Utility of M-mode ultrasound for pupillary assessment in patients with traumatic brain injury

doi:10.21203/rs.3.rs-2315094/v1

Background

Pupillary assessment is an important index to evaluate changes in the conditions of patients with traumatic brain injury (TBI). This study assessed the utility of M-mode ultrasound as a non-invasive bedside assessment to evaluate pupillary light reflex (PLR) sensitivity in patients with TBI.

Methods

This is a prospective observational study of patients with TBI. Patients were divided into brisk, sluggish, or absent groups based on their PLR sensitivity. M-mode ultrasound was performed according to standard operation guidelines using a standardized light stimulus.Pupillary diameter (PD) and PLR sensitivity were recorded. At the same time, the pupil was examined by M-mode ultrasound, and the diameter and pupillary contraction time (PCT) were measured at rest, ipsilateral opposite PLR, and contralateral opposite PLR.

Results

A total of 150 participants were included. In the briskgroup, during the ipsilaterallight reflex, the left and right PCTs were 0.09 ± 0.02s and 0.10 ± 0.09s, respectively, and the pupillary diameter variation rates (PDVRs) were 0.36 ± 0.10 and 0.35 ± 0.09. In the sluggish group, during the ipsilateral light reflex, the left and right PCTs were 0.20 ± 0.05s and 0.19 ±0.03s, respectively. PDVRs were 0.18 ± 0.07 and 0.19 ± 0.11, respectively. In the brisk group, the cut-off value of PDVR of ipsilateral PLR was 0.205, AUC value was 0.957, and sensitivity and specificity were 95.3% and 90.8%, the cut-off value of PDVR of contralateral PLR was 0.146, AUC value was 0.962, and sensitivity and specificity were 95.3% and 86.2%.

Conclusions

This study demonstrated the usefulness of M-mode ultrasound for quantitative evaluation of pupillary changes. It is a simple, rapid, and objective method that can accurately monitor PD and sensitivity to light reflex, especially in patients with eyelid edema or TBI, where pupils cannot be examined visually.

M-mode ultrasound

pupillary diameter

pupillary diameter variation rate

sensitivity to light reflex

pupillary contraction time

Pupillary change is considered an important clinical observation index because pupillary size, light reflex, and differences in size between bilateral pupils can provide information about the functional statuses of the optic nerve and oculomotor nerve. Pupillary change helps assess the conditions of patients with coma, convulsion, shock, and poisoning ¹ and evaluate the effects of drugs, such as painkillers, sedatives, and anesthetics^2,3. Pupillary monitoring is particularly important in patients with severe traumatic brain injury (TBI), where it can help evaluate the changes in the condition of a patient and the trend in intracranial pressure, as well as predict the occurrence of cerebral herniation^4-7.

In current clinical practice, the pupillary examination is usually performed using a hand-held light (e.g., penlight), such that the assessment of pupillary size and responsiveness (that is, non-existence or existence, or brisk or dull) is based on visual qualitative assessment. However, such evaluation is limited by its subjective nature and also the experience of the evaluating medical personnel. Moreover, up to a 40% difference has been detected between tests using the visual examination of PLR, especially in the presence of pupil dilation, and the difference may further increase in the presence of other confounding factors, such as alcohol, drugs, or hypothermia⁸. Furthermore, an error rate of 20% and a diagnosis failure rate of 50% were observed with qualitative examination, even in a medium-sized pupil⁹. Larson et al. demonstrated that a qualitative examination at a reflex amplitude of <0.3mm failed to detect PLR¹⁰. Importantly, qualitative pupillary examination is not possible in patients whose eyelids cannot be easily opened, as well as those with severe orbital edema; severe TBI is extremely challenging to detect in these patients. While infrared video pupillography (IVP) is currently considered the gold standard for pupillary monitoring, it is not routinely available in the intensive care unit (ICU) and also cannot be used in cases of severe eyelid swelling that is common in TBI patients¹¹.

A bedside ultrasound is widely used in the ICU as a diagnostic and monitoring tool that can be a useful auxiliary examination to detect the changes not observed by subjective visual qualitative examination^12,13. At present, few studies have examined pupillary function by ultrasound. The purpose of this study is to assess the usefulness of M-mode ultrasound as an alternative examination method to measure pupillary diameter (PD) and evaluate PLR sensitivity in patients with TBI where the visual examination of pupils is not possible.

Study design

This is a prospective observational study approved by the Ethics Committee of Dong E Hospital. An informed consent form was signed by the patient or their family member before the examination. All methods were performed in accordance with the relevant guidelines and regulations^13,14.

Participants

This study involved consecutive patients admitted to the Department of Critical Care Medicine of Dong E Hospital from January 30, 2021, to October 30, 2021. The inclusion criteria were patients with TBI who were ≥18 years old and ≤80 years old and who were available for a pupil ultrasound examination. Exclusion criteria were patients with any history of eye disease (such as glaucoma, cataract, or diabetic retinopathy), those with a history of eye surgery or laser treatment, or those taking local or systemic drugs (e.g. Atropine, sedatives, hypnotics) that may affect pupillary function.

Pupillary examination

Before ultrasound examination, the pupil of the patient was assessed using IVP monitoring. The PD of the bilateral pupil was measured under natural light, ipsilateral light reflex, and contralateral light reflex, and the sensitivity of pupillary reflex was diagnosed (brisk, sluggish, or absent).

M-mode ultrasound pupillary examination

All examinations were performed by a single experienced physician using a Mindray M7 portable color Doppler ultrasound 12Hz linear array probe (Mindray, Shenzhen, China). The linear probe was smeared with ultrasound gel and placed on the right side of the patient below the orbit above the cheekbone, and mild pressure was applied to the patient's face at an angle of 10°-20°. The pupil presented a circular structure with no echo, surrounded by an ultra-echo ring, the iris. The pupil was displayed in the center of the screen, the M-mode ultrasound was turned on, and a clear display was obtained. Next, an assistant used a penlight to illuminate the patient's ipsilateral pupil and observed and recorded the image of ipsilateral PLR using the M-mode ultrasound. The assistant then irradiated the patient's contralateral pupil and observed and recorded the image of contralateral PLR using M-mode ultrasound (Figure 1). The frozen M-mode ultrasound images were stored. The maximum PD at rest and the minimum PD at light reflex were marked using the built-in measurement tool in the ultrasonic system. The pupillary contraction time (PCT) was defined as the time interval between the maximum and minimum PD during the process of light reflex; this was calculated using the timestamps recorded by the ultrasound instrument.

Data collection

The collected data included patient demographics (age, sex), under direct observation, the bilateral PD under natural light and the PD of direct light reflex measured using IVP monitoring, and the sensitivity of pupillary reflex (brisk, sluggish, absent). The PD, PCT, and pupillary diameter variation rate (PDVR) were recorded using M-mode ultrasound under natural light, ipsilateral light stimulation, and contralateral light stimulation. PDVR was determined using the following equation: (PD under natural light – PD under light reflex)/PD under natural light. The pupillary light reflex sensitivity was determined using PDVR under light stimulation.

Primary outcome

The primary outcome was PD measurements using M-mode ultrasound examination and sensitivity to light reflex.

Data analysis

Continuous data were expressed as mean ± standard deviation (normal distribution data) and analyzed using a t-test. Non-normally distributed data were expressed as median and interquartile range (Q1, Q3), and Mann-Whitney U test was used for inter-group comparison. The frequency was expressed as percentage (%), and a chi-square test was used for comparison between groups. The Bland-Altman test was used to compare the consistency of M-mode ultrasound and IVP. The sensitivity of pupil reflex was evaluated by analyzing the PDVR based on the area under the receiver operating characteristic (ROC) curve. All data were tested by bilateral test, and the difference was considered to be statistically significant at P < 0.05. Statistical analysis was performed using SPSS 22.0.

Study participants

A total of 150 patients with TBI (mean age 55.45 ±13.77 years; 63.3% male [95/150]) were included in this study. According to the sensitivity of PLR, they were divided into brisk (n=85 cases; 56.5% male [48/85]), sluggish (n=23; 78.3% male [18/23]), and absent (n=42; 69.0% male [29/42]) groups (Table 1). All participants tolerated the examination well and no adverse events or patient discomfort were reported.

Table 1. Patient demographics and pupillary measurement results

	All patients (n=150)	Brisk group (n=85)	Sluggish group (n=23)	Absent group (n=42)
Age, years	55.45±13.77	56.05±14.17	59.30±14.87	52.12±11.75
Gender
Male, n (%)	95（63.33）	48（56.47）	18（78.26）	29（69.05）
Female, n (%)	55（36.67）	37（43.53）	5（21.74）	13（30.95）
PD using IVP
Left eye (mm)	2.69±0.91	2.59±0.71	2.41±0.90	3.04±1.16
Right eye mm)	2.78±1.01	2.59±0.72	2.41±0.90	3.37±1.30
Pupillary parameters using ultrasound
PD at rest
Left eye (mm)	2.78±0.94	2.69±0.75	2.47±0.93	3.11±1.20
Right eye (mm)	2.85±1.02	2.66±0.74	2.47±0.89	3.45±1.31
PD during ipsilateral light stimulus
Left eye (mm)	2.15±1.01	1.71±0.48	2.05±0.88	3.10±1.20
Right eye (mm)	2.24±1.14	1.71±0.49	2.03±0.92	3.41±1.32
PCT after ipsilateral light stimulus
Left eye (s)	0.08±0.07	0.09±0.02	0.20±0.05	0.01±0.03
Right eye (s)	0.09±0.09	0.10±0.09	0.19±0.03	0.01±0.04
PDVR during ipsilateral light stimulus
Left eye	0.23±0.18	0.36±0.10	0.18±0.07	0.003±0.01
Right eye	0.23±0.17	0.35±0.09	0.19±0.11	0.004±0.01
PD during contralateral light stimulus
Left eye (mm)	2.24±0.99	1.84±0.54	2.13±0.85	3.11±1.20
Right eye (mm)	2.31±1.13	1.79±0.52	2.12±0.89	3.45±1.31
PCT after contralateral light stimulus
Left eye (s)	0.09±0.08	0.10±0.03	0.22±0.05	0.01±0.03
Right eye (s)	0.09±0.08	0.10±0.02	0.21±0.03	0.01±0.04
PDVR during contralateral light stimulus
Left eye	0.20±0.16	0.32±0.09	0.14±0.06	0.003±0.01
Right eye	0.20±0.17	0.32±0.11	0.15±0.08	0.002±0.01

Data presented as mean ±standard deviation or median (Q1, Q3) or n(%).

PD: pupillary diameter; PCT: pupillary constriction time; PDVR: pupillary diameter variation rate；IVP: infrared video pupillography

Pupillary parameters at rest and during light stimulus

Table 1 summarizes the results of pupillary measurements at rest and during ipsilateral, and contralateral light reflex for all patients as well as for the three subgroups. At rest, the bilateral PD differences were ≤1mm, so it was considered that the physiological pupillary size was different. The results of the Bland-Altman test show that the average PD measured by IVP and M-mode ultrasound is -0.069, and the 95% CI of the difference is - 0.515 - 0.376. Of the measured data, 96.66% fall within the 95% CI, indicating that the two methods have good consistency (Figure 2). The changes in bilateral PD at rest and during ipsilateral and contralateral light reflex were similar among the three groups. The bilateral PCT and PDVR were also similar during ipsilateral and contralateral light reflex among the three groups.

Diagnostic sensitivity of PLR based on PDVR

Tables 2 and 3 show the analysis of PLR sensitivity based on the ultrasonic PDVR using the right eye as an example. In the brisk group, the cut-off value of PDVR of ipsilateral light reflex was 0.205, AUC value was 0.957, and sensitivity and specificity were 95.3% and 90.8%, respectively; in the contralateral light reflex, the cut-off value of PDVR was 0.146, AUC value was 0.962, and sensitivity and specificity were 95.3% and 86.2%, respectively (Figure 3, Table 2).

In the sluggish group, the cut-off value of the PDVR of the ipsilateral light reflex was 0.255, AUC value was 0.589, and the sensitivity and specificity were 82.6% and 59.1%, respectively; the cut-off value of the PDVR of the contralateral light reflex was 0.211, AUC value was 0.597, and the sensitivity and specificity were 87.0% and 55.5%, respectively (Figure 4, Table 3).

Table 2. Diagnosis of brisk PLR using PDVR

Indicator	AUC	P Value	95% CI		Youden index	Cut-off (%)	Sensitivity	Specificity
Indicator	AUC	P Value	Lower limit	Upper limit	Youden index	Cut-off (%)	Sensitivity	Specificity
PDVR during ipsilateral light stimulus	0.957	0.000	0.916	0.998	0.861	0.205	0.953	0.908
PDVR during contralateral light stimulus	0.962	0.000	0.930	0.993	0.815	0.146	0.953	0.862

PLR: pupillary light reflex; PDVR: pupillary diameter variation rate

Table 3. Diagnosis of sluggish PLR using PDVR

Indicator	AUC	P Value	95% CI		Youden index	Cut-off (%)	Sensitivity	Specificity
Indicator	AUC	P Value	Lower limit	Upper limit	Youden index	Cut-off (%)	Sensitivity	Specificity
PDVR during ipsilateral light stimulus	0.589	0.175	0.486	0.692	0.417	0.255	0.826	0.591
PDVR during contralateral light stimulus	0.597	0.141	0.506	0.688	0.445	0.211	0.870	0.555

PD: pupillary diameter; PDVR: pupillary diameter variation rate

This study demonstrated the accuracy of M-mode ultrasound to monitor pupillary changes in patients with TBI at the bedside in order to detect the changes in the disease state as soon as possible. This method offers a fast, accurate, and convenient method to monitor PD, PDVR, and PLR sensitivity in patients with TBI. Particularly, this study introduced the concept of PDVR and used objective data to reflect PLR sensitivity compared to traditional subjective qualitative visual examination. Our findings are consistent with a previous report that used B-mode ultrasound to assess pupillary function¹⁵.

Abnormal pupillary response is often used in clinical decision-making to predict the occurrence of intracranial hypertension in severe TBI¹⁶. The monitoring of pupillary function contributes to a better understanding of secondary brain injury because persistent or new abnormal PLR is associated with a worse outcome. PLR is a known predictor of prognosis in patients with TBI and was used as an effective variable in prognostic models in the CRASH ¹⁷ and IMPACT ¹⁸ clinical trials. However, severe TBI is often accompanied by periorbital hematoma and ocular trauma^19,20, limiting pupillary assessment.

Compared with IVP, ultrasound pupillary monitoring is a simple, safe, bedside, and non-invasive imaging technology, which can provide reliable pupillary parameters with several advantages. Although ultrasound pupillary assessment requires a certain degree of experience, this method provides the possibility to monitor pupillary parameters, especially pupillary size, symmetry, changes in contraction under light stimulation, and dilation/contraction speed. Previously, studies by Schmidt et al. and Farina et al. confirmed the feasibility of monitoring pupillary size and pupillary constriction velocity by ultrasound^15,21; however, both used B-mode ultrasound. In this study, we evaluated the utility of M-mode ultrasound in monitoring PD and introduced the concept of PDVR, using objective data to reflect PLR sensitivity. Additionally, PLR assessment can be performed with the patients' eyes closed, allowing assessment in patients whose eyelid contraction is hindered by poor cooperation or severe periorbital edema.

Also, the new method proposed here may be a useful and practical tool to reveal subclinical changes in pupillary function. For example, in patients with mild clinical symptoms, with clinically suspected carotid dissection or brainstem injury, pupillary ultrasound assessment may help select patients suitable for emergency neuroimaging examination²². This technique may have potential applications in the study of pupillary function in neurodegenerative and neuroinflammatory diseases.

However, compared to IVP, ultrasound has some limitations. IVP allows a more detailed analysis of PLR beyond PD and PCT to assess pupil latency, speed, dilation, contraction, and photoreceptor function²³. In our study, ultrasound is performed with patients’ eyes closed, so it is difficult to determine the irradiance that reaches the retina, thus distinguishing rod cells, cones, and melanin functions²⁴. However, IVP is difficult to obtain routinely in general ICU, and the clinical use is not straightforward.

This study demonstrated the usefulness and accuracy of using M-mode ultrasound for pupillary assessment in patients with TBI. This innovative method can directly measure PD and PLR sensitivity by measuring the PDVR and PCT. This method is widely available as well as time- and cost-effective and can have a wide range of applications in clinical practice.

IVP: infrared video pupillometry

PCT: pupillary constriction time

PD: pupillary diameter

PDVR: pupillary diameter variation rate

PLR: pupillary light reflex

TBI: traumatic brain injury

Acknowledgements:

None

Authors' contributions:

XS contributed to the conception, MF, XL and DY contributed to the design, MF and XL contributed to the drafting of the article, XG and ZL performed statistical analysis. XS contributed to the critical revision of the article for important intellectual content, and XS conducted the final approval of the article. All authors read and approved the final manuscript.

Competing interests:

The authors report no declarations of interest.

Availability of data and materials:

All data generated or analyzed during this study are included in this article.

Ethics approval and consent to participate:

This study was approved by Ethics Committee of Dong E Hospital. An informed consent form was signed by the patient or their family member before the examination.

Consent for publication:

Not applicable

Funding:

This study is funded by the Medical and Health Science and Technology Development Plan of Shandong Province (2019WS098).

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Utility of M-mode ultrasound for pupillary assessment in patients with traumatic brain injury

Status:

Version 1

Abstract

Figures

Introduction

Materials And Methods

Results

Discussion

Conclusion

Abbreviations

Declarations

References

Status:

Version 1