- Email: [email protected]
Ultrasound assessment of optic nerve sheath diameter in healthy volunteers
Ultrasound Assessment of Optic Nerve Sheath Diameter (ONSD) in Healthy Volunteers Patrick Goeres, Frederick A. Zeiler MD, Bertram Unger MD, PhD, Dimitrios Karakitsos MD, PhD, DSc, Lawrence M. Gillman MD, MMedEd, FRCSC FACS PII: DOI: Reference:
S0883-9441(15)00538-9 doi: 10.1016/j.jcrc.2015.10.009 YJCRC 51981
To appear in:
Journal of Critical Care
Please cite this article as: Goeres Patrick, Zeiler Frederick A., Unger Bertram, Karakitsos Dimitrios, Gillman Lawrence M., Ultrasound Assessment of Optic Nerve Sheath Diameter (ONSD) in Healthy Volunteers, Journal of Critical Care (2015), doi: 10.1016/j.jcrc.2015.10.009
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT ULTRASOUND ASSESSMENT OF OPTIC NERVE SHEATH DIAMETER (ONSD) IN HEALTHY VOLUNTEERS
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Patrick Goeres1 ([email protected])
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Frederick A. Zeiler MD1 ([email protected])
Bertram Unger MD PhD2 ([email protected])
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Dimitrios Karakitsos MD, PhD, DSc 3 ([email protected])
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Lawrence M Gillman MD MMedEd FRCSC FACS1 ([email protected])
Departments of Surgery1 and Medical Education2
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University of Manitoba, Winnipeg, Manitoba
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Department of Internal Medicine, University of South Carolina, Columbia, SC, USA 3
Presented as a podium presentation at the Trauma Association of Canada (TAC)
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Meeting in Calgary, Alberta, April 2015.
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Keywords: Point of Care Ultrasound; Optic nerve sheath diameter; Ultrasound; Intracranial Pressure
* Corresponding Author
Z3053 – 409 Tache Avenue Winnipeg, Manitoba, Canada, R2H 2A6 Phone: (204) 258-1408 Fax: (204) 237-3429 Email: [email protected]
ACCEPTED MANUSCRIPT
Abstract: Background: Ultrasound assessment of optic nerve sheath diameter (ONSD) has been suggested
T
as a non-invasive measure of intracranial pressure (ICP). Numerous small studies suggest its
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validity however discrepancy exists around normal values for ONSD. In this study we sought to
SC
define a normal value range for ONSD in a population of healthy adult volunteers. Methods: ONSD was measured in healthy adult volunteers and a normal range was defined using
MA
measurements and sex, age, height and weight.
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descriptive statistics. A regression analysis was used to determine relationship between ONSD
Results: 120 adults were recruited (age 18 - 65 (mean 29.3)) with 55 male and 65 female
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subjects. Mean ONSD was 3.68mm (2.85-4.40 95% Confidence Interval (CI)). Upon regression analysis, mean ONSD did not vary with age, weight or height but did vary with sex. Mean ONSD
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95% CI) for females.
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measurements for males were 3.78mm (3.23-4.48 95% CI) compared with 3.60mm (2.83-4.11
Conclusion: This study has defined the range of ONSD in a healthy cohort of volunteers. The
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lack of relationship to age, weight and height is similar to other studies but this is the first study to find a difference depending on sex suggesting the possible need for separate reference ranges for males and females.
ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
ACCEPTED MANUSCRIPT
Introduction Ultrasound assessment of optic nerve sheath diameter (ONSD) has been suggested as a non-
T
invasive measure of intracranial pressure (ICP) and was first described in 1987 (1). Elevated ICP is
RI P
associated with worse outcomes in head injured patients. Hence, close ICP monitoring is a fundamental strategy enabling prompt and aggressive therapy (2). Current literature supports the correlation between
SC
increased ONSD and increased ICP in a variety of adult and pediatric patient populations (3), including those with traumatic brain injury, mass lesions, infection and in transplant recipients with reperfusion
NU
injury (4, 5, 6, 7, 8).
MA
Invasive ICP monitoring via intra- parenchymal or ventricular monitors is the gold standard method in assessing ICP, but carries risks such as infection and bleeding (9). Other techniques, such as detection of papilledema via fundoscopy, have significant limitations including high operator dependence,
ED
and only qualitative rather than quantitative results. (7). Studies supporting ONSD measurements show low inter and intra observer variability (10, 11, 12, 13). Numerous small studies suggest its validity however
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discrepancy exists around thresholds for elevated ONSD and normal reference ranges, as most
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measurements are derived from unhealthy subjects who have abnormal invasive ICP measurements (7, 14, 15, 16, 17) Potential exists for a clinically useful and rapid assessment of ICP by ocular ultrasound,
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although a well-defined, large control population has yet to be studied. In this study, we sought to define a normal value range for ONSD in a large population of healthy adult volunteers.
Methods Subjects Healthy volunteers over the age of 18 were recruited via email and print advertisement to participate in this study. Subjects were excluded if they had any history of ocular disease/pathology or intra-cranial pathology. All subjects signed a consent form in accordance with the University of Manitoba Health Research Ethics Board. Sample Size
ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
ACCEPTED MANUSCRIPT Based on a previous study (10) we predicted a standard deviation of 0.5 in our sample and therefore power sample analysis revealed that 120 subjects would be required to predict the population’s ONSD mean to an accuracy of +/- 0.1 mm. In addition, research in laboratory medicine has shown that a
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sample of 120 participants is adequate to determine the normal range of a population for a given test (18). Previous research of Magnetic Resonance Imaging measurements of ONSD had shown that ONSD in adults does not vary significantly by age and therefore a balanced sample covering all age ranges was felt
SC
to be unnecessary and thus 120 random subjects were sought (19). Measurement technique
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All measurements were performed by a single trained expert (LG). All patients were placed in a
MA
supine position with no elevation of the head of the bed and images were obtained through a closed eyelid using a generous amount of ultrasound gel. Utilizing a standard technique most widely reported in the literature (7, 20), a 13-6 MHz linear array ultrasound transducer (L25x transducer with a Sonosite M-Turbo
ED
Ultrasound Machine, SonoSite Inc, Bothell, WA) was used to measure the ONSD in a direction perpendicular to the axis of the nerve, in two planes for each eye, 3 mm behind the optic nerve head, for a
Statistical Analysis
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total of four measurements per subject.
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Mean ONSD, standard deviation and 95% confidence interval (CI) was calculated for each of the ONSD measurements, mean of all four measurements and the maximum of all four measurements. Each of the four ONSD measurements were compared for agreement by analysis of variance (ANOVA) and Bland Altman Plot. Main effect linear regression modeling was used to compare the relationship between mean ONSD and sex, weight and height. Analysis was completed using both the Statistical Analysis Software version 9.3 (SAS Institute, Cary NC) and R Statistical Library (R Core Team, 2013).
Results Subjects included 65 males and 55 females. Mean age was 29.3 (Range 18 – 65). Overall mean ONSD measurement was 3.68 (95% CI 2.85 – 4.40) (Table 1). Overall, there were no significant differences between any of the four measurements (p=0.87) (Figure 1). Bland Altman Plot did not ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
ACCEPTED MANUSCRIPT demonstrate any evidence of systematic bias within the data (data not shown). However, intraclass correlations (ICC) between each of the four individual measurements revealed an overall ICC of 0.765 (95% confidence interval (CI) 0.705 – 0.818) (Table 2). Linear regression revealed a relationship between
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mean ONSD and sex but no change with age, weight or height (Table 3). By gender, the mean ONSD was significantly different (p=0.0001); 3.54 (95% CI 2.83 – 4.11) for females and 3.80 (95% CI 3.23 – 4.48) for
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males (Figure 2). Discussion
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Ultrasound measurement of ONSD appears to be a promising, rapid, non-invasive bedside tool for identification of elevated ICP. There are a number of other novel, non-invasive technologies for ICP
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measurement including HeadSense (Headsense Medical Ltd, Netanya, Israel) and Vittamed 205 (UAB Vittamed, Kaunas, Lithuania). While HeadSense remains still early in development and testing phases with
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no current published trials, Vittamed on the other hand has shown some success in a number of smaller prospective trials (21, 22). Despite this, ONSD measurement remains the most widely studied, non-invasive
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technique for ICP estimation and has the advantage of not requiring any proprietary software or hardware and can be carried out using equipment already widely available in many emergency departments.
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However, an accurate cut-off value for normal versus elevated ICP has yet to be conclusively established. To date, most studies advocate a threshold of 5 mm (14, 23, 24, 25) with some studies suggesting
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thresholds as high as 5.7 - 5.9 mm (5, 7, 20, 26). However, this has been based mainly on small studies in non-healthy individuals and the true range of ONSD measurements in a healthy population is still not known. In our study, overall mean ONSD measurement was 3.68 mm (95% CI 2.85 – 4.40), which is consistent with other European studies (12) but lower than a recent Bangladeshi population (27). The authors of the Bangladeshi study wondered if the difference could be related to ethnicity. Unfortunately, we did not record ethnic origin as part of our data, though our Canadian population would likely be very similar in diversity to the other European study populations. Another reason for the lower mean measurements could relate to the technique. The technique we utilized is often referred to as the ―black stripe‖ technique and is the most common technique currently advocated in the literature (5, 7, 14, 20, 21, 24-26). However, new quality criteria recently introduced (following the data collection for this study) by Sargsyan et al. (28) may help eliminate some of this variation in results. Studies comparing these criteria to ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
ACCEPTED MANUSCRIPT the standard ―black stripe‖ technique have yet to be published however and this is an exciting area in need of further study. Our current findings suggest that the ONSD range in the general healthy population is reasonably
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wide and this could have implications for the clinical utility of ONSD ultrasound. The extent of nerve sheath dilation with increased ICP has not been clearly demonstrated, however acute increases during transplant reperfusion are shown to be approximately 0.4mm (8). Therefore, if a patient’s baseline ONSD
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was at the lower end of our demonstrated range, an increased ONSD may not be detectable with a single measurement, especially if a threshold of 5 mm or higher is used.
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The presence of a predictor of expected ONSD would be extremely helpful in better defining a
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specific threshold for elevated ICP for an individual patient. Past studies have unfortunately failed to demonstrate any relationship between ONSD and age, weight, height, sex or head circumference (11, 19, 27) in the adult population. To our knowledge, our data is the first to demonstrate a different ONSD range
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between men and women. This is however consistent with a previous study measuring optic disc size for stereoscopic optic disc photographs (29) and may relate to variations in nerve fiber density between sexes
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(30).
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This study represents the largest group studied to date with a reasonably balanced number of males and females and hence previous studies may have been underpowered to detect this difference. This
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data suggests the possible need for different reference ranges and thresholds between sexes. We demonstrate an upper limit with 95% CI to be 4.11 mm and 4.48 mm in women and men respectively, and these limits could potentially have more clinical utility than the traditional upper limit of 5 mm. While the technique of measuring the ONSD 3mm behind the optic nerve head is for the most part consistent across studies, the choice of which measure that should be used has been quite variable. The most commonly used reference is the mean of four measurements (two from each eye: horizontal and saggital) (7, 20), however, the largest of four measurements (5), the mean of two measurements (one from each eye) (14, 15) and even the mean of 6 measurements from each eye (16) have also been used. This may explain some of the variation in reference ranges and thresholds of elevated ICP seen in the literature. Our data, as in other studies, showed no significant difference overall between the mean of each of the four measurements (p=0.87), however intraclass correlations between the four measurements was only ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
ACCEPTED MANUSCRIPT 0.765 (95% confidence interval (CI) 0.705 – 0.818). This distinction is significant as it suggests that in an individual patient measurements are related, but cannot be used interchangeably. In other words, when looking at a large cohort of patients any differences in measurement between eyes averages out, but on an
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individual basis a single measurement in one eye may not be reflective of the value obtained if the opposite eye or another plane was imaged. This could be related to variability in the measurement or anatomical variation within the individual. This is an area in need of further study. Additionally, we demonstrated that
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a mean of four measurements is more precise than a single measurement. With respect to clinical utility, it would increase the rapidity of bedside ONSD assessment if one could use a single measurement, but our
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data suggests this is less likely to produce an accurate measurement.
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With respect to the choice of the mean value of four measurements or maximum value of the four measurements, we found that that the mean was the most precise measurement (smallest variance). However, since the appeal of this technique is as a rapid point of care screening test for increased ICP, the
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maximum value of the four measurements would certainly increase the sensitivity of the test though potentially at the cost of specificity.
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There are a number of limitations to our study. First the measurements are taken by a single,
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although expert, operator. Other potential variables not accounted for were ethnicity and anatomical variations, such as head circumference, although the latter has been shown not to be significant in prior
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study (27). The previously mentioned new sonographic quality criteria for ONSD measurements (28) were not utilized in this study and their possible effect on establishing a definitive range of ultrasound detected normal values is currently unknown. Work to validate these new criteria is ongoing by our group. Finally, the subjects for this study were healthy volunteers. While, the results suggest a possible sex difference in ONSD measurements and a possible alternative threshold for definition of abnormal ONSD measurement this clearly requires further study and confirmation in patients with elevated ICP measurements.
Conclusions This study has helped define the range of ONSD in a healthy cohort of volunteers. The determined range and lack of relationship to age, weight and height is similar to other studies but this is the first study
ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
ACCEPTED MANUSCRIPT to find a difference in sex amongst ONSD measurements suggesting the possible need for separate reference ranges for males and females.
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Acknowledgements
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This research was supported by a General Operating Grant from the Health Science Centre Foundation in Winnipeg, Manitoba, Canada.
ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
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Tables
3.68
Maximum
3.86
.39
2.90 – 4.40
.36
2.85 – 4.40
.38
3.00 – 4.50
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Overall Mean
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3.70
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Right Saggital
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Table 1 – Mean optic nerve sheath diameter (ONSD) , standard deviation (SD) and 97.5 % confidence intervals (CI) for each eye in both the saggital and horizontal plane, as well as mean and Measurement Mean (mm) SD 95% CI (mm) maximum of each of Left Horizontal 3.66 .42 2.80 - 4.50 the four measureme Left Saggital 3.69 .39 2.80 – 4.40 nts per Right Horizontal 3.66 .39 2.80 – 4.40 subject.
Table 2 – Intraclass correlations (ICC) between each of the four measurements of ONSD. Left Sagittal
Right Horizontal
Right Sagittal
Left Horizontal
1.0000
0.8107
0.7634
0.7735
Left Sagittal
0.8107
1.0000
0.7734
0.7523
Right Horizontal
0.7634
0.7734
1.0000
0.7160
Right Sagittal
0.7735
0.7523
0.7160
1.0000
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Left Horizontal
ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
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0.586
Height
0.537
Weight
0.681
Sex
0.015*
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Age
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P-value
* indicated statistical significance p<0.05.
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Figure Legends
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Variable
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Table 3 – Results of main effects linear regression modeling comparing mean ONSD to height, weight and sex.
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Figure 1 : Boxplot demonstrating relationship between ONSD measurement in four planes, mean of the four measurements and the maximum (largest) of the four measurements.
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Figure 2 : Boxplot demonstrating difference between mean ONSD by gender (p=0.0001).
ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
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References 1. Gangemi M, Cennamo G, Maiuri F, D’Andrea F. Echographic measurement of optic
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nerve in patients with intracranial hypertension. Neurochirurgia (Stuttg). 1987;30:53-5.
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2. Trauma Foundation. Guidelines for the management of severe traumatic brain injury, 3rd edition (2008).
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3. Newman WD, Hollman AS, Dutton GN, Carachi R. Measurement of optic nerve sheath
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diameter by ultrasound: a means of detecting acute raised intracranial pressure in hydrocephalus. Br J Ophthalmol. 2002;86:1109-13.
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4. Dubourg J, Javouhey E, Geeraerts T, Messerer M, Kassai B. Ultrasonography of optic nerve sheath diameter for detection of raised intracranial pressure: a systematic review
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pressure after severe brain injury. Intensive Care Med. 2007;33:1704-11. 6. Moretti R, Pizzi B. Ultrasonography of the optic nerve in neurocritically ill patients. Acta
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Anaesthesiol Scand. 2011;55:644 7. Geeraerts T, Merceron S, Benhamou D, Vigué B, Duranteau J. Non-invasive assessment of intracranial pressure using ocular sonography in neurocritical care patients. Intensive Care Med. 2008;34:2062–7. 8. Seo H, Kim Y, Shin WJ, Hwang GS. Ultrasonographic Optic Nerve Sheath Diameter Is Correlated With Arterial Carbon Dioxide Concentration During Reperfusion in Liver Transplant Recipients. Transplantation Proceedings. 2013;45:2272–2276. 9. Bernuau J, Durand F. Intracranial pressure monitoring in patients with acute liver failure: a questionable invasive surveillance. Hepatology. 2006;44:502.
ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
ACCEPTED MANUSCRIPT 10. Bäuerle J, Schuchardt F, Schroeder L, Egger K, Weigel M, Harloff A. Reproducibility and accuracy of optic nerve sheath diameter assessment using ultrasound compared to
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magnetic resonance imaging. BMC Neurology. 2013;13:187.
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11. Ballantyne SA, Neill GO, Hamilton R, Hollman AS. Observer variation in the sonographic measurement of optic nerve sheath diameter in normal adults. European
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Journal of Ultrasound. 2002;15:145–149.
12. Bäuerle J, Lochner P, Kaps M, Nedelmann M. Intra- and Inter-obsever Reliability of
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Sonographic Assessment of the Optic Nerve Sheath Diameter in Healthy Adults. J Neuroimaging. 2010;22:42–5.
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13. Zeiler FA, Unger B, Zhu Q, Xiao J, Kirkpatrick AW, Kramer AH, et al. A Unique Model for ONSD Part II: Inter/Intra-operator Variability. Can J Neurol Sci. 2014;41:430–5.
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14. Blaivas M, Theodoro D, Sierzenski PR. Elevated intracranial pressure detected by
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bedside emergency ultrasonography of the optic nerve sheath. Academic Emergency Medicine. 2003;10:376–81.
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15. Tayal VS, Neulander M, Norton HJ, Foster T, Saunders T, Blaivas M. Emergency department sonographic measurement of optic nerve sheath diameter to detect findings of
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increased intracranial pressure in adult head injury patients. Ann Emerg Med. 2007;49:508–14. 16. Kimberly HH, Shah S, Marill K, Noble V. Correlation of optic nerve sheath diameter with direct measurement of intracranial pressure. Acad Emerg Med. 2008;15:201–4. 17. Goel RS, Goyal NK, Dharap SB, Kumar M, Gore MA. Utility of optic nerve ultrasonography in head injury. Injury. 2008;39:519–24. 18. Clinical Laboratory and Standards Institute. ―How to Define and Determine Reference Intervals in the Clinical Laboratory; Approved Guideline—Second Edition‖ CLSI document C28-A2. Wayne, PA: 2000; 13-22. ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
ACCEPTED MANUSCRIPT 19. Ozgen A, Aydingöz U. Normative measurements of orbital structures using MRI. J Comput Assist Tomogr. 2000;24:493–6.
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20. Soldatos T, Karakitsos D, Chatzimichail K, Papathanasiou M, Gouliamos A, Karabinis
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A. Optic nerve sonography in the diagnostic evaluation of adult brain injury. Crit Care. 2008;12:R67.
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21. Ragauskas A, Bartusis L, Piper I, Zakelis R, Matijosaitis V, Petrikonis K, et al. Improved diagnostic value of a TCD-based non-invasive ICP measurement method compared with
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the sonographic ONSD method for detecting elevated intracranial pressure. Neurol Res. 2014;36:607–14.
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22. Ragauskas A, Matijosaitis V, Zakelis R, Petrikonis K, Rastenyte D, Piper I, Daubaris G. Clinical assessment of noninvasive intracranial pressure absolute value measurement
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method. 2012;78:1684–91.
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23. Tayal VS, Neulander M, Norton HJ, Foster T, Saunders T, Blaivas M. Emergency department sonographic measurement of optic nerve sheath diameter to detect findings of
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increased intracranial pressure in adult head injury patients. Ann Emerg Med. 2007;49:508–14.
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24. Kimberly HH, Shah S, Marill K, Noble V. Correlation of optic nerve sheath diameter with direct measurement of intracranial pressure. Acad Emerg Med. 2008;15:201–4. 25. Goel RS, Goyal NK, Dharap SB, Kumar M, Gore MA. Utility of optic nerve ultrasonography in head injury. Injury. 2008;39:519–24. 26. Geeraerts T, Newcombe VFJ, Coles JP, Abate MG, Perkes IE, Hutchinson PJA, et al. Use of T2-weighted magnetic resonance imaging of the optic nerve sheath to detect raised intracranial pressure. Crit Care. 2008;12:R114, 27. Maude RR, Hossain MA, Hassan MU, Osbourne S, Langan K, Sayeed A, et al. Transorbital sonographic evaluation of normal optic nerve sheath diameter in healthy volunteers in Bangladesh. PloS One, 2013;8:e81013. ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
ACCEPTED MANUSCRIPT 28. Sargsyan AE, Blaivas M, Geeraerts T, Karakitsos D. ―Ocular Ultrasound in the Intensive Care Unit‖ in Critical Care Ultrasound by Lumb & Karakitsos, Elsevier, 2014
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29. Varma R, Tielsch JM, Quigley HA, Hilton SC, Katz J, Spaeth GL, et al. Race-, age-,
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gender-, and refractive error-related differences in the normal optic disc. Arch Ophthalmol. 1994;112:1068-76.
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30. Jonas JB, Schmidt AM, Müller-Bergh JA, Schlötzer-Schrehardt UM, Naumann GO. Human Optic Nerve Fiber Count And Optic Disc Size. Invest. Ophthalmol. Vis. Sci.
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1992;33:2012-2018.
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Figure 1
ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
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Figure 2
ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
S0883-9441(15)00538-9 doi: 10.1016/j.jcrc.2015.10.009 YJCRC 51981
To appear in:
Journal of Critical Care
Please cite this article as: Goeres Patrick, Zeiler Frederick A., Unger Bertram, Karakitsos Dimitrios, Gillman Lawrence M., Ultrasound Assessment of Optic Nerve Sheath Diameter (ONSD) in Healthy Volunteers, Journal of Critical Care (2015), doi: 10.1016/j.jcrc.2015.10.009
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT ULTRASOUND ASSESSMENT OF OPTIC NERVE SHEATH DIAMETER (ONSD) IN HEALTHY VOLUNTEERS
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Patrick Goeres1 ([email protected])
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Frederick A. Zeiler MD1 ([email protected])
Bertram Unger MD PhD2 ([email protected])
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Dimitrios Karakitsos MD, PhD, DSc 3 ([email protected])
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Lawrence M Gillman MD MMedEd FRCSC FACS1 ([email protected])
Departments of Surgery1 and Medical Education2
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University of Manitoba, Winnipeg, Manitoba
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Department of Internal Medicine, University of South Carolina, Columbia, SC, USA 3
Presented as a podium presentation at the Trauma Association of Canada (TAC)
CE
PT
Meeting in Calgary, Alberta, April 2015.
AC
Keywords: Point of Care Ultrasound; Optic nerve sheath diameter; Ultrasound; Intracranial Pressure
* Corresponding Author
Z3053 – 409 Tache Avenue Winnipeg, Manitoba, Canada, R2H 2A6 Phone: (204) 258-1408 Fax: (204) 237-3429 Email: [email protected]
ACCEPTED MANUSCRIPT
Abstract: Background: Ultrasound assessment of optic nerve sheath diameter (ONSD) has been suggested
T
as a non-invasive measure of intracranial pressure (ICP). Numerous small studies suggest its
RI P
validity however discrepancy exists around normal values for ONSD. In this study we sought to
SC
define a normal value range for ONSD in a population of healthy adult volunteers. Methods: ONSD was measured in healthy adult volunteers and a normal range was defined using
MA
measurements and sex, age, height and weight.
NU
descriptive statistics. A regression analysis was used to determine relationship between ONSD
Results: 120 adults were recruited (age 18 - 65 (mean 29.3)) with 55 male and 65 female
ED
subjects. Mean ONSD was 3.68mm (2.85-4.40 95% Confidence Interval (CI)). Upon regression analysis, mean ONSD did not vary with age, weight or height but did vary with sex. Mean ONSD
CE
95% CI) for females.
PT
measurements for males were 3.78mm (3.23-4.48 95% CI) compared with 3.60mm (2.83-4.11
Conclusion: This study has defined the range of ONSD in a healthy cohort of volunteers. The
AC
lack of relationship to age, weight and height is similar to other studies but this is the first study to find a difference depending on sex suggesting the possible need for separate reference ranges for males and females.
ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
ACCEPTED MANUSCRIPT
Introduction Ultrasound assessment of optic nerve sheath diameter (ONSD) has been suggested as a non-
T
invasive measure of intracranial pressure (ICP) and was first described in 1987 (1). Elevated ICP is
RI P
associated with worse outcomes in head injured patients. Hence, close ICP monitoring is a fundamental strategy enabling prompt and aggressive therapy (2). Current literature supports the correlation between
SC
increased ONSD and increased ICP in a variety of adult and pediatric patient populations (3), including those with traumatic brain injury, mass lesions, infection and in transplant recipients with reperfusion
NU
injury (4, 5, 6, 7, 8).
MA
Invasive ICP monitoring via intra- parenchymal or ventricular monitors is the gold standard method in assessing ICP, but carries risks such as infection and bleeding (9). Other techniques, such as detection of papilledema via fundoscopy, have significant limitations including high operator dependence,
ED
and only qualitative rather than quantitative results. (7). Studies supporting ONSD measurements show low inter and intra observer variability (10, 11, 12, 13). Numerous small studies suggest its validity however
PT
discrepancy exists around thresholds for elevated ONSD and normal reference ranges, as most
CE
measurements are derived from unhealthy subjects who have abnormal invasive ICP measurements (7, 14, 15, 16, 17) Potential exists for a clinically useful and rapid assessment of ICP by ocular ultrasound,
AC
although a well-defined, large control population has yet to be studied. In this study, we sought to define a normal value range for ONSD in a large population of healthy adult volunteers.
Methods Subjects Healthy volunteers over the age of 18 were recruited via email and print advertisement to participate in this study. Subjects were excluded if they had any history of ocular disease/pathology or intra-cranial pathology. All subjects signed a consent form in accordance with the University of Manitoba Health Research Ethics Board. Sample Size
ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
ACCEPTED MANUSCRIPT Based on a previous study (10) we predicted a standard deviation of 0.5 in our sample and therefore power sample analysis revealed that 120 subjects would be required to predict the population’s ONSD mean to an accuracy of +/- 0.1 mm. In addition, research in laboratory medicine has shown that a
RI P
T
sample of 120 participants is adequate to determine the normal range of a population for a given test (18). Previous research of Magnetic Resonance Imaging measurements of ONSD had shown that ONSD in adults does not vary significantly by age and therefore a balanced sample covering all age ranges was felt
SC
to be unnecessary and thus 120 random subjects were sought (19). Measurement technique
NU
All measurements were performed by a single trained expert (LG). All patients were placed in a
MA
supine position with no elevation of the head of the bed and images were obtained through a closed eyelid using a generous amount of ultrasound gel. Utilizing a standard technique most widely reported in the literature (7, 20), a 13-6 MHz linear array ultrasound transducer (L25x transducer with a Sonosite M-Turbo
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Ultrasound Machine, SonoSite Inc, Bothell, WA) was used to measure the ONSD in a direction perpendicular to the axis of the nerve, in two planes for each eye, 3 mm behind the optic nerve head, for a
Statistical Analysis
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total of four measurements per subject.
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Mean ONSD, standard deviation and 95% confidence interval (CI) was calculated for each of the ONSD measurements, mean of all four measurements and the maximum of all four measurements. Each of the four ONSD measurements were compared for agreement by analysis of variance (ANOVA) and Bland Altman Plot. Main effect linear regression modeling was used to compare the relationship between mean ONSD and sex, weight and height. Analysis was completed using both the Statistical Analysis Software version 9.3 (SAS Institute, Cary NC) and R Statistical Library (R Core Team, 2013).
Results Subjects included 65 males and 55 females. Mean age was 29.3 (Range 18 – 65). Overall mean ONSD measurement was 3.68 (95% CI 2.85 – 4.40) (Table 1). Overall, there were no significant differences between any of the four measurements (p=0.87) (Figure 1). Bland Altman Plot did not ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
ACCEPTED MANUSCRIPT demonstrate any evidence of systematic bias within the data (data not shown). However, intraclass correlations (ICC) between each of the four individual measurements revealed an overall ICC of 0.765 (95% confidence interval (CI) 0.705 – 0.818) (Table 2). Linear regression revealed a relationship between
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mean ONSD and sex but no change with age, weight or height (Table 3). By gender, the mean ONSD was significantly different (p=0.0001); 3.54 (95% CI 2.83 – 4.11) for females and 3.80 (95% CI 3.23 – 4.48) for
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males (Figure 2). Discussion
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Ultrasound measurement of ONSD appears to be a promising, rapid, non-invasive bedside tool for identification of elevated ICP. There are a number of other novel, non-invasive technologies for ICP
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measurement including HeadSense (Headsense Medical Ltd, Netanya, Israel) and Vittamed 205 (UAB Vittamed, Kaunas, Lithuania). While HeadSense remains still early in development and testing phases with
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no current published trials, Vittamed on the other hand has shown some success in a number of smaller prospective trials (21, 22). Despite this, ONSD measurement remains the most widely studied, non-invasive
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technique for ICP estimation and has the advantage of not requiring any proprietary software or hardware and can be carried out using equipment already widely available in many emergency departments.
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However, an accurate cut-off value for normal versus elevated ICP has yet to be conclusively established. To date, most studies advocate a threshold of 5 mm (14, 23, 24, 25) with some studies suggesting
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thresholds as high as 5.7 - 5.9 mm (5, 7, 20, 26). However, this has been based mainly on small studies in non-healthy individuals and the true range of ONSD measurements in a healthy population is still not known. In our study, overall mean ONSD measurement was 3.68 mm (95% CI 2.85 – 4.40), which is consistent with other European studies (12) but lower than a recent Bangladeshi population (27). The authors of the Bangladeshi study wondered if the difference could be related to ethnicity. Unfortunately, we did not record ethnic origin as part of our data, though our Canadian population would likely be very similar in diversity to the other European study populations. Another reason for the lower mean measurements could relate to the technique. The technique we utilized is often referred to as the ―black stripe‖ technique and is the most common technique currently advocated in the literature (5, 7, 14, 20, 21, 24-26). However, new quality criteria recently introduced (following the data collection for this study) by Sargsyan et al. (28) may help eliminate some of this variation in results. Studies comparing these criteria to ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
ACCEPTED MANUSCRIPT the standard ―black stripe‖ technique have yet to be published however and this is an exciting area in need of further study. Our current findings suggest that the ONSD range in the general healthy population is reasonably
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wide and this could have implications for the clinical utility of ONSD ultrasound. The extent of nerve sheath dilation with increased ICP has not been clearly demonstrated, however acute increases during transplant reperfusion are shown to be approximately 0.4mm (8). Therefore, if a patient’s baseline ONSD
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was at the lower end of our demonstrated range, an increased ONSD may not be detectable with a single measurement, especially if a threshold of 5 mm or higher is used.
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The presence of a predictor of expected ONSD would be extremely helpful in better defining a
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specific threshold for elevated ICP for an individual patient. Past studies have unfortunately failed to demonstrate any relationship between ONSD and age, weight, height, sex or head circumference (11, 19, 27) in the adult population. To our knowledge, our data is the first to demonstrate a different ONSD range
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between men and women. This is however consistent with a previous study measuring optic disc size for stereoscopic optic disc photographs (29) and may relate to variations in nerve fiber density between sexes
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(30).
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This study represents the largest group studied to date with a reasonably balanced number of males and females and hence previous studies may have been underpowered to detect this difference. This
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data suggests the possible need for different reference ranges and thresholds between sexes. We demonstrate an upper limit with 95% CI to be 4.11 mm and 4.48 mm in women and men respectively, and these limits could potentially have more clinical utility than the traditional upper limit of 5 mm. While the technique of measuring the ONSD 3mm behind the optic nerve head is for the most part consistent across studies, the choice of which measure that should be used has been quite variable. The most commonly used reference is the mean of four measurements (two from each eye: horizontal and saggital) (7, 20), however, the largest of four measurements (5), the mean of two measurements (one from each eye) (14, 15) and even the mean of 6 measurements from each eye (16) have also been used. This may explain some of the variation in reference ranges and thresholds of elevated ICP seen in the literature. Our data, as in other studies, showed no significant difference overall between the mean of each of the four measurements (p=0.87), however intraclass correlations between the four measurements was only ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
ACCEPTED MANUSCRIPT 0.765 (95% confidence interval (CI) 0.705 – 0.818). This distinction is significant as it suggests that in an individual patient measurements are related, but cannot be used interchangeably. In other words, when looking at a large cohort of patients any differences in measurement between eyes averages out, but on an
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individual basis a single measurement in one eye may not be reflective of the value obtained if the opposite eye or another plane was imaged. This could be related to variability in the measurement or anatomical variation within the individual. This is an area in need of further study. Additionally, we demonstrated that
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a mean of four measurements is more precise than a single measurement. With respect to clinical utility, it would increase the rapidity of bedside ONSD assessment if one could use a single measurement, but our
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data suggests this is less likely to produce an accurate measurement.
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With respect to the choice of the mean value of four measurements or maximum value of the four measurements, we found that that the mean was the most precise measurement (smallest variance). However, since the appeal of this technique is as a rapid point of care screening test for increased ICP, the
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maximum value of the four measurements would certainly increase the sensitivity of the test though potentially at the cost of specificity.
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There are a number of limitations to our study. First the measurements are taken by a single,
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although expert, operator. Other potential variables not accounted for were ethnicity and anatomical variations, such as head circumference, although the latter has been shown not to be significant in prior
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study (27). The previously mentioned new sonographic quality criteria for ONSD measurements (28) were not utilized in this study and their possible effect on establishing a definitive range of ultrasound detected normal values is currently unknown. Work to validate these new criteria is ongoing by our group. Finally, the subjects for this study were healthy volunteers. While, the results suggest a possible sex difference in ONSD measurements and a possible alternative threshold for definition of abnormal ONSD measurement this clearly requires further study and confirmation in patients with elevated ICP measurements.
Conclusions This study has helped define the range of ONSD in a healthy cohort of volunteers. The determined range and lack of relationship to age, weight and height is similar to other studies but this is the first study
ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
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Acknowledgements
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This research was supported by a General Operating Grant from the Health Science Centre Foundation in Winnipeg, Manitoba, Canada.
ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
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Tables
3.68
Maximum
3.86
.39
2.90 – 4.40
.36
2.85 – 4.40
.38
3.00 – 4.50
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Overall Mean
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3.70
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Right Saggital
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Table 1 – Mean optic nerve sheath diameter (ONSD) , standard deviation (SD) and 97.5 % confidence intervals (CI) for each eye in both the saggital and horizontal plane, as well as mean and Measurement Mean (mm) SD 95% CI (mm) maximum of each of Left Horizontal 3.66 .42 2.80 - 4.50 the four measureme Left Saggital 3.69 .39 2.80 – 4.40 nts per Right Horizontal 3.66 .39 2.80 – 4.40 subject.
Table 2 – Intraclass correlations (ICC) between each of the four measurements of ONSD. Left Sagittal
Right Horizontal
Right Sagittal
Left Horizontal
1.0000
0.8107
0.7634
0.7735
Left Sagittal
0.8107
1.0000
0.7734
0.7523
Right Horizontal
0.7634
0.7734
1.0000
0.7160
Right Sagittal
0.7735
0.7523
0.7160
1.0000
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Left Horizontal
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0.586
Height
0.537
Weight
0.681
Sex
0.015*
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Age
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P-value
* indicated statistical significance p<0.05.
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Figure Legends
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Variable
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Table 3 – Results of main effects linear regression modeling comparing mean ONSD to height, weight and sex.
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Figure 1 : Boxplot demonstrating relationship between ONSD measurement in four planes, mean of the four measurements and the maximum (largest) of the four measurements.
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Figure 2 : Boxplot demonstrating difference between mean ONSD by gender (p=0.0001).
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Figure 1
ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation
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Figure 2
ONSD – optic nerve sheath diameter ICP – intracranial pressure CI – confidence interval ICC – intraclass correlation