥ 18 years (mean age, 57.3 years; standard deviation, 15.8 years) with confirmed BD, as defined by German Guidelines for the determination of BD. The PLR was tested using the NPi®-200 Pupillometer (Neuroptics, Laguna Hill, USA), a handheld infrared device automatically tracking and analyzing pupil dynamics over 3 s. In addition, pupil diameter and neurological pupil index (NPi) were also evaluated. RESULTS: Intracerebral bleeding, subarachnoid hemorrhage, and hypoxic encephalopathy were the most prevalent causes of BD. In all patients, the NPi was 0 for both eyes, indicating the cessation of mid-brain function. The mean diameter was 4.9 mm (± 1.3) for the right pupil and 5.2 mm (±1.2) for the left pupil. CONCLUSIONS: QP is a valuable tool for the BD certification process to assess the loss of PLR due to the cessation of brain stem function. Furthermore, implementing QP before the withdrawal of life-sustaining therapy in brain-injured patients may reduce the rate of missed organ donation opportunities. Further studies are warranted to substantiate the feasibility and potential of this technique in treating patients and identify suitable candidates for this technique during the BD certification process.

Analysis of pupillary responses in pediatric patients with vitamin D deficiency.

PURPOSE: To evaluate the effects of vitamin D deficiency on pupillary responses in the pediatric population. METHODS: The study was conducted using data from the right eyes of 52 children with vitamin D deficiency and 52 healthy children. Measurements were taken under static and dynamic conditions with automatic pupillometry. Static measurements were performed at scotopic, mesopic, and photopic light intensities. The mean pupil dilation speed was calculated by observing the changes in pupil dilation over time according to dynamic measurements. Differences between patient and control groups were analyzed for the static and dynamic measurements and the mean pupil dilation speed. RESULTS: While the two groups were similar in terms of scotopic, mesopic, the first dynamic measurements, and the pupil dilation speed data (p > 0.05), a significant difference was found in the photopic conditions (p = 0.001). The mean pupil diameter of the patient group was 4.46 ± 0.928 mm and 3.95 ± 0.556 mm in the control group under photopic conditions. CONCLUSIONS: Pediatric patients with vitamin D deficiency have significantly larger pupil diameters in photopic conditions than healthy children. These results suggest that there is an autonomic dysfunction in vitamin D deficiency in the pediatric population, especially pointing to the parasympathetic system.

High-speed eye tracking based on a synchronized imaging mechanism by a dual-ring infrared lighting source.

It is a challenge for conventional monocular-camera single-light source eye-tracking methods to achieve high-speed eye tracking. In this work, a dual-ring infrared lighting source was designed to achieve bright and dark pupils in high speed. The eye-tracking method used a dual-ring infrared lighting source and synchronized triggers for the even and odd camera frames to capture bright and dark pupils. A pupillary corneal reflex was calculated by the center coordinates of the Purkinje spot and the pupil. A map function was established to map the relationship between the pupillary corneal reflex and gaze spots. The gaze coordinate was calculated based on the mapping function. The average detection time of each gaze spot was 3.76 ms.

Altered pupil light and darkness reflex and eye-blink responses in late-life depression.

BACKGROUND: Late-life depression (LLD) is a prevalent neuropsychiatric disorder in the older population. While LLD exhibits high mortality rates, depressive symptoms in older adults are often masked by physical health conditions. In younger adults, depression is associated with deficits in pupil light reflex and eye blink rate, suggesting the potential use of these responses as biomarkers for LLD. METHODS: We conducted a study using video-based eye-tracking to investigate pupil and blink responses in LLD patients (n = 25), older (OLD) healthy controls (n = 29), and younger (YOUNG) healthy controls (n = 25). The aim was to determine whether there were alterations in pupil and blink responses in LLD compared to both OLD and YOUNG groups. RESULTS: LLD patients displayed significantly higher blink rates and dampened pupil constriction responses compared to OLD and YOUNG controls. While tonic pupil size in YOUNG differed from that of OLD, LLD patients did not exhibit a significant difference compared to OLD and YOUNG controls. GDS-15 scores in older adults correlated with light and darkness reflex response variability and blink rates. PHQ-15 scores showed a correlation with blink rates, while MoCA scores correlated with tonic pupil sizes. CONCLUSIONS: The findings demonstrate that LLD patients display altered pupil and blink behavior compared to OLD and YOUNG controls. These altered responses correlated differently with the severity of depressive, somatic, and cognitive symptoms, indicating their potential as objective biomarkers for LLD.

The value of pupillary diameter in evaluating pain perception after awakening in patients undergoing general anesthesia during orthopedic surgery.

BACKGROUND: The pupillary response to tetanic electrical stimulation reflects the balance between nociceptive stimulation and analgesia. Although pupillary pain index (PPI) was utilized to predict postoperative pain, it depended on tetanic stimulation and was complex. We aim to describe the potential relationship between PD in the presence of surgical stimulation and pain levels after awakening. METHODS: According to the Verbal Rating Scale (VRS) score after extubation, the patients were divided into painless group (VRS = 0) and pain group (VRS ≥ 1). Pupillary diameter (PD) and pupillary light reflex velocity (PLRV) were compared between two groups when patients entered the operating room (T1), before incision (T2), 10 s after incision (T3), 30 s after incision (T4), 1 h after incision (T5), at the end of surgery (T6), shortly after extubation (T7), and when patients expressed pain clearly (T8). The magnitude of PD change (ΔPD) compared to the baseline value after anesthesia induction (T2) was calculated. The correlations between pupillary parameters and pain after awakening were calculated. RESULTS: Patients with VRS ≥ 1 had greater PD than painless patients at T3-7 (P = 0.04, 0.04, 0.003, <0.001, <0.001), and it was positively correlated with VRS score after awakening at T4-7 (r = 0.188, 0.217, 0.684, 0.721). The ability of T6ΔPD to predict VRS ≥ 1 was strong [threshold: 20.53%, area under the curve (AUC): 0.93, 95% confidence interval (CI): 0.89-0.97 ]. CONCLUSION: Our study indicates that PD is a useful index to direct the individualized analgesics used during operation, to better avoid the occurrence of pain during the postoperative emergence period. TRIAL REGISTRATION: This study was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR2000040908, registration date: 15/12/2020).

Utility of iPhone-Based Pupillometry in Comparing Pupillary Dynamics Between Sport Concussed Subjects With Photosensitivity and Healthy Controls.

BACKGROUND: To compare the pupillary dynamics using an iPhone-based pupillometry technique in subjects with sports concussion with photosensitivity and aged-matched controls. METHODS: Fifty subjects with sports concussion were compared with 50 aged-matched healthy controls. Athletes with persistent concussive symptoms for 1 year or more after the initial injury were included. All the subjects underwent a Post-Concussion Symptom Scale (PCSS) administration followed by pupillary dynamics measurement using an iPhone-based application (Reflex-Pro PLR analyzer). RESULTS: The mean age was 27 ± 4 years in the concussed group and 26 ± 5 years in the control group. In subjects with concussion, there was a significant decrease in the mean of the following parameters: average constriction speed (1.10 ± 0.15 vs 1.78 ± 0.12 mm/s; P < 0.001), maximum constriction speed (2.05 ± 0.26 vs 3.84 ± 0.28 mm/s; P < 0.001), average diameter (3.64 ± 0.12 vs 0.36 ± 0.05 mm; P < 0.001), maximum diameter (4.75 ± 0.17 vs 5.23 ± 0.16 mm; P < 0.001), and minimum diameter (2.75 ± 0.17 vs 3.64 ± 0.11 mm; P < 0.001). An increase in the following parameters was noted in concussion vs age-matched controls: dilation release amplitude (0.54 ± 0.96 vs 0.36 ± 0.05 mm; P < 0.001) and latency (0.25 ± 0.05 vs 0.21 ± 0.02 s; P < 0.001). Subjects with concussion with photosensitivity exhibited increased dilation release amplitudes ( P < 0.001). CONCLUSIONS: Individuals with sport concussion had impairment in pupillary constriction velocities, latency, and diameter in more than 1 year after concussion. The increase in dilation release amplitude among subjects with concussion might serve as a biomarker in diagnosing the underlying symptom of photosensitivity. The iPhone-based pupillometry could serve as a convenient and diagnostic tool in diagnosing these symptoms.

Feasibility of USG-Guided Objective Initial Assessment of Pupillary Size and Pupillary Reflexes Versus Clinical Examination in Patients With Altered Mental Status: A Cross-Sectional Study.

BACKGROUND: Pupillary assessment is an important part of the neurological assessment which provides vital information in critically ill patients. However, clinical pupillary assessment is subjective. The ultrasound-guided pupillary examination is objective. There are limited pieces of literature regarding its use in assessing patients with altered mental status. So, we studied the extent of agreement of B-mode ultrasound with clinical examination for assessment of the pupillary size and reflex in patients with altered mental status. OBJECTIVES: The primary objective was to determine the extent of agreement between clinical examination and ultrasound-based examination for assessing pupillary reflex and size in patients with altered mental status in two settings (trauma and non-trauma patients). METHODS: Exactly 200 subjects (158 males, mean [range] age 43.56 [18-92 years]) with no history of partial globe rupture or dementia were included in this cross-sectional study from March 2019 to March 2020. B-mode ultrasound was performed with the subject's eyes closed using a 7-12 MHz linear probe and a standardized light stimulus. ICC score, paired t-test, kappa, Wilcoxon signed-rank test, and Bland-Altman plots were used for statistical analysis. RESULTS: The clinical-USG agreement for pupillary light reflex examination (Pupillary Diameter [PD] at rest, after direct light stimulation [Dstim ] and consensual light stimulation [Cstim ]) was excellent (ICC, 0.93-0.96). The Kappa coefficient (0.74 ± 0.07) showed an agreement of 87.36% between clinical and USG examination for pupillary reflex (reactive or non-reactive). CONCLUSION: USG-guided pupillary examination proves to be a better adjunct to neurological assessment in patients with altered mental status.

Quantitative pupillometry as a biomarker for prediction of return to play in mild traumatic brain injury: a Military Traumatic Brain Injury Initiative study.

OBJECTIVE: This study aimed to determine the validity of quantitative pupillometry to predict the length of time for return to full activity/duty after a mild traumatic brain injury (mTBI) in a cohort of injured cadets at West Point. METHODS: Each subject received baseline (T0) quantitative pupillometry, in addition to evaluation with the Balance Error Scoring System (BESS), Standardized Assessment of Concussion (SAC), and Sport Concussion Assessment Tool 5th Edition Symptom Survey (SCAT5). Repeat assessments using the same parameters were conducted within 48 hours of injury (T1), at the beginning of progressive return to activity (T2), and at the completion of progressive return to activity protocols (T3). Pupillary metrics were compared on the basis of length of time to return to full play/duty and the clinical scores. RESULTS: The authors' statistical analyses found correlations between pupillometry measures at T1, including end-initial diameter and maximum constriction velocity, with larger change and faster constriction predicting earlier return to play. There was also an association with maximum constriction velocity at baseline (T0), predicting faster return to play. CONCLUSIONS: The authors conclude that that pupillometry may be a valuable tool for assessing time to return to duty from mTBI by providing a measure of baseline resiliency to mTBI and/or autonomic dysfunction in the acute phase after mTBI.

Quantitative Pupillometry for Intracranial Pressure (ICP) Monitoring in Traumatic Brain Injury: A Scoping Review.

The neurological examination has remained key for the detection of worsening in neurocritical care patients, particularly after traumatic brain injury (TBI). New-onset, unreactive anisocoria frequently occurs in such situations, triggering aggressive diagnostic and therapeutic measures to address life-threatening elevations in intracranial pressure (ICP). As such, the field needs objective, unbiased, portable, and reliable methods for quickly assessing such pupillary changes. In this area, quantitative pupillometry (QP) proves promising, leveraging the analysis of different pupillary variables to indirectly estimate ICP. Thus, this scoping review seeks to describe the existing evidence for the use of QP in estimating ICP in adult patients with TBI as compared with invasive methods, which are considered the standard practice. This review was conducted in accordance with the Joanna Briggs Institute methodology for scoping reviews, with a main search of PubMed and EMBASE. The search was limited to studies of adult patients with TBI published in any language between 2012 and 2022. Eight studies were included for analysis, with the vast majority being prospective studies conducted in high-income countries. Among QP variables, serial rather than isolated measurements of neurologic pupillary index, constriction velocity, and maximal constriction velocity demonstrated the best correlation with invasive ICP measurement values, particularly in predicting refractory intracranial hypertension. Neurologic pupillary index and ICP also showed an inverse relationship when trends were simultaneously compared. As such, QP, when used repetitively, seems to be a promising tool for noninvasive ICP monitoring in patients with TBI, especially when used in conjunction with other clinical and neuromonitoring data.

Covert Consciousness in Acute Brain Injury Revealed by Automated Pupillometry and Cognitive Paradigms.

BACKGROUND: Identifying covert consciousness in intensive care unit (ICU) patients with coma and other disorders of consciousness (DoC) is crucial for treatment decisions, but sensitive low-cost bedside markers are missing. We investigated whether automated pupillometry combined with passive and active cognitive paradigms can detect residual consciousness in ICU patients with DoC. METHODS: We prospectively enrolled clinically low-response or unresponsive patients with traumatic or nontraumatic DoC from ICUs of a tertiary referral center. Age-matched and sex-matched healthy volunteers served as controls. Patients were categorized into clinically unresponsive (coma or unresponsive wakefulness syndrome) or clinically low-responsive (minimally conscious state or better). Using automated pupillometry, we recorded pupillary dilation to passive (visual and auditory stimuli) and active (mental arithmetic) cognitive paradigms, with task-specific success criteria (e.g., ≥ 3 of 5 pupillary dilations on five consecutive mental arithmetic tasks). RESULTS: We obtained 699 pupillometry recordings at 178 time points from 91 ICU patients with brain injury (mean age 60 ± 13.8 years, 31% women, and 49.5% nontraumatic brain injuries). Recordings were also obtained from 26 matched controls (59 ± 14.8 years, 38% women). Passive paradigms yielded limited distinctions between patients and controls. However, active paradigms enabled discrimination between different states of consciousness. With mental arithmetic of moderate complexity, ≥ 3 pupillary dilations were seen in 17.8% of clinically unresponsive patients and 50.0% of clinically low-responsive patients (odds ratio 4.56, 95% confidence interval 2.09-10.10; p < 0.001). In comparison, 76.9% healthy controls responded with ≥ 3 pupillary dilations (p = 0.028). Results remained consistent across sensitivity analyses using different thresholds for success. Spearman's rank analysis underscored the robust association between pupillary dilations during mental arithmetic and consciousness levels (rho = 1, p = 0.017). Notably, one behaviorally unresponsive patient demonstrated persistent command-following behavior 2 weeks before overt signs of awareness, suggesting prolonged cognitive motor dissociation. CONCLUSIONS: Automated pupillometry combined with mental arithmetic can identify cognitive efforts, and hence covert consciousness, in ICU patients with acute DoC.

Illusory light drives pupil responses in primates.

In humans, the eye pupils respond to both physical light sensed by the retina and mental representations of light produced by the brain. Notably, our pupils constrict when a visual stimulus is illusorily perceived brighter, even if retinal illumination is constant. However, it remains unclear whether such perceptual penetrability of pupil responses is an epiphenomenon unique to humans or whether it represents an adaptive mechanism shared with other animals to anticipate variations in retinal illumination between successive eye fixations. To address this issue, we measured the pupil responses of both humans and macaque monkeys exposed to three chromatic versions (cyan, magenta, and yellow) of the Asahi brightness illusion. We found that the stimuli illusorily perceived brighter or darker trigger differential pupil responses that are very similar in macaques and human participants. Additionally, we show that this phenomenon exhibits an analogous cyan bias in both primate species. Beyond evincing the macaque monkey as a relevant model to study the perceptual penetrability of pupil responses, our results suggest that this phenomenon is tuned to ecological conditions because the exposure to a "bright cyan-bluish sky" may be associated with increased risks of dazzle and retinal damages.

Nursing insights on the effectiveness of automated pupillometry in two distinct pediatric intensive care units.

PURPOSE: Automated pupillometry (AP) facilitates objective pupillary assessment. In this study, we aimed at assessing nursing perspective about the utility of AP in neurocritically ill children to understand acceptance and usage barriers to guide development of a standardized use protocol. METHODS: We conducted a web-based, cross-sectional, anonymous, Google™ survey of nurses at two independent pediatric ICUs which have been using AP over last four years. The survey included questions related to user-friendliness, barriers, acceptance, frequency of use, and method of documenting AP findings. RESULTS: A total of 31 nurses responded to the survey. A total of 25 nurses (80.6%) used the automated pupillometer and 19 (61.3%) nurses preferred to use the automated pupillometer on critically ill intubated patients. Respondents rated the pupillometer a median [IQR] frequency of use of 7/10 [4-9] and a mean user-friendliness of 8/10 [7-10]. Barriers to pupillometer use included pupillometer unavailability, technical issues, lack of perceived clinical significance, and infection control. CONCLUSION: Nurses have widely adopted the use of automated pupillometer in the PICU especially for critically ill intubated patients and rate it favorably for user-friendliness. Barriers against its use include limited resources, infection concerns, technical issues, and a lack of perceived clinical significance and training. Implementation of standardized PICU protocol for AP usage in critically ill children, may enhance the acceptance, increase usage and aid in objective assessments. PRACTICE IMPLICATIONS: These findings can be used to create a standardized protocol on implementing automated pupillometry in the PICU for critically ill children.

Smartphone pupillometry for detection of cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

OBJECTIVES: Vasospasm is a complication of aneurysmal subarachnoid hemorrhage (aSAH) that can change the trajectory of recovery and is associated with morbidity and mortality. Earlier detection of vasospasm could improve patient outcomes. Our objective is to evaluate the accuracy of smartphone-based quantitative pupillometry in the detection of radiographic vasospasm and delayed cerebral ischemia (DCI) after aSAH. MATERIALS AND METHODS: We prospectively collected pupillary light reflex (PLR) parameters from patients with aSAH admitted to a neurocritical care unit at a single hospital twice daily using quantitative smartphone pupillometry recordings. PLR parameters included: Maximum pupil diameter, minimum pupil diameter, percent change in pupil diameter, latency in beginning of pupil constriction to light, mean constriction velocity, maximum constriction velocity, and mean dilation velocity. Two-tailed t-tests for independent samples were performed to determine changes in average concurrent PLR parameter values between the following comparisons: (1) patients with and without radiographic vasospasm (defined by angiography with the need for endovascular intervention) and (2) patients with and without DCI. RESULTS: 49 subjects with aSAH underwent 323 total PLR recordings. For PLR recordings taken with (n=35) and without (n=241) radiographic vasospasm, significant differences were observed in MIN (35.0 ± 7.5 pixels with vasospasm versus 31.6 ± 6.2 pixels without; p=0.002). For PLR recordings taken with (n=43) and without (n=241) DCI, significant differences were observed in MAX (48.9 ± 14.3 pixels with DCI versus 42.5 ± 9.2 pixels without; p<0.001). CONCLUSIONS: Quantitative smartphone pupillometry has the potential to be used to detect radiographic vasospasm and DCI after aSAH.

The pupillary dilation reflex to a nociceptive stimulus as a tool for analgesia management: A diagnostic study.

BACKGROUND: More than 70% of patients demonstrate pain after endotracheal aspiration. Tools are needed to objectify the need for analgesia in non-communicative critically ill patients. OBJECTIVE: The objective of this study was to identify the lowest intensity electrical stimulus for detecting pain before daily care interventions. METHODS: Study of diagnostic tests to assess pupillometry to detect pain through the pupillary dilation response to noxious stimuli versus the Behavioural Pain Scale. Patients older than 18 years, under analgosedation, subjected to invasive ventilation, baseline Behavioural Pain Scale of 3, and Richmond Agitation-Sedation Scale between -1 and -4 were studied. We assessed the Behavioural Pain Scale and the pupillary dilation response to 10, 20, 30, and 40 mA stimuli. We studied the diagnostic performance based on sensitivity and specificity, negative predictive value, positive predictive value, and accuracy of the selected points after the different stimulations. AlgiScan® Pupillometer measured the pupillary dilation response. The presence of pain was considered as a Behavioural Pain Scale score of ≥4. Significance was defined as p <0.05. RESULTS: Measurements were performed on 31 patients. In the 20 mA stimulus, we found an area under the curve of 0.85 (0.69-1.0). The cut-off point of pupillary dilation was 11.5%, with a sensitivity of 100% (34.2-100) and a specificity of 75.9% (57.9-87.8). This point had an accuracy of 77.4 (60.2-88.6) and a Youden's Index of 0.8. CONCLUSIONS: Pupillary variation measurement during a 20 mA stimulus could help assess the need for analgesia before potentially painful interventions. Further studies are needed to confirm this. REGISTRATION: Phase 1 of the project PUPIPAIN ClinicalTrials.gov Identifier: NCT04078113.

Nociception assessment with videopupillometry in deeply sedated intensive care patients: Discriminative and criterion validations.

BACKGROUND: Nociceptive assessment in deeply sedated patients is challenging. Validated instruments are lacking for this unresponsive population. Videopupillometry is a promising tool but has not been established in intensive care settings. AIM/OBJECTIVE: To test the discriminate validity of pupillary dilation reflex (PDR) between non-noxious and noxious procedures for assessing nociception in non-neurological intensive care unit (ICU) patients and to test the criterion validity of pupil dilation using recommended PDR cut-off points to determine nociception. METHODS: A single-centre prospective observational study was conducted in medical-surgical ICU patients. Two independent investigators performed videopupillometer measurements during a non-noxious and a noxious procedure, once a day (up to 7 days), when the patient remained deeply sedated (Richmond Agitation-Sedation Scale score: -5 or -4). The non-noxious procedures consisted of a gentle touch on each shoulder and the noxious procedures were endotracheal suctioning or turning onto the side. Bivariable and multivariable general linear mixed models were used to account for multiple measurements in same patients. Sensitivity and specificity, and areas under the curve of the receiver operating characteristic curve were calculated. RESULTS: Sixty patients were included, and 305 sets of 3 measurements (before, during, and after), were performed. PDR was higher during noxious procedures than before (mean difference between noxious and non-noxious procedures = 31.66%). After testing all variables of patient and stimulation characteristics in bivariable models, age and noxious procedures were kept in the multivariable model. Adjusting for age, noxious procedures (coefficient = -15.14 (95% confidence interval = -20.17 to -15.52, p < 0.001) remained the only predictive factor for higher pupil change. Testing recommended cut-offs, a PDR of >12% showed a sensitivity of 65%, and a specificity of 94% for nociception prediction, with an area under the receiver operating curve of 0.828 (95% confidence interval = 0.779-0.877). CONCLUSIONS: In conclusion, PDR is a potentially appropriate measure to assess nociception in deeply sedated ICU patients, and we suggest considering its utility in daily practices. REGISTRATION: This study was not preregistered in a clinical registry. TWEETABLE ABSTRACT: Pupillometry may help clinicians to assess nociception in deeply sedated ICU patients.