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ORIGINAL RESEARCH

Optic Nerve Sheath Diameter Increase on Ascent to High Altitude Correlation With Acute Mountain Sickness Nicholas C. Kanaan, MD, Grant S. Lipman, MD, Benjamin B Constance, MD, Peter S. Holck, PhD, James F. Preuss, MBBS, Sarah R. Williams, MD, for the PAINS Group Objectives—Elevated optic nerve sheath diameter on sonography is known to correlate with increased intracranial pressure and is observed in acute mountain sickness. This study aimed to determine whether optic nerve sheath diameter changes on ascent to high altitude are associated with acute mountain sickness incidence. Methods—Eighty-six healthy adults enrolled at 1240 m (4100 ft), drove to 3545 m (11,700 ft) and then hiked to and slept at 3810 m (12,500 ft). Lake Louise Questionnaire scores and optic nerve sheath diameter measurements were taken before, the evening of, and the morning after ascent.

Received October 22, 2014, from the University of Utah, Salt Lake City, Utah USA (N.C.K.); Stanford University School of Medicine, Palo Alto, California USA (G.S.L., S.R.W.); Tacoma General Hospital, Tacoma, Washington USA (B.B.C.); University of Hawaii, Honolulu, Hawaii USA (P.S.H.); and Royal Perth Hospital, Perth, Western Australia, Australia (J.F.P.). Revision requested November 18, 2014. Revised manuscript accepted for publication December 16, 2014. We thank the University of California White Mountain Research Station for allowing the use of their facilities, SonoSite, Inc, for their generous provision of ultrasound machines, Andy Fields, PhD, for logistic support, and the hikers whose participation and enthusiasm made this study possible. We also thank the fellow researchers in the PAINS (Prevention of Altitude Illness With Nonsteroidal Anti-inflammatories) Group for their hard work: Bryan M. Corbett, MD, Jeffery H. Gertsch, MD, Erica Lewis, MD, Jessica Pierog DO, and Bryan A. Zorko, MD. This research was made possible by a research grant from the Division of Emergency Medicine, Stanford University School of Medicine. It was presented in oral format at the American College of Emergency Physicians National Meeting; October 15, 2011; San Francisco, California. Address correspondence to Nicholas C. Kanaan, MD, Division of Emergency Medicine, University of Utah, 30 N 1900 E Medical Dr, Room 1C026, Salt Lake City, UT 84132 USA. E-mail: [email protected] doi:10.7863/ultra.15.14.10060

Results—The incidence of acute mountain sickness was 55.8%, with a mean Lake Louise Questionnaire score ± SD of 3.81 ± 2.5. The mean maximum optic nerve sheath diameter increased on ascent from 5.58 ± 0.79 to 6.13 ± 0.73 mm, a difference of 0.91 ± 0.55 mm (P = .09). Optic nerve sheath diameter increased at high altitude regardless of acute mountain sickness diagnosis; however, compared to baseline values, we observed a significant increase in diameter only in those with a diagnosis of acute mountain sickness (0.57 ± 0.77 versus 0.21 ± 0.76 mm; P = .04). This change from baseline, or Δ optic nerve sheath diameter, was associated with twice the odds of developing acute mountain sickness (95% confidence interval, 1.08–3.93). Conclusions—The mean optic nerve sheath diameter increased on ascent to high altitude compared to baseline values, but not to a statistically significant degree. The magnitude of the observed Δ optic nerve sheath diameter was positively associated with acute mountain sickness diagnosis. No such significant association was found between acute mountain sickness and diameter elevation above standard cutoff values, limiting the utility of sonography as a diagnostic tool. Key Words—acute mountain sickness; emergency ultrasound; high altitude; intracranial pressure; ocular ultrasound; optic nerve sheath diameter

A

cute mountain sickness commonly occurs in those who travel expeditiously to elevations above 2500 m (8250 ft) and is characterized by a syndrome of headache, fatigue, nausea and vomiting, sleep disturbance, and dizziness.1 It occurs in upwards of 25% to 70% of the millions of tourists and trekkers who travel to high altitude around the world.2,3 Although the exact pathophysiologic mechanism of acute mountain sickness is unknown, it is often considered to be a disorder of cerebral inflammation and blood-brain barrier permeability.4,5 Normal cerebral responses to

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Kanaan et al—Optic Nerve Sheath Diameter Increase on Ascent to High Altitude

hypobaric hypoxia at high altitude include increased cerebral blood flow6–9 and ensuing mechanical stress, increased hypoxia-induced biochemical mediators,10,11 and increased blood-brain barrier permeability. The culmination of these stresses leads to the formation of mild vasogenic (extracellular) cerebral edema, which can be seen on magnetic resonance imaging and retinal scans, regardless of acute mountain sickness symptoms.12–14 It has been theorized that elevated intracranial pressure from intracranial hypertension arising from intracellular (cytotoxic) edema seen in severe acute mountain sickness and high-altitude cerebral edema may be a causative agent in the pathophysiologic mechanism of acute mountain sickness. Although lumbar puncture opening pressure15 has not been shown to correlate with intracranial pressure and acute mountain sickness, direct measurements in one case series have.16 It is well accepted that optic nerve sheath diameter is associated with elevated intracranial pressure,17–19 as the intraorbital subarachnoid space expands with increased intracranial pressure. A large cross-sectional study showed a positive association between acute mountain sickness severity and increased optic nerve sheath diameter on sonography20; however, 2 more recent prospective studies found a weak or no relationship between optic nerve sheath diameter and high-altitude headache or acute mountain sickness.21,22 The goal of this study was to evaluate optic nerve sheath diameter changes and acute mountain sickness diagnosis in a hiking population after a single-day ascent to high altitude, using, to our knowledge, the largest prospective cohort study to date.

Materials and Methods This study was part of a double-blind randomized placebocontrolled trial comparing ibuprofen and a placebo in the prevention of acute mountain sickness.23 Healthy lowaltitude–dwelling adults were randomly assigned to 600 mg of ibuprofen or a visually matched placebo 3 times daily for 4 consecutive doses starting 6 hours before ascent. Participants were enrolled at 1240 m (4100 ft), drove to 3545 m (11,700 ft), and then hiked to and slept at 3810 m (12,500 ft). At the enrollment site, initial measurements of acute mountain sickness incidence and severity were recorded by the self-reported symptom-based Lake Louise Questionnaire,1,24 and optic nerve sheath diameter was measured by portable sonography (Altimaxx; SonoSite, Inc, Bothell, WA). These measurements were repeated on arrival to the 3810-m altitude the same evening and once again the following morning.

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Participants Eligible participants were healthy, residing below 1240 m (4100 ft), and able to complete a moderately strenuous hike at high altitude. Exclusion criteria included participants who were younger than 18 or older than 65 years; were pregnant or thought to be pregnant; had slept at altitudes higher than 1240 m (4100 ft) in the past week; had taken diuretics, steroids, acetazolamide, or nonsteroidal anti-inflammatory drugs the week before the study; had an allergy to nonsteroidal anti-inflammatory drugs or aspirin; had symptoms consistent with acute mountain sickness at baseline; and had a history of a brain tumor, loss of an eye, elevated intracranial or intraocular pressure, severe asthma, gastrointestinal bleeding, or high-altitude cerebral or pulmonary edema. Participants gave informed consent and were given information on acute mountain sickness and were discouraged from using personal medications, alcohol, or tobacco. The Stanford University School of Medicine and University California San Diego Institutional Review Boards approved the study. Procedures Participants’ optic nerve sheath diameters were measured by sonography with a 7–10-MHz high-frequency linear transducer using standard techniques described in the literature.25–27 Researchers were required to have more than 30 prior optic nerve sheath diameter scans, with accuracy and technique validated by a trained sonography instructor. Participants were positioned supine, and ultrasound gel was applied to their closed eyelids. The probe was placed over the orbit without applying pressure, maintaining corneal convexity. Longitudinal and transverse still images as well as 3-second video clips of the optic nerve positioned in the plane of the posterior lens of both eyes were captured. Investigators blinded to the participants’ Lake Louise Questionnaire scores obtained measurements of the optic nerve 3 mm posterior to the globe using on-screen calipers (Figure 1). The mean of both longitudinal and transverse measurements from both eyes (total of 4 measurements) was calculated and recorded as the mean optic nerve sheath diameter for each participant. To address potential interobserver differences, deidentified image clips from 30 randomly selected participants were remeasured by a second blinded investigator and found to be in agreement with the recorded average measurements. If participants requested, a physician provided treatment for severe or debilitating acute mountain sickness symptoms, although no participants required descent. Before treatment, Lake Louise Questionnaire scores and optic nerve sheath diameter measurements

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were obtained, and the participants were withdrawn from further study participation to avoid confounding results. Statistical Analysis The primary outcomes were optic nerve sheath diameter changes on ascent and incidence of acute mountain sickness as calculated on the Lake Louise Questionnaire, with acute mountain sickness diagnosis determined by a questionnaire score higher than 3, including the presence of headache. Since acute mountain sickness has differing timelines of presentation, the maximums of the 2 questionnaire scores and diameter measurements at high altitude were used to compare to baseline. Multivariate analysis examined the association between maximum optic nerve sheath diameter at high altitude and acute mountain sickness, adjusting for potential confounders of age, sex, race, oxygenation, and diameter change between low and high altitudes. All analyses were conducted with R version 2.6.0 software.28 P < .05 was considered significant.

Figure 1. Optic nerve sheath diameter measured by sonography. A indicates on-screen calipers used to measure 3 mm posterior to the globe; and B, on-screen calipers used to measure the optic nerve sheath diameter.

Results Although 89 participants were initially enrolled in the study, 3 were excluded post hoc for meeting exclusion criteria, resulting in 86 participants. There was no significant difference in optic nerve sheath diameter between treatment groups (ibuprofen and placebo) at baseline (P = .09) or at either of the high-altitude measurements (P = .25 and .45), suggesting the combination of the 2 treatment arms as a single cohort to be reasonable (Table 1). The incidence of acute mountain sickness was 55.8% (n = 48), with a mean Lake Louise Questionnaire score ± SD 3.81 ± 2.5. Substantial variation of diameter measurements was noted in those with and without acute mountain sickness (Figure 2). There was no significant difference in optic nerve sheath diameter at baseline in those who would eventually develop acute mountain sickness and those who remained asymptomatic (P = .13). For the entire cohort, the maximum optic nerve sheath diameter increased on ascent from 5.58 ± 0.79 to 6.13 ± 0.73 mm, a difference of 0.91 ± 0.55 mm (P = .09), regardless of acute mountain sickness diagnosis. When separating the cohort by eventual acute mountain sickness diagnosis, there was statistically larger change in diameter from baseline to peak, or Δ optic nerve sheath diameter, in those with a diagnosis of acute mountain sickness (0.57 ± 0.77 versus 0.21 ± 0.76 mm; P = .04; Table 2). Multivariate analysis found no significant association of acute mountain sickness with age, sex, or oxygen saturation change. Statistically significant differences were observed in the Δ optic nerve sheath diameter in those with acute mountain sickness (P = .03), with an odds ratio of 1.99 (95% confidence interval, 1.08–3.93; Table 3).

Discussion Our results demonstrate an association between acute mountain sickness and increased Δ optic nerve sheath diameter in a group of high-altitude hikers. Given that, to our knowledge, this study is the largest prospective cohort study to date with a low-altitude baseline examining optic Table 1. Optic Nerve Sheath Diameter by Treatment Group and Combined Altitude, ft 4,000 12,500 (day 1) 12,500 (day 2)

Participants 86 86 78

Optic Nerve Sheath Diameter, mm Ibuprofen Placebo Combined 5.45 ± 0.78 5.72 ± 0.65 5.58 ± 0.91

5.71 ± 0.77 5.79 ± 0.82 5.79 ± 0.83

5.58 ± 0.79 5.76 ± 0.73 5.68 ± 0.87

P .09 .45 .25

Data are presented as mean ± SD where applicable.


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nerve sheath diameter and ascent to high altitude, the results support the theory of increased intracranial pressure in acute mountain sickness. However, we interpret the findings with caution, as we found a generalized, but not statistically significant, increase in optic nerve sheath diameter in all hikers on ascent regardless of acute mountain sickness symptoms. The mean baseline optic nerve sheath diameter of 5.58 mm was larger than the clinical threshold for raised intracranial pressure of 5 mm17,19 but within the ranges noted in one meta-analysis.29 If the threshold for a “normal” diameter is raised to 5.7 mm, the sensitivity for detecting computed tomographic evidence of elevated intracranial pressure improves from 83% to 100%, with a negative predictive value of 100%.30 Clinicians using this higher threshold of 5.7 mm may have improved screening potential.18 The observed increase in optic nerve sheath diameter is consistent with other longitudinal studies14,31 and supports the prevailing theory of vasogenic edema occurring in all brains when exposed to the hypoxic hypobaric conditions of high altitudes.4,32 Although our study identified an optic Figure 2. Baseline versus maximum optic nerve sheath diameter (ONSD) by acute mountain sickness (AMS) diagnosis; ibu indicates ibuprofen.

nerve sheath diameter increase in participants with acute mountain sickness, smaller increases were also observed in participants who did not develop acute mountain sickness, although not statistically significant. This variability may reflect subtle cerebral volume shifts in those better able to adapt and tolerate the vascular stresses of high altitude, although identification of nuances of this relationship is outside the scope of our study. These findings suggest the potential clinical importance of individuals’ optic nerve sheath diameter variations rather than set population-wide cutoff values defining an abnormal diameter at high altitude. Thus, the term Δ optic nerve sheath diameter seems to correlate better with acute mountain sickness status than standardized cutoffs.33 Several studies have evaluated the utility of portable sonography in prehospital environments,34,35 but we are cautious in promoting sonographic optic nerve sheath diameter measurement as a clinical adjunct for acute mountain sickness diagnosis. Although this caution likely limits the point-of-care application of sonography in wilderness environments to diagnose acute mountain sickness, using Δ optic nerve sheath diameter may provide a clearer clinical picture versus a single cutoff value to screen for disease. Although we show an association between Δ optic nerve sheath diameter and the presence of acute mountain sickness, the diagnosis and treatment of acute mountain sickness should be based on clinical guidelines. This study had limitations. It was conducted during an ongoing randomized controlled trial investigating ibuprofen for the prevention of acute mountain sickness. Although the relationship between nonsteroidal antiinflammatory drug ingestion and optic nerve sheath diameter has not been causally established, it is possible that changes in the intervention group’s diameters may have been affected. The sonographers doing the measurements were physicians trained to perform optic nerve sheath diameter measurements; however, they lacked formal ultrasound certification. Furthermore, whereas these physicians were blinded to the participants’ Lake Louise Questionnaire scores, they were understandably aware of the examining elevation and participants’ appearance of health.

Table 2. Optic Nerve Sheath Diameter by Eventual Acute Mountain Sickness Diagnosis Parameter Baseline optic nerve sheath diameter 4,000 ft, mm Peak optic nerve sheath diameter 12,500 ft, mm Δ optic nerve sheath diameter

Acute Mountain Sickness

No Acute Mountain Sickness

P

5.46 6.02 ± 0.74 0.57 ± 0.77

5.72 ± 0.86 5.94 ± 0.76 0.21 ± 0.76

.13 .58 .04

Data are presented as mean ± SD where applicable.

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Table 3. Multivariate Logistic Regression Analysis of Factors Associated With Development of Acute Mountain Sickness Variable Male Age White Δ optic nerve sheath diameter

OR (95% CI)

P

0.80 (0.29–2.17) 1.01 (0.98–1.05) 1.33 (0.34–5.37) 1.99 (1.08–3.93)

.67 .55 .68 .03

CI indicates confidence interval; and OR, odds ratio.

In conclusion, optic nerve sheath diameter increased on ascent to high altitude compared to baseline values, but not to a statistically significant degree. The magnitude of the observed Δ optic nerve sheath diameter was positively associated with acute mountain sickness diagnosis. No such significant association was found between acute mountain sickness and diameter elevation above standard cutoff values, limiting the utility of sonography as a diagnostic tool.

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