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York, Rahman, and Bauerschmidt: Use of quantitative pupillometry in the neuro intensive care unit setting
Review Article

J Neurocrit Care 2025;18(2):41-51.

Published online: 24 December 2025

DOI: https://doi.org/10.18700/jnc.250020

Use of quantitative pupillometry in the neuro intensive care unit setting

Alizabeth York, BS1, *, Farial Rahman, BSPH1, *, Andrew Bauerschmidt, MD1, 2

1New York Medical College, Valhalla, NY, USA

2Department of Neurology, Westchester Medical Center, Valhalla, NY, USA

Corresponding Author: Andrew Bauerschmidt, MD Department of Neurology, Westchester Medical Center, 100 Woods Rd, Valhalla, NY 10595, USA Tel: +1-516-376-7920, Email: Andrew.bauerschmidt@wmchealth.org

* These authors contributed equally to this work as co-first authors.

Received 15 July 2025       Revised 30 September 2025       Accepted 14 November 2025

© 2025 The Korean Neurocritical Care Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Since the early second century, the pupillary light response (PLR) has been utilized in neurological examinations to gain insight into patient conditions and neuroprognostication. Traditionally, manual pupillometry has been employed to evaluate PLRs. However, this method is subjective and exhibits low interexaminer consistency and reliability. The advent of quantitative pupillometry (QP) has provided clinicians with an objective and reliable method to evaluate and standardize pupillary metrics, most notably, the Neurological Pupil index (NPi). QP protocols have been instituted in many neuro intensive care units (ICUs) as a tool for quickly assessing patients and informing clinical decision-making. A literature review was conducted to understand the use of QP in neuro ICUs and document the relationships between pupillary measurements and clinical consequences. The databases PubMed, Embase, and Scopus were systematically searched for original research articles from 1995 to 2025 in which QP was used for adult patients in the neuro ICU. Using 21 search terms, a total of 52 articles were identified and analyzed. The findings demonstrated the widespread use of QP in patients with acute brain injuries, such as traumatic brain injury, aneurysmal subarachnoid hemorrhage, intracerebral hemorrhage, and stroke. Many studies have established NPi as a non-invasive surrogate measure of intracranial pressure (ICP), which is particularly useful in screening for elevated ICP owing to its high negative predictive value. Correlations were noted between abnormal NPi, poor neurological outcomes, and a greater risk of mortality in many types of brain injury. The identification of the relationship between NPi and clinical events in specific patient populations may aid clinicians in tailoring QP usage to patients.

Keywords: Neurology, Critical care, Quantitative pupillometry, Neurological Pupil index

INTRODUCTION

Abnormal pupillary light response (PLR), anisocoria, and abnormal pupil size are well-established signs of neurological dysfunction and act as signals of increased injury severity and potential clinical decline. Manual pupillometry has historically been used to evaluate the PLR; however, it is subjective and has low inter-examiner consistency and reliability [1,2]. Quantitative pupillometry (QP) was developed in an attempt to standardize pupillary examinations using objective metrics. Unlike manual pupillometry, QP reliably and reproducibly measures maximum pupil size, minimum pupil size, constriction velocity (CV), dilation velocity (DV), constriction amplitude (CA), response latency, and percent change (%CH) [3,4]. The Neurological Pupil index (NPi) is calculated using pupil size, response latency, CV/DV, and %CH using a proprietary algorithm developed by NeurOptics, with an NPi <3 considered abnormal [1]. QP evaluation has shown excellent reliability in both healthy patients and those with acute brain injury [3]. In a 2022 validation study, QP demonstrated twice the reproducibility and repeatability of manual pupillometry [4]. QP allows clinicians to detect minute changes in PLR with a higher degree of accuracy than previously possible and enables longitudinal comparison within a single patient as well as between patients.
Similar to manual pupillometry, QP data provide a quick, easy, and non-invasive way to assess patient conditions. QP usage in intensive care units (ICUs) has risen as clinicians recognize its usefulness in objectively measuring injury severity, early detection of clinical deterioration, and as a prognostic tool. However, it is unclear which patient populations QP is most useful for and how exactly QP data should be integrated into clinical decision-making. In this review, we provide a broad overview of how QP, specifically NPi, is currently used in ICUs. Further, this review compiles the relationships between QP measurements and clinical consequences that have been established in previous literature. Analyzing these patterns, stratified by condition, as well as documenting the relationships between NPi and clinical events, will aid clinicians in tailoring interventions based on their patients’ pupillometry data.

METHODOLOGY

The PubMed, Embase, and Scopus digital databases were searched using predetermined search terms in August 2025. Before article screening, the researchers defined acute brain injury syndromes that would affect pupillary function in adult patients in the neuro ICU, as well as established possible synonyms and associated terms for QP. Overall, search terms related to QP (i.e., pupillometers, quantitative pupillometry, and Neurological Pupil Index [NPi]) were combined with acute brain injury categories (i.e., intracranial hemorrhage, cerebral edema, and traumatic brain injury [TBI]) and the ICU. The full list of search terms can be found in Supplementary Fig. 1.

Inclusion and exclusion criteria

Full-text articles containing original research or case reports involving adult patients admitted to the ICU were reviewed. Articles published before 1995, the year QP was first developed, and those not written in English were excluded. Additional exclusion criteria included the use of animal subjects or pediatric patients, the use of manual pupillometry instead of QP, studies with non-ICU settings, and studies in which the aim of the study was not related to QP. Non-original research articles, including opinion pieces, reviews, and guidelines, were also excluded. The articles were screened by two independent researchers (AY and FR). For ambiguous articles, a consensus was reached regarding exclusion versus inclusion by the two reviewers. Articles that met the criteria were stratified based on usage/patient population to identify patterns in NPi measurements and QP prognostic value.

RESULTS

Initially, 1,030 articles were identified based on the search criteria. Upon screening based on the aforementioned exclusion criteria, 52 articles were included in the review (Fig. 1). The included articles were stratified into five categories based on the outcome and patient population included in the study: QP and intracranial pressure (ICP), QP and acute brain injury, QP and intracerebral hemorrhage (ICH), QP and subarachnoid hemorrhage (SAH), and QP and TBI.

QP as a surrogate measure of ICP

A total of thirteen papers were directly related to the use of QP as a measure or predictor of ICP. While ICP is most accurately measured through an intracerebral catheter, QP has been studied as a possible non-invasive surrogate measure of ICP. A 2020 study found a significant correlation between NPi and invasive ICP measures, such as intracerebral catheters [5]. Although the relationship was considered weak compared with other measures, this still provides evidence that pupillometry data can be used as an indicator of intracerebral conditions. A study of 102 patients with intraparenchymal hemorrhage, TBI, and SAH found that NPi was inversely correlated with ICP, particularly in patients with a lower NPi [6]. Similarly, a 2025 study focusing on moderate to severe found a statistically significant and strong inverse correlation (ρ=−0.71) between NPi and measured ICP values, with patients having a median NPi of 4.2 (range, 3.8–4.6) and a median ICP of 21 (range, 14–29) [7]. In emergency situations where invasive monitoring is not possible, QP provides clinicians with a relative idea of ICP to inform clinical decision-making.
Abnormal NPi (<3) is strongly correlated with elevated ICP, often preceding episodes of increased ICP [8-10]. A study of 76 patients performed hourly pupillometry using QP along with hourly ICP measurements for the first 72 hours of ICU admission. Pupillometry data were significantly negatively correlated with ICP values in both bivariate (P<0.001, r=0.13–0.23) and multivariate regression models (F(6)=17.63, P<0.001). Compared with other pupillometry metrics, both the left and right eye NPi provided the strongest predictive value for ICP [9]. Moreover, a 2019 observational cohort study of 54 patients with ICH found that as ICP increased from a baseline of 14 to 30 mm Hg, NPi had a concomitant decrease from baseline 4.2 to 2.8. As the elevated ICP was treated and lowered, the NPi values increased and normalized. Abnormal NPi values were also associated with unfavorable 6-month outcomes [11], indicating that NPi has a strong ability to track clinical courses related to ICP. A 2011 study of 134 ICU patients noted a predictive value for ICP, with abnormal NPi readings preceding elevated ICP events by almost 16 hours [8]. Similarly, a prospective observational study of 40 patients with TBIs found an average lag of 9.5 hours between abnormal NPi reading and elevated ICP event [10]. The regular collection of pupillary responses using QP can indicate to neurocritical care teams the patients at risk of decline who may require closer monitoring or preventative care.
The literature establishes that NPi is particularly useful in screening for elevated ICP (>20 mm Hg) due to its high negative predictive value [5,12,13]. In a retrospective observational study, Pansell et al. [12] analyzed the association between NPi and ICP in ICU patients routinely monitored using invasive measures. The study identified a mean NPi value of 3.85 and a minimum NPi value of 3.7 as effective cutoff values for identifying elevated ICP, indicating that some patients with elevated ICP may nonetheless still have normal NPi. Furthermore, this analysis found that the probability of elevated ICP decreased with increasing NPi readings [12]. A prospective study of 31 patients found that an NPi less than 4.15 corresponded with a 7.7 times greater likelihood of ICP crisis [14]. The screening value of NPi can allow increased ICP levels to be addressed sooner, particularly in patients who are not being monitored invasively. Sustained abnormal NPi values are associated with more complex ICP courses, overall severity of increased ICP values, and decreased Glasgow Outcome Score (GOS) at 6 months [11]. However, it is important to note that a 2025 mixed etiology acute brain trauma study found no significant association between abnormal NPi and elevated ICP, cautioning that QP’s predictive value may vary by population and context [15].
Although NPi has the strongest correlation with ICP, pupillometry metrics such as CV, DV, and %CH have also been noted to have significant negative correlations with ICP [9,16]. A 2003 study analyzed the relationships between ICP and other pupillometry metrics aside from NPi. In 31 patients with acute brain injury, pupil asymmetry (>0.5 mm) was more frequent when the ICP was >30 mm Hg. However, pupil symmetry is rarely observed in either healthy volunteers or patients with brain injury with normal ICP readings. Thirteen patients with brain injury presented with midline shifts (MLS) >3 mm and an associated rise in ICP >20 mm Hg. A decrease in mean CV to <0.6 mm/sec (normal=0.8 mm/sec) on the side of the mass effect was seen in these patients. The authors concluded that a mean CV <0.6 mm/sec is indicative of increased brain volume and warn clinicians of elevated ICP [17].
Overall, the literature supports pupillometry data, most notably NPi, as valid surrogate measures for ICP. Although not as accurate as invasive measures, NPi can help clinicians identify patients at higher risk of developing elevated ICP and subsequent clinical deterioration. Furthermore, pupillometry data can help physicians monitor patient responses to medications and decompressive measures.

QP usage for acute brain injury

Eleven papers were related specifically to QP and acute brain injury, in which data were consolidated, and data from multiple types of pathologies were reported in aggregates. A retrospective study of 41 patients with ischemic stroke, hemorrhage, and brain masses showed significant correlations between abnormal NPi values and MLS [18]. Specifically, right pupil NPi values <3 were associated with left-to-right MLS, and left pupil NPi values were inversely correlated with MLS measured in the pineal gland, emphasizing the value of QP in detecting ICP changes without invasive techniques. In a large multicenter prospective cohort study involving 514 patients with TBI (n = 224), aneurysmal SAH (n = 139), or ICH (n = 151), abnormal NPi values were recorded in nearly half of the cohort [19]. NPi values of <3 were found to be strongly associated with higher mortality rates, particularly in patients with deteriorating NPi values of zero. Furthermore, abnormal NPi values were more prevalent when the ICP exceeded 20 mm Hg, highlighting the utility of NPi as an early indicator of poor outcomes.
Complementing these associations, a 2015 neuro ICU study found a marked separation of initial NPi by prognosis, with those having poor outcomes (defined by GOS 1 month after the injury <3) having lower average initial NPi of 0.88 compared to an average initial NPi of 3.8 in those with favorable outcome. With a cutoff NPi value of 3.4, NPi had an 86% sensitivity and 84.6% specificity in predicting outcome 1 month after acute injury [20]. Another key study on large hemispheric strokes found that patients with NPi <2.8 were more likely to experience neurological deterioration [21]. A 2025 cohort of 71 middle cerebral artery stroke patients showed that NPi significantly decreased both 4-6 hours (4.38–3.79) and 0–2 hours (4.38–3.88) prior to decline in the neurological deterioration group, while NPi values did not change significantly for the matched controls. Further, this study found a significant difference in DV (0.38 vs. 0.74 mm/sec) and CV values (0.89 vs. 1.52 mm/sec) between patients that experienced neurological deterioration versus those that did not. The authors concluded that QP data could be used to predict neurological decline prior to it becoming clinically evident, but emphasize the importance of monitoring an individual’s QP trends, rather than focusing on abnormal versus normal NPi values. The data specifically suggests that an NPi decrease of 0.63 or greater below 4 should raise concern for impending neurological deterioration [22]. Similarly, a large retrospective cohort study with 2,208 patients demonstrated a strong association between pupillary DV and Glasgow Coma Scale (GCS) scores, with faster DV linked to higher GCS scores at the time of measurement [23]. This suggests that QP can provide valuable insights into neurological function, even in patients with limited traditional exams. In a prospective neuro ICU cohort of 117 patients with acute brain injury, NPi tracked clinical severity (lower with GCS <9) and dropped when ICP exceeded 30 cm H2O. An initial NPi of ≤3.4 predicted poor 1-month outcomes with high accuracy (area under the receiver operating characteristic curve [AUC], 0.92; sensitivity, 86%; specificity, 84.6%), supporting QP as an objective bedside tool for monitoring and prognosis in acute brain injury [20]. Finally, a single-center retrospective analysis of 145 patients with severe acute brain injuries revealed that NPi values <3 within the first three days of admission were strongly predictive of unfavorable neurological outcomes at 6 months [24]. This early prognostic value provides clinicians with critical information for making informed decisions regarding patient care.
The prognostic utility of NPi differentials has been explored in patients with stroke and TBI [25]. A cohort study of 1,200 patients with stroke and 185 patients with TBI found that the presence of an NPi differential, particularly when combined with abnormal NPi values, was associated with higher modified Rankin scores (mRS) at discharge, suggesting worse functional outcomes. A retrospective analysis of 2,258 neurocritical care patients further examined NPi trajectories, categorizing patients based on changes in their NPi over time [26]. Patients whose NPi values deteriorated from ≥3 to <3 without recovery were more likely to require tracheostomy and a transition to palliative care. Temporal patterns of NPi changes were strongly linked to hospital discharge outcomes, making NPi a valuable predictor of patient trajectories during critical care.
QP also holds a predictive value for clinical complications in specific scenarios. In a study of 284 patients undergoing mechanical thrombectomy for large-vessel occlusions, abnormal ipsilateral NPi was independently associated with the development of malignant cerebral edema, further underscoring the role of QP in stroke management [27]. A preliminary study also found a statistically significant decrease in the median NPi (3.9 vs. 3.8) following surgical decompression, which was associated with neuroworsening, specifically cranial nerve deficits, motor decline, and increased ICP episodes [28]. Taken together, QP metrics, particularly the NPi, have demonstrated robust correlations with patient outcomes, neurological deterioration, and complications across a wide range of brain injuries, and are particularly powerful when tracked serially and interpreted in patient-specific trends.

QP usage for ICH and ischemic stroke

QP has emerged as an important tool for the assessment of neurological injuries, including those in patients with ICH and acute ischemic stroke. Seven studies demonstrated the utility of QP metrics for predicting neurological outcomes and correlating them with radiographic markers of brain injury, particularly MLS and ICP.
In a retrospective study focusing on patients with large acute supratentorial ischemic stroke and primary ICH, QP showed significant associations between MLS and pupillary responses [29]. The study found that the decrease in ipsilateral size relative to the contralateral size affected the contralateral pupil’s resting size and CV. Specifically, in patients with ICH, there was a notable association between the difference in NPi and MLS, suggesting that increased MLS corresponds to changes in pupillary reactivity. This relationship was more pronounced when the ipsilateral NPi and hematoma volumes were compared. Similarly, a prospective database study of 134 patients with ischemic stroke and ICH found that the NPi and CV, rather than pupil size, were strongly correlated with MLS [30]. In cases of a leftward shift, the NPi of the right pupil exhibited a strong correlation (coefficient of –0.43) with the degree of MLS. However, a similar correlation between the left pupil NPi and the rightward shift was not statistically significant. Further evidence supporting the prognostic value of QP in ICH was provided by a retrospective study that examined patients with supratentorial ICH [31]. This study revealed that hematoma volume and MLS were the strongest predictors of NPi changes, with ICH volume accounting for approximately 40% of the variation in NPi values. Notably, the ipsilateral NPi values showed a greater correlation with these factors. Interestingly, a case series of three patients with acute ischemic stroke found notable clinical use of serial QP measurements. In all three patients, the presence of a sudden abnormal NPi prompted emergent imaging, which revealed significant cerebral edema and MLS. Although the sample size was limited, this study further highlights the clinical utility of regular QP exams [32]. Complementing these pathophysiologic correlations, a 24-hour neuro ICU monitoring study of 35 patients with large hemispheric stroke showed modest nocturnal increases in raw pupillary dynamics (size, % constriction, CV/MCV, DV), but no meaningful diurnal shift in NPi, which was unchanged by dexmedetomidine, supporting NPi as a time-of-day robust signal for serial stroke surveillance [33]. In a study on malignant anterior circulation stroke in 59 patients, sequential QP flagged impending transtentorial herniation: ipsilateral NPi fell to roughly 1.8 three hours before diagnosis with concurrent pupil enlargement, and a 0–3 hours model using constriction change achieved outstanding discrimination, outperforming NPi alone, while earlier windows were best signaled by pupil size and dilation-velocity [34].
In another retrospective study involving 221 ICU patients with intracranial pathology, QP was used to identify early signs of anisocoria and poor pupil reactivity [35]. The presence of new-onset anisocoria was significantly associated with MLS and disease severity markers, such as mechanical ventilation and uncal herniation. Moreover, subclinical pupil size differences were detected up to 8 hours before the clinical recognition of anisocoria, suggesting that QP can provide early, objective indicators of worsening neurological status before the appearance of more overt clinical signs. The strong correlations among pupillary responses, hematoma volume, and MLS highlight the potential role of QP in early intervention and outcome prediction in patients with severe brain injury.

QP usage for SAH

Nine studies were specifically related to QP use in patients with SAH. SAH is a medical emergency that often occurs after trauma or a ruptured aneurysm, resulting in bleeding between the brain and arachnoid layer. QP data have been evaluated specifically in patients with SAH to help determine the severity of bleeding and prognosis.
A 2019 exploratory study followed 19 patients with SAH throughout their illness, collecting 4,456 NPi measurements, and found that NPi trends followed their clinical course. Importantly, mean NPi was significantly lower in those with clinically severe SAH versus non-severe SAH: the mean NPi for severe SAH was 3.75 versus 4.56 for those with non-severe SAH. Further, the mean NPi was lower in those with unfavorable outcomes versus those with favorable outcomes, 3.64 versus 4.50, respectively, with an even further pronounced difference when comparing NPi in those with in-hospital mortality versus those who survived, with a mean NPi of 3.03 and 4.37, respectively. Overall, the number of pathological NPi measurements was higher in patients with severe SAH, unfavorable outcomes, and/or in-hospital mortality [36]. Similarly, a 2022 study found that NPi was useful for prognostication following SAH, with an average NPi of 4.25 for those with poor neurological outcomes (PNOs) and 4.5 in those without [37].
Pupillometry variance also shows prognostic value, with higher variance in pupillometry data noted in patients with higher clinical severity and unfavorable outcomes [36,38]. Interestingly, patients with increased variability in pupillometric readings had significantly lower mRS at discharge, indicating better clinical outcomes [38]. The authors hypothesized that better adaptability in the pupillary response, as evidenced by changes in the NPi, was a signal of a more robust patient response to treatment. Clinically, tracking the variance in NPi measurements can help physicians evaluate the effectiveness of treatment and individual patient responses to treatment.
QP can be used to understand the severity of a patient’s condition and may have a predictive value for complications in patients with SAH. A 2018 case study reported changes in QP measurements before transtentorial herniation in a patient with SAH [39]. Similarly, a 2019 case study observed decreases in NPi that preceded clinical deficits by 12 hours and improved 24 hours before symptom improvement [40]. A 2022 study of 43 patients with SAH found that the NPi scores did not significantly correlate with acute hydrocephalus, a common complication after SAH. Nevertheless, the authors of this study emphasized that NPi decrease correlated with SAH severity and recognized that their findings could be due to their limited sample size [41]. However, delayed cerebral ischemia (DCI), another complication that occurs in approximately 30% of patients after SAH, is correlated with NPi [42,43]. Two studies within this category specifically explored the relationship between changes in the NPi and the risk of DCI following SAH. In a 2020 study, 56 patients with SAH were retrospectively followed up, and a significant relationship between an abnormal decrease in NPi and DCI was found. Of the 12 patients who developed DCI, seven had abnormal decreases in NPi after previously having normal NPi readings during their time in the ICU. In five of these patients, the change in NPi readings occurred over 8 hours before neurological decline. All patients’ NPi returned to baseline following treatment and the subsequent resolution of their clinical symptoms [42]. This supports the idea that NPi can be used both as a metric to detect deterioration and as a metric for the success of therapeutic interventions. A 2023 study found a similar relationship between NPi and DCI in a cohort of 210 patients with SAH. The proportion of abnormal NPi readings was higher in 85 patients who developed DCI versus 125 who did not. The lowest NPi was significantly lower in patients who developed DCI, with an average minimum of 3.1 versus an average minimum of 3.7 for those who did not develop DCI. However, this study did not find an independent association between abnormal NPi readings and DCI development. Instead, the authors hypothesized that their findings were more likely related to NPi as a marker of injury severity [43]. NPi, along with other diagnostic tools, could still be beneficial for identifying patients at risk of DCI and prognosis in general. Interestingly, abnormal NPi was shown to predict external ventricular drain-clamp wean failure, providing a low-cost, non-invasive way to assess the readiness for drain-clamp removal [44].
Current literature indicates that QP is a useful tool for neuroprognostication in patients with SAH. NPi values can help clinicians grade injury severity and formulate an appropriate treatment plan based on the level of intervention indicated by injury severity. Furthermore, NPi trends may allow physicians to predict patient outcomes in terms of acute treatment responsiveness, complication risks, long-term recovery, and prognosis.

QP usage for TBI

QP has demonstrated significant potential as an objective tool for evaluating neurological function and predicting outcomes in patients with TBI. Seven studies explored the relationship between pupillary metrics, NPi, anisocoria, severity of injury, and patient prognosis. In a retrospective review of 118 patients with TBI, pathological anisocoria was found to be strongly associated with greater injury severity and worse outcomes [45]. Patients with more severe anisocoria had lower GCS scores and higher mRS scores at discharge. This study highlights that post-stimulus anisocoria is a more robust indicator of neurological dysfunction than anisocoria at baseline. Similarly, a prospective observational study of 95 TBI patients found that an NPi of ≤3 was significantly associated with clinical deterioration within 24 hours of admission [46]. However, the sensitivity of NPi in predicting clinical deterioration was low (51.4%), whereas its specificity was high (91.7%), suggesting that while abnormal NPi is a strong indicator of worsening conditions, it may not detect all instances of decline.
Further support for the prognostic value of QP in TBI came from a pilot study that investigated the utility of automated pupillometry as a triage and assessment tool [47]. In a cohort of 36 patients with TBI, lower NPi scores were associated with worse outcomes, including higher mRS scores at 3 months. In patients who underwent surgical decompression, the eye with abnormal NPi was typically on the side with the worse injury. This finding suggests that QP can provide early indications of hemispheric injury and identify patients who may require surgical intervention. A pilot study of 36 TBI patients found no association between NPi and loss of consciousness, but contributed to the growing evidence that QP metrics reflect neurological status and outcomes following TBI [48]. A registry-based observational study of 214 patients with hospital-onset unresponsiveness (a condition frequently associated with brain herniation syndrome) found that abnormal NPi values were predictive of PNOs [49]. This study identified an optimal NPi cutoff of <3.0 for predicting PNOs at 3 months, with a positive predictive value of 85%. Additionally, patients with in-hospital mortality had significantly lower NPi values than those who survived, reinforcing the role of QP in the prognosis and decision-making for critically ill patients with TBI. In a retrospective ICU cohort of 100 patients with TBI, lower admission NPi (including NPi <3) was associated with unfavorable discharge outcomes and greater ICP-directed therapy intensity, but discrimination was only modest (AUC, 0.66–0.68), and the independent prognostic contribution of early NPi was limited relative to other clinical factors [50]. Finally, in 175 patients with TBI, GCS, GCS-P, GCS-NPi, and average NPi independently predicted discharge mRS with similar strength (all P<0.001), with no clear advantage to combining NPi with GCS over GCS (or NPi) alone [51]. NPi is an objective alternative, but it did not improve prognostic performance when added to GCS. Age also independently predicted worse mRS.
Collectively, these studies underscore the value of QP in the management of TBI. Despite the variation in sensitivity across studies, QP has demonstrated high specificity in predicting worsening conditions and poor outcomes, making it a useful adjunct in the triage and assessment of patients with TBI, especially when the GCS exam is confounded.

QP usage for cardiac patients

Five studies highlighted QP as an emerging tool for predicting neurological outcomes in cardiac patients, particularly in those who suffer from CA or require cardiac surgery. In an international prospective multicentric cohort study of 456 comatose ICU patients who underwent extracorporeal membrane oxygenation after CA, the NPi was a significant predictor of PNO [52]. An NPi ≤2 measured at 24–48 hours post-arrest had 100% specificity for predicting PNO, defined as a cerebral performance category of 3–5 at 3 months. The NPi measured on admission had a lower sensitivity (30%) but maintained a high specificity (91%) for predicting PNO in patients with CA. The study showed that patients with good neurological outcomes had a mean NPi of 3.9 on admission, while those with poor outcomes had a mean NPi of 3.6. Similarly, another observational study involving 77 patients admitted to the ICU within 6 hours of out-of-hospital cardiac arrest (OHCA) found that QP within the first 6 hours could help identify patients with a very low chance of neurologically intact survival [53]. Of the seven patients who had an NPi ≤2.3 within this time frame, none survived. However, the predictive value of QP measurements from 24 to 72 hours post-admission was not significant, highlighting the need for additional studies geared towards establishing prognostic data with high specificity for poor outcomes. A retrospective observational study of 221 comatose patients in a cardiac ICU demonstrated the prognostic value of QP, particularly in patients with OHCA [54]. Higher NPi values were independently associated with lower 30-day mortality in patients with OHCA. However, no significant association between NPi and outcomes was observed in patients who experienced in-hospital cardiac arrest or other conditions. In a multicenter post-hoc cohort of adults after cardiac arrest, an abnormal NPi (≤2) showed moderate to high concordance with prognostic markers. Abnormal NPi was strongly correlated with a neuron-specific enolase level of >60 μg/L, discontinuous electroencephalogram results, bilaterally absent N20, and myoclonus. Low NPi tracked with more concordant poor-outcome markers, supporting NPi as a valid bedside component of multimodal coma prognostication [55].
QP also appears to have potential utility in the postoperative care of patients after cardiac surgery. In an observational study of 28 cardiac surgery patients, those with lower NPi (≤2) had longer extracorporeal circulation times and higher ischemia times than those with higher NPi (>3) [56]. Although ischemia times were not statistically significant, patients with NPi ≤2 were extubated later than those with better NPi scores. This indicates that NPi evaluation could serve as a valuable tool for assessing neurological function and guiding clinical decisions, such as the timing of extubation and management of postoperative care. Overall, QP and NPi hold significant promise for assessing and predicting neurological outcomes in cardiac patients, particularly in those who experience cardiac arrest or undergo cardiac surgery.

DISCUSSION

In recent years, there has been an increased research and clinical interest in QP, indicating the perceived benefits of the medical community of QP as a clinical tool. Unlike other neuroprognostic tools, QP is non-invasive and relatively cost-effective. It is easily performed and operator independent, allowing the technology to be widely accessible in almost all care settings.
Historically, the pupillary reflex has been used as a rough tool for neuroprognostication, as it provides clinicians with a simple assessment of oculomotor nerve function and the degree of brain injury. However, as has been recognized in previous studies, QP shows higher accuracy and sensitivity than manual pupillometry and provides a better overall assessment of pupillary function, particularly when employed over serial measurements. Pupillary asymmetry greater than 0.5 mm was detected by QP in 81% of the paired observations but was detected by nurses using manual pupillometry only 22% of the time [3]. Furthermore, multiple studies have demonstrated that QP can detect the presence of pupillary constriction despite multiple medications, including paralytics, opioids, and benzodiazepines [1]. Qualitatively, a 2018 study found that ICU staff believed that QP data were useful in clinical decision-making and felt comfortable using this technology [2]. In contrast, manual pupillary assessments are not useful for monitoring clinical pupillary changes and reactivity [17]. QP has proven to be a more effective tool than the standard manual PLR examination and, therefore, must be better utilized and integrated into care by neuro ICU staff.
Although QP has demonstrated utility in objectively assessing neurological and physiological status, it has a few limitations. QP is integrated into clinical practice, often complementing other diagnostic tools rather than serving as a standalone metric. This multifactorial reliance makes it difficult to isolate and quantify the exact effect of QP on patient outcomes, leading to challenges in drawing strong conclusions regarding its definitive role in clinical decision-making. Heterogeneity in reporting QP measurements and the lack of accessible raw data have limited the ability to perform robust meta-analyses. The role of QP also varies widely among studies depending on the institutional protocols, study objectives, and specific patient populations being examined. This variability introduces potential biases when comparing outcomes across studies and makes it challenging to standardize the conclusions regarding clinical utility.
Several factors may confound the interpretation of the QP data. Pharmacological agents such as opioids and anesthetics can alter pupillary responses by affecting the autonomic nervous system, complicating the attribution of QP changes to clinical conditions. Similarly, diabetic neuropathy, which independently lowers NPi values, may bias the results if not properly accounted for. Additionally, variability in patient populations, such as differences in age, baseline health, comorbidities, and treatment protocols, can introduce inconsistencies, particularly when stratification and adjustments are insufficient. Lastly, many studies fail to distinguish between immediate changes in pupillary responses, such as those occurring within minutes to hours of a neurological event, and long-term alterations that may develop over days or weeks. This lack of temporal resolution complicates the interpretation of QP, highlighting the need for study designs that can differentiate and account for these evolving patterns.
QP is a validated clinical tool; therefore, it is important to explore how it can best be used in clinical practice. Future studies should focus on prospectively documenting NPi measurements in patient populations stratified by injury type. The establishment of validated trends within specific injury types can provide clinicians with better insight into the meaning of NPi values and patterns that should be expected for specific patients. Increased documentation and investigation will enable the creation of standards for clinically relevant changes in NPi, changes that should raise alarms for clinicians, and whether these standards/changes vary based on injury type. It would be useful to understand whether QP is more sensitive to specific injury types and provide clinicians with data showing which patient populations benefit most from regular QP measurements. Standardized comparisons between patient populations also allow researchers to differentiate whether NPi changes are related to specific brain injuries or whether NPi changes are correlated with injury severity in general. Many studies included in this review compiled QP data for all ICU patients without stratifying by injury, making it difficult to understand whether and how pupillometric data differ by patient type.
Furthermore, it would be useful to understand whether the use of QP itself has any effect on patient outcomes. Prospective studies examining the outcomes between patients monitored with QP and those monitored using traditional pupillometry examination methods would help quantify the value of QP as a clinical tool. As QP usage increases, it is increasingly important to explore the value of QP as a neuroprognostic tool and understand the extent of clinical insight provided by NPi.

CONCLUSIONS

The ability of QP to provide information rapidly and noninvasively makes it an appealing tool for critical care teams. Overall, the literature suggests that QP is useful for the initial screening of injury severity, tracking of clinical courses, and warning of clinical deterioration. In all the patient populations included in this review, abnormal NPi was associated with PNOs, worse prognosis, and increased mortality. Therefore, owing to its ease and reliability, the implementation of a QP protocol in neuro ICUs is beneficial and can aid in clinical decision-making.

Notes

Ethics statement

This study is a secondary analysis of previously published literature and therefore did not require Institutional Review Board approval. No new data were collected from human subjects, and patient consent was not applicable. All included studies obtained their own ethical approvals and patient consent, as detailed in the original publications.

Conflict of interest

None.

Funding

None.

Acknowledgments

None.

Author contributions

Conceptualization: AB. Methodology: AY, FR, AB. Formal analysis: AY, FR. Data curation: AY, FR. Visualization: AY. Writing - original draft: AY, FR. Writing - review & editing: AY, FR, AB. All authors read and agreed to the published version of the manuscript.

Supplementary materials

Supplementary materials can be found via https://doi.org/10.18700/jnc.250020.
Supplementary Fig. 1.
Search terms used. ICU, intensive care unit; NPi, Neurological Pupil index.
jnc-250020-Supplementary-Fig-1.pdf

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Fig. 1.
Flow diagram of literature search results with included and excluded studies.
jnc-250020f1.tif
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