September 2012
Volume 53, Issue 10
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Cornea  |   September 2012
Is Whole-Body Hydration an Important Consideration in Dry Eye?
Author Affiliations & Notes
  • Neil P. Walsh
    From the College of Health and Behavioural Sciences, Bangor University, Bangor, United Kingdom;
  • Matthew B. Fortes
    From the College of Health and Behavioural Sciences, Bangor University, Bangor, United Kingdom;
  • Philippa Raymond-Barker
    From the College of Health and Behavioural Sciences, Bangor University, Bangor, United Kingdom;
  • Claire Bishop
    Geriatric Medicine, Gwynedd Hospital, Bangor, United Kingdom; the
  • Julian Owen
    From the College of Health and Behavioural Sciences, Bangor University, Bangor, United Kingdom;
  • Emma Tye
    From the College of Health and Behavioural Sciences, Bangor University, Bangor, United Kingdom;
  • Marieh Esmaeelpour
    Department of Ophthalmology, Ludwig Boltzmann Institute, Rudolph Foundation Hospital, Vienna, Austria; and the
    Center of Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria.
  • Christine Purslow
    School of Optometry and Vision Sciences, Cardiff University, Cardiff, United Kingdom; the
  • Salah Elghenzai
    Geriatric Medicine, Gwynedd Hospital, Bangor, United Kingdom; the
  • Current affiliation: *Peninsula Allied Health Centre, Plymouth University, Plymouth, United Kingdom. 
  • Corresponding author: Neil P. Walsh, College of Health and Behavioural Sciences, Bangor University, Bangor, LL57 2PZ, UK; n.walsh@bangor.ac.uk
Investigative Ophthalmology & Visual Science September 2012, Vol.53, 6622-6627. doi:10.1167/iovs.12-10175
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      Neil P. Walsh, Matthew B. Fortes, Philippa Raymond-Barker, Claire Bishop, Julian Owen, Emma Tye, Marieh Esmaeelpour, Christine Purslow, Salah Elghenzai; Is Whole-Body Hydration an Important Consideration in Dry Eye?. Invest. Ophthalmol. Vis. Sci. 2012;53(10):6622-6627. doi: 10.1167/iovs.12-10175.

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Abstract

Purpose.: To identify if whole-body hydration plays an important role in dry eye (DE). We hypothesized that individuals classified as DE have higher plasma osmolality (Posm), indicating suboptimal hydration, compared with those classified as non-DE.

Methods.: Using a hospital-based observational cross-sectional design, assessment of DE and hydration was performed upon admission in 111 participants (N = 56 males and 55 females; mean ± SD age 77 ± 8 years). Assessments of DE included tear osmolarity (Tosm), the 5-item dry eye questionnaire (DEQ-5), rating of eye dryness using a visual analogue scale (VAS), and noninvasive tear film breakup time (NITBUT). Hydration assessment was performed by measuring Posm using freezing-point depression osmometry.

Results.: Posm was higher in DE than control (CON), indicating suboptimal hydration when using the 316 mOsm/L Tosm cutoff for DE (mean Posm + 11 mOsm/kg versus CON, P = 0.004, Cohen's effect size [d]) = 0.83) and the more conservative Tosm classification for DE where Tosm >324 and CON <308 mOsm/L (mean Posm + 12 mOsm/kg versus CON, P = 0.006, d = 0.94). Posm was also higher in DE than CON when using composite DE assessments, including Tosm and DEQ-5 (P = 0.021, d = 1.07); Tosm and NITBUT (P = 0.013, d = 1.08); and the VAS and DEQ-5 (P = 0.034, d = 0.58).

Conclusions.: These are the first published data to show that individuals classified as DE have higher Posm, indicating suboptimal hydration, compared with non-DE. These findings indicate that whole-body hydration is an important consideration in DE.

Introduction
Dry eye (DE) affects the tears and ocular surface resulting in symptoms of discomfort, visual disturbance, and tear film instability with potential for damage to the ocular surface. 1 Depending upon the population studied, and the clinical assessment methods and definitions adopted, 2 the incidence of DE ranges from 0.1% to as high as 33%. 3 The etiology of DE is, at best, little understood and the current consensus is that DE is of multifactorial origin. 4 There is though widespread agreement that DE is more common in the elderly than the young, 5 and in women than men 5 and also in patients on diuretics, 6 antianxiety drugs, 5 and sex hormone medication. 7,8 A recent study estimated that the overall economic burden on the US healthcare system due to DE is close to $4 billion each year. 9 Interestingly, the losses due to decreased productivity (e.g., due to absenteeism) considerably outweighed the direct costs of care. It goes without saying that DE significantly impacts upon the individual's quality of life 10 and that additional insights to better understand both the etiology of DE, and potential therapeutic treatments for DE are welcome. 
The clinical methods often used to identify DE include: questionnaires that assess symptomatology (e.g., the dry-eye questionnaire [DEQ]) 11,12 and the ocular surface disease index 13 ; tear film breakup time (TBUT) by instilling fluorescein stain 14 ; noninvasive TBUT (NITBUT) 15 ; conjunctival staining 16 ; and the Schirmer test of tear secretion. 14 Tear film osmolarity (Tosm) is currently recognized as a primary biomarker of DE 14,17 ; this is largely because raised Tosm is involved in the ocular inflammation in DE 4 and also because measurement of Tosm can now be made using a portable device 18 that avoids the subjectivity inherent in some DE detection methods. 
To the best of our knowledge, there are no published studies that have investigated the concept that whole-body dehydration may have a role in DE. We have recently shown progressive increases in Tosm during modest, whole-body dehydration evoked by exercise and overnight fluid restriction; albeit, we used healthy, non-DE adult males and females. 19 Although we evoked only modest dehydration (2%–3% body mass loss), Tosm was greater than the recently proposed 308 mOsm/L threshold for mild/moderate DE 18 in 10 of our 14 moderately dehydrated participants, all of whom had Tosm <308 mOsm/L at the start of the trial (mean Tosm 293 mOsm/L). In addition, providing fluid boluses to improve our participants' whole-body hydration status decreased Tosm. These recent data fuel speculation that whole-body dehydration may play a role in DE 19,20 and that improving whole-body hydration by increasing fluid intake may have a therapeutic effect for DE patients. Considering this, it might not be a coincidence that DE is more common in the elderly than the young 5 as clinical whole-body dehydration (e.g., increase in extracellular tonicity), and its associated impact on morbidity and mortality, 21 is also more prevalent in this population. 22,23 To this end, we recruited an elderly cohort and assessed suitable markers of DE (e.g., Tosm, DEQ, and NITBUT) 11,14,15,17 and whole-body hydration status (plasma osmolality) 23,24 to test the hypothesis that those classified as DE have higher plasma osmolality than those classified as non-DE. 
Methods
Participants
New admissions to the acute medical unit of Gwynedd Hospital, Bangor, between July and December 2011, were targeted to participate in the study. Those over 60 years of age with capacity to consent were deemed eligible, whilst exclusion criteria for participation included recent eye surgery, contact lens wear within 8 hours, use of eye drops within 2 hours, 14 and known chronic kidney disease. All participants provided fully informed written consent. The study adhered to the Declaration of Helsinki and was approved by the North West Wales Research Ethics Committee. A total of 146 participants met the inclusion/exclusion criteria, with 35 declining to participate. Therefore, data were collected from 111 participants (N = 56 males and 55 females; mean age 77 ± 8 years). Of these, tear fluid samples were collected from 99 participants, with seven unable to tolerate the test, and five unable to provide tear fluid. 
Experimental Procedures
The study was conducted using a hospital-based observational cross-sectional model. Dry eye assessment and whole-body hydration assessment measures were performed, on admission, within a 30-minute period with no disruption to routine care. Dry eye assessment measures included, in the following order, the 5-item dry eye questionnaire (DEQ-5), rating of eye dryness using a visual analogue scale (VAS), NITBUT, and Tosm. The investigator performing NITBUT and Tosm measurements was not aware of the DEQ-5 or VAS result. Finally, for the whole-body hydration assessment, a blood sample was obtained and analyzed for plasma osmolality (Posm): the kidneys tightly regulate blood osmolality normally between 277 and 281 mOsm/kg. 25 Plasma osmolality is a widely accepted marker of whole-body hydration 24 that has been used to assess static (at one point in time) hydration in the elderly. 23 This approach enabled us to identify if participants classified as DE (see data analysis) have higher Posm than those classified as non-DE (CON). The patient's medical records were accessed to identify those taking medications known to affect tear production (e.g., diuretics, antihistamines, antidepressants, corticosteroids, immunomodulators, and sex hormone medication) 6,14 for further subanalysis. 
Dry Eye Assessment
DEQ-5.
The DEQ-5 is a validated questionnaire that has been shown to discriminate between different severities of DE. 11 Participants self-assessed the frequency and severity of eye discomfort, eye dryness and watery eyes experienced during the evening 12 of a typical day within the last month. Responses were given using a Likert scale with scoring criteria from 0 = never experienced the symptom to 5 = extremely severe experience of symptom. The sum of the scores from the five questions was used in the analysis. 
VAS.
Similar to others, 11 participants were asked to place a pencil mark on a 100-mm horizontal line corresponding to their perceived eye dryness in response to the question, “How dry do your eyes feel right now?” The scale was anchored on the left- and right-hand side of the line with the phrases “not at all dry” and “very dry,” respectively. The length in mm from the left end of the line to the pencil mark was measured to provide a rating of perceived eye dryness. 
NITBUT.
Tear film stability was assessed noninvasively using the Tearscope-Plus (Keeler Instruments, Windsor, UK) as previously described. 15,26 The Tearscope-Plus is a handheld device which fits over the eye socket. A light within the device (Keeler Instruments) illuminates the eye and a grid is reflected onto the cornea. Participants were instructed to blink once and then refrain from blinking for as long as possible while the investigator looked for distortion in the reflected pattern. The investigator recorded NITBUT as the elapsed time in seconds between the blink and distortion. This procedure was repeated three times and the median value used in analyses. 
Tosm.
Tear fluid was collected and analyzed for Tosm using a commercially available device (TearLab Osmolarity System, San Diego, CA) as previously described. 19 Tear fluid was collected from the same eye on which the NITBUT measurement was performed. 
Whole-Body Hydration Assessment
Blood samples were collected from an antecubital vein or from the back of the hand into a vacutainer tube containing lithium heparin (Becton Dickinson, Oxford, UK). Blood samples were spun at 1500g for 10 minutes at 4°C in a centrifuge. Triplicate measurements of Posm were made using a freezing point depression osmometer (Model 330 MO; Advanced Instruments, Norwood, MA) as described. 19 The analytical coefficient of variation for repeated Posm measurements was 0.7% (2 mOsm/kg). 
Data Analysis
To identify participants with DE, we have used three different approaches for group comparisons. The first approach classified DE using Tosm alone. Here we used the recently proposed single Tosm cutoff value of 316 mOsm/L, 27 whereby participants with a Tosm >316 mOsm/L formed the DE group and those with a Tosm ≤316 mOsm/L formed the CON group. We also used a Tosm grouping based upon the modified DEWS Severity Scale, 14 whereby those with a Tosm >324 mOsm/L formed the DE group, and those with a Tosm <308 mOsm/L formed the CON group. For the second, more conservative approach to DE classification, we adopted composite measures of DE as recently recommended. 14 Participants had to fulfill two criteria to be classified as DE, which included a Tosm >324 mOsm/L and a DEQ-5 score ≥6, as previously described. 11 In this classification, CON were those with Tosm <308 mOsm/L and DEQ-5 <6. Also, participants were classified based upon a composite of Tosm >324 mOsm/L and a NITBUT <10 seconds, as previously described. 15,26 In this classification, CON were those with Tosm <308 mOsm/L and NITBUT ≥10 seconds. The data for each of the classifications described above are presented two ways; first, excluding those participants taking medications known to cause eye dryness (e.g., diuretics, antihistamines, antidepressants, corticosteroids, immunomodulators, and sex hormone medications) 6,14 ; and second, by presenting the data for all participants, regardless of medication. The group means ± SD for each ocular measurement for each of the above approaches to classify DE and CON are presented in Table 1. The third and final approach we have adopted to classify groups used only self-reported subjective measures of DE, where those participants who demonstrated both a VAS ≥6 (mean ± SD, 7.5 ± 1.0) and a DEQ-5 ≥6 (mean ± SD 9.7 ± 3.5) formed the DE group, while those with a VAS <6 (mean ± SD, 1.2 ± 1.5) and a DEQ-5 <6 (mean ± SD, 1.9 ± 1.8), formed the CON group. A sample size calculation was performed to determine the minimum N to identify a significant difference in Posm between DE and CON. An N = 11 in each group was required to detect a meaningful difference in Posm of 9 mOsm/kg, 24 using a population standard deviation from an elderly cohort, 28 with α and β set at 0.05 and 0.8, respectively. All between group differences (CON and DE) were analyzed using independent t-tests. In addition, the meaningfulness of group differences was also calculated using a Cohen's d effect size using the following equation: where 1 is the mean of DE, and 2 is the mean of CON. Cohen's d effect sizes greater than 0.2, 0.5, and 0.8 represent small, medium, and large effects, respectively. 29 Finally, a Pearson's correlation was performed to determine the association between Posm and Tosm. All data were analyzed using statistical software (SPSS version 14; MathWorks, Natick, MA). Data in the text and figures are presented as mean ± SD. Statistical significance was accepted at P < 0.05. 
Table 1. 
 
Ocular Characteristics for DE and CON Groupings
Table 1. 
 
Ocular Characteristics for DE and CON Groupings
Tosm, DE >316† Tosm, DE >324‡ Tosm and DEQ-5§ Tosm and NITBUT||
Tosm, mOsm/L Tosm, mOsm/L Tosm, mOsm/L DEQ-5 Tosm, mOsm/L NITBUT, s
No medications
 DE 346 ± 28* 354 ± 27* 356 ± 30* 10.1 ± 3.9* 361 ± 31* 6.2 ± 2.0*
 CON 297 ± 14 291 ± 12 286 ± 11 2.0 ± 2.4 292 ± 13 15.8 ± 5.3
All participants
 DE 347 ± 28* 356 ± 27* 356 ± 28* 8.9 ± 3.2* 357 ± 27* 6.8 ± 2.2*
 CON 300 ± 13 293 ± 11 290 ± 10 2.1 ± 2.0 294 ± 11 21.1 ± 10.9
Results
DE Classified Using Tosm
In participants who were not taking any medication known to cause eye dryness, those classified as DE using Tosm alone presented with a significantly higher Posm than CON using both the single Tosm 316 mOsm/L cutoff (mean Posm + 11 mOsm/kg versus CON, P = 0.004, Cohen's d = 0.83, Fig. 1A) and the more conservative classification where DE Tosm >324 and CON <308 mOsm/L (mean Posm + 12 mOsm/kg versus CON, P = 0.006, Cohen's d = 0.94; Fig. 1B). This finding was highly significant and gave large effect sizes. There were also significant differences and small-medium effect sizes when all participants, including those taking medications known to cause eye dryness, were included. For example, Posm was higher in DE than CON when using the single Tosm 316 mOsm/L cutoff (P = 0.039, Cohen's d = 0.36; Table 2) and the more conservative Tosm classification where DE Tosm >324 and CON <308 mOsm/L (P = 0.045, Cohen's d = 0.42; Table 2). There was a small but significant correlation between Tosm and Posm (r = 0.34, r 2 = 0.12, P = 0.021). The mean Posm for the five participants for whom tear fluid samples could not be collected after three attempts (even though they could all tolerate the procedure) was 292 ± 5 mOsm/kg. 
Figure 1. 
 
Whole-body hydration status assessed using plasma osmolality in participants classified as DE using Tosm after removal of participants on known ocular drying medications. Data for plasma osmolality shown in panel A use a single Tosm cutoff of 316 mOsm/L (DE >316, CON ≤316 mOsm/L), and panel B where DE Tosm >324 mOsm/L and CON <308 mOsm/L. Data are mean ± SD. Cohen's d effect sizes were 0.83 and 0.94 for (A) and (B) indicating “large” effects. Panel A: DE N = 26 and CON N = 15. Panel B: DE N = 20 and CON N = 10.
Figure 1. 
 
Whole-body hydration status assessed using plasma osmolality in participants classified as DE using Tosm after removal of participants on known ocular drying medications. Data for plasma osmolality shown in panel A use a single Tosm cutoff of 316 mOsm/L (DE >316, CON ≤316 mOsm/L), and panel B where DE Tosm >324 mOsm/L and CON <308 mOsm/L. Data are mean ± SD. Cohen's d effect sizes were 0.83 and 0.94 for (A) and (B) indicating “large” effects. Panel A: DE N = 26 and CON N = 15. Panel B: DE N = 20 and CON N = 10.
Table 2. 
 
Whole-Body Hydration Status Measured by Posm in All Participants (Including Those Taking Medication) for DE and Non-DE CON Groups
Table 2. 
 
Whole-Body Hydration Status Measured by Posm in All Participants (Including Those Taking Medication) for DE and Non-DE CON Groups
Tosm Alone, 316 Cutoff Tosm Alone, >324 and <308 Cutoff Tosm and DEQ-5§ Tosm and NITBUT||
Plasma osmolality, mOsm/kg
 DE (N) 288 ± 11* (54) 288 ± 10* (31) 288 ± 12* (17) 287 ± 10 (22)
 CON (N) 284 ± 10 (45) 284 ± 11 (28) 279 ± 13 (14) 283 ± 10 (17)
 Cohen's d 0.36 0.42 0.70 0.44
DE Classified Using Composite Assessments
Using composite measures to classify DE—and with medications known to cause eye dryness excluded—once again, participants classified as DE exhibited significantly higher Posm than CON which, despite the small sample size, resulted in very large effect sizes (Figs. 2A, 2B). For example, Posm was higher in DE than CON when using Tosm and DEQ-5 to classify DE (mean Posm + 14 mOsm/kg versus CON, P = 0.021, Cohen's d = 1.07; Fig. 2A) and when using Tosm and NITBUT to classify DE (mean Posm + 13 mOsm/kg versus CON, P = 0.013, Cohen's d = 1.08; Fig. 2B). When all participants were considered, including those taking medications known to cause eye dryness, there was a significant effect upon hydration when groups were stratified using Tosm and DEQ-5 (P = 0.024, Cohen's d = 0.70; Table 2). There was a trend for a higher Posm in DE than CON when groups were stratified using Tosm and NITBUT (P = 0.089, Cohen's d = 0.44; Table 2). 
Figure 2. 
 
Whole-body hydration status assessed using plasma osmolality in participants classified as DE using composite DE assessments after removal of participants on known ocular drying medications. Data for plasma osmolality are shown in panel A where DE Tosm >324 mOsm/L and DEQ-5 ≥6 and CON Tosm <308 mOsm/L and DEQ-5 <6. Data shown in panel B where DE Tosm >324 mOsm/L and NITBUT <10 seconds and CON where Tosm <308 mOsm/L and NITBUT ≥10 seconds. Data are mean ± SD. Cohen's d effect sizes were 1.07 and 1.08 for (A) and (B) indicating “large” effects. Panel A: DE N = 8 and CON N = 6. Panel B: DE N = 12 and CON N = 6.
Figure 2. 
 
Whole-body hydration status assessed using plasma osmolality in participants classified as DE using composite DE assessments after removal of participants on known ocular drying medications. Data for plasma osmolality are shown in panel A where DE Tosm >324 mOsm/L and DEQ-5 ≥6 and CON Tosm <308 mOsm/L and DEQ-5 <6. Data shown in panel B where DE Tosm >324 mOsm/L and NITBUT <10 seconds and CON where Tosm <308 mOsm/L and NITBUT ≥10 seconds. Data are mean ± SD. Cohen's d effect sizes were 1.07 and 1.08 for (A) and (B) indicating “large” effects. Panel A: DE N = 8 and CON N = 6. Panel B: DE N = 12 and CON N = 6.
DE Classified Using Self-Report Assessments
Using this approach, Posm in DE was significantly higher than CON (mean Posm + 6 mOsm/kg versus CON, P = 0.034; Fig. 3), where Cohen's d = 0.58 indicated a medium effect. 
Figure 3. 
 
Whole-body hydration status assessed using plasma osmolality in all participants classified as DE where the VAS reading for eye dryness was ≥6 cm and DEQ-5 was ≥6 (N = 12) and CON where VAS <6 cm and DEQ-5 <6 (N = 57). Data are mean ± SD. Cohen's d effect size = 0.58 indicates a “medium” effect.
Figure 3. 
 
Whole-body hydration status assessed using plasma osmolality in all participants classified as DE where the VAS reading for eye dryness was ≥6 cm and DEQ-5 was ≥6 (N = 12) and CON where VAS <6 cm and DEQ-5 <6 (N = 57). Data are mean ± SD. Cohen's d effect size = 0.58 indicates a “medium” effect.
Discussion
The aim of the present study was to identify whether whole-body hydration status is an important consideration in DE. To achieve this aim, we recruited an elderly cohort in an observational, cross-sectional design and assessed suitable markers of DE (e.g., Tosm, DEQ, and NITBUT) 11,14,15,17 and whole-body hydration status (Posm). 23,24 The data support our hypothesis and, to the best of our knowledge, are the first to show that participants classified as DE have higher Posm, indicating suboptimal whole body hydration, than those classified as non-DE. This effect was apparent using a number of different methods to classify DE. Future studies should identify whether improving whole body hydration in a rigorous fluid intervention experimental model confers important therapeutic effects for patients with DE. Besides the widely accepted advantages of maintaining euhydration for optimal cognitive function, physical function and health, 2123 the current findings indicate that whole-body hydration status is also an important consideration in DE, at least in the elderly. 
The current findings support our hypothesis, and our recent speculation, 19,20 that whole-body hydration may play a role in DE. Recently, in healthy young adults, we showed a progressive increase in Tosm during modest, whole-body dehydration and a decrease in Tosm after fluid boluses to improve our participants' whole-body hydration. 19 Although the mechanism(s) by which whole body hydration influences Tosm remains to be elucidated, we hypothesize that tear secretion decreases with progressive dehydration, thus concentrating the tear fluid (i.e., increasing Tosm) in a manner similar to which the decrease in saliva flow rate with progressive whole body dehydration is known to increase saliva osmolality. 30,31 This hypothesis requires investigation in appropriately designed whole-body dehydration studies that make parallel measures of tear secretion and Tosm. Given that raised Tosm is involved in the ocular inflammation in DE, 4 any variable that influences Tosm must be given due consideration in the context of both the etiology of DE and the treatment of the various types of DE. Future studies should identify whether whole-body hydration is an important consideration in the various types and subcategories of DE as described in the DEWS report (e.g., aqueous-deficient DE and evaporative DE), as we recognize that we didn't make such distinctions in the present study. 1 Although we did not assess inter-eye Tosm variability, as has recently been suggested to be a hallmark of DE, 18 we have shown a significant and meaningful difference in whole-body hydration status between participants categorized as DE and CON using a stringent Tosm stratification (whereby DE Tosm >324 mOsm/L using the modified DEWS Severity Scale; Fig. 1B). 14 Also, when using a range of composite DE clinical assessment tools as recently recommended (Figs. 2A, 2B) 14 and when using our total participant cohort in comparisons, the significant difference in whole body hydration between DE and CON was still evident when including participants on medications known to cause eye dryness (Table 2). 
Whole-body hydration status has been assessed with varying degrees of success using urine, 32,33 saliva, 30,31 and tears, 19 but Posm is the most widely accepted whole-body hydration marker. 24 Studies investigating whole-body hydration in the elderly often adopt a Posm dehydration threshold of 295 mOsm/kg 23,34 ; but due to the ease and availability of automated analyzers, Posm is often “calculated” rather than “directly measured.” The direct measurement of Posm using freezing point depression is the preferred method. 35 The calculation of Posm has also been performed various ways, further adding to the confusion—for example, using Equation (1): (2 × [sodium + potassium]) + (glucose) 23 or Equation (2): (2 × [sodium + potassium]) + (glucose) + (blood urea nitrogen), 34 where units are mmol/L. Calculating Posm typically results in higher readings than directly measuring Posm. 36 In a separate study in our laboratory, we collected 94 blood samples and measured Posm using freezing point depression and calculated Posm using Equations (1) and (2). We found that calculating Posm resulted in a mean bias of +3 mOsm/kg for Equation (1) and +12 mOsm/kg for Equation (2) (Fortes MB, unpublished observation, 2011). Taking this positive bias for calculated Posm into account, the measured Posm in our participants classified as DE (Figs. 13, and Table 2) are equivalent to, or exceed, the 295 mOsm/kg dehydration threshold adopted in studies of whole-body hydration in the elderly using calculated Posm. 23,34 In addition, it is important to reiterate our finding that the difference in measured Posm between participants classified as DE and CON (e.g., DE Posm +14 mOsm/kg versus CON, Fig. 2A) is meaningful 24 and represents suboptimal whole-body hydration in DE. 
The present findings showing suboptimal whole-body hydration in DE versus non-DE individuals raise the exciting prospect that improving whole-body hydration with fluid intervention might confer important therapeutic effects for patients with DE. Indeed, under tightly controlled laboratory conditions, we have recently shown—albeit in non-DE individuals—that fluid boluses decrease Tosm to baseline levels after Tosm was raised by whole-body dehydration. 19 Also, reducing the osmolarity of the tear film using hypotonic eye drops (150 mOsm/L) rather than isotonic eye drops (300 mOsm/L) has been shown to decrease DE symptoms in DE patients: 37 this lends further support to the premise that raised Tosm is central in DE 4 and the concept that decreasing Tosm through improvements in whole body hydration might also decrease DE symptoms. To examine this further, we performed a small pilot study where we collected plasma and tear fluid samples in an elderly mild/moderate DE 18 cohort (N = 8) whose initial Tosm was >308 mOsm/L and who showed an improvement in whole-body hydration (decrease in Posm) during a 48-hour hospital stay. The improvement in whole-body hydration in these modestly dehydrated patients (decrease in Posm from 296 ± 14 to 289 ± 13 mOsm/kg) was accompanied by a significant decrease in Tosm from 335 ± 33 to 308 ± 10 mOsm/L (P = 0.038, Cohen's d = 0.96 indicating a large effect; Fortes MB, unpublished observations, 2011). After excluding patients on ocular drying medications, the remaining five patients still showed a large effect for the reduction in Tosm from 336 ± 36 to 312 ± 10 mOsm/L with improved whole-body hydration (Cohen's d = 0.86), albeit this did not reach statistical significance (P = 0.112). Clearly, large-scale studies are needed to confirm that improving whole-body hydration status in a rigorous fluid intervention experimental model confers important therapeutic effects for patients with DE. 
In conclusion, these are the first published data to show that individuals classified as DE using a number of different methods have higher Posm, indicating suboptimal whole-body hydration, compared with those classified as non-DE. Large-scale studies are required in DE patients to identify whether improving whole-body hydration may serve as a therapy to reduce DE symptoms. 
References
The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop. Ocul Surf . 2007;5:75–92. [CrossRef] [PubMed]
McCarty CA Bansal AK Livingston PM Stanislavsky YL Taylor HR. The epidemiology of dry eye in Melbourne, Australia. Ophthalmology . 1998;105:1114–1119. [CrossRef] [PubMed]
Pflugfelder SC. Prevalence, burden, and pharmacoeconomics of dry eye disease. Am J Manag Care . 2008;14:S102–S106. [PubMed]
Lemp MA. Advances in understanding and managing dry eye disease. Am J Ophthalmol . 2008;146:350–356. [CrossRef] [PubMed]
Moss SE Klein R Klein BE. Long-term incidence of dry eye in an older population. Optom Vis Sci . 2008;85:668–674. [CrossRef] [PubMed]
Smidt D Torpet LA Nauntofte B Heegaard KM Pedersen AM. Associations between oral and ocular dryness, labial and whole salivary flow rates, systemic diseases and medications in a sample of older people. Community Dent Oral Epidemiol . 2011;39:276–288. [CrossRef] [PubMed]
Schaumberg DA Buring JE Sullivan DA Dana MR. Hormone replacement therapy and dry eye syndrome. JAMA . 2001;286:2114–2119. [CrossRef] [PubMed]
Sullivan DA. Tearful relationships? Sex, hormones, the lacrimal gland, and aqueous-deficient dry eye. Ocul Surf . 2004;2:92–123. [CrossRef] [PubMed]
Yu J Asche CV Fairchild CJ. The economic burden of dry eye disease in the United States: a decision tree analysis. Cornea . 2011;30:379–387. [CrossRef] [PubMed]
Mertzanis P Abetz L Rajagopalan K The relative burden of dry eye in patients' lives: comparisons to a U.S. normative sample. Invest Ophthalmol Vis Sci . 2005;46:46–50. [CrossRef] [PubMed]
Chalmers RL Begley CG Caffery B. Validation of the 5-Item Dry Eye Questionnaire (DEQ-5): Discrimination across self-assessed severity and aqueous tear deficient dry eye diagnoses. Cont Lens Anterior Eye . 2010;33:55–60. [CrossRef] [PubMed]
Begley CG Caffery B Chalmers RL Mitchell GL. Use of the dry eye questionnaire to measure symptoms of ocular irritation in patients with aqueous tear deficient dry eye. Cornea . 2002;21:664–670. [CrossRef] [PubMed]
Schiffman RM Christianson MD Jacobsen G Hirsch JD Reis BL. Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol . 2000;118:615–621. [CrossRef] [PubMed]
Sullivan BD Whitmer D Nichols KK An objective approach to dry eye disease severity. Invest Ophthalmol Vis Sci. 2010;51:6125–6130. [CrossRef] [PubMed]
Srinivasan S Joyce E Senchyna M Simpson T Jones L. Clinical signs and symptoms in post-menopausal females with symptoms of dry eye. Ophthalmic Physiol Opt . 2008;28:365–372. [CrossRef] [PubMed]
Pult H Purslow C Murphy PJ. The relationship between clinical signs and dry eye symptoms. Eye (Lond) . 2011;25:502–510. [CrossRef] [PubMed]
Tomlinson A McCann LC Pearce EI. Comparison of human tear film osmolarity measured by electrical impedance and freezing point depression techniques. Cornea . 2010;29:1036–1041. [CrossRef] [PubMed]
Lemp MA Bron AJ Baudouin C Tear osmolarity in the diagnosis and management of dry eye disease. Am J Ophthalmol . 2011;151:792–798. [CrossRef] [PubMed]
Fortes MB Diment BC Di Felice U Tear fluid osmolarity as a potential marker of hydration status. Med Sci Sports Exerc . 2011;43:1590–1597. [CrossRef] [PubMed]
Walsh NP Fortes MB Esmaeelpour M. Influence of modest changes in whole-body hydration on tear fluid osmolarity: Important considerations for dry eye disease detection. Cornea . 2011;30:1517–1518. [CrossRef] [PubMed]
Grandjean AC Reimers KJ Buyckx ME. Hydration: issues for the 21st century. Nutr Rev . 2003;61:261–271. [CrossRef] [PubMed]
Ferry M. Strategies for ensuring good hydration in the elderly. Nutr Rev . 2005;63:S22–S29. [CrossRef] [PubMed]
Stookey JD. High prevalence of plasma hypertonicity among community-dwelling older adults: results from NHANES III. J Am Diet Assoc . 2005;105:1231–1239. [CrossRef] [PubMed]
Cheuvront SN Ely BR Kenefick RW Sawka MN. Biological variation and diagnostic accuracy of dehydration assessment markers. Am J Clin Nutr . 2010;92:565–573. [CrossRef] [PubMed]
Armstrong LE. Assessing hydration status: the elusive gold standard. J Am Coll Nutr . 2007;26:575S–584S. [CrossRef] [PubMed]
Mengher LS Bron AJ Tonge SR Gilbert DJ. A non-invasive instrument for clinical assessment of the pre-corneal tear film stability. Curr Eye Res . 1985;4:1–7. [CrossRef] [PubMed]
Tomlinson A Khanal S Ramaesh K Diaper C McFadyen A. Tear film osmolarity: determination of a referent for dry eye diagnosis. Invest Ophthalmol Vis Sci . 2006;47:4309–4315. [CrossRef] [PubMed]
McLean KA O'Neill PA Davies I Morris J. Influence of age on plasma osmolality: a community study. Age Ageing . 1992;21:56–60. [CrossRef] [PubMed]
Cohen J. Statistical Power Analysis for the Behavioral Sciences . 2nd ed. Hillsdale, NJ: Erlbaum Associates; 1988.
Walsh NP Laing SJ Oliver SO Montague JC Walters R Bilzon JL. Saliva parameters as potential indices of hydration status during acute dehydration. Med Sci Sports Exerc . 2004;36:1535–1542. [CrossRef] [PubMed]
Walsh NP Montague JC Callow N Rowlands AV. Saliva flow rate, total protein concentration and osmolality as potential markers of whole body hydration status during progressive acute dehydration in humans. Arch Oral Biol . 2004;49:149–154. [CrossRef] [PubMed]
Armstrong LE Maresh CM Castellani JW Urinary indices of hydration status. Int J Sport Nutr . 1994;4:265–279. [PubMed]
Armstrong LE Pumerantz AC Fiala KA Human hydration indices: acute and longitudinal reference values. Int J Sport Nutr Exerc Metab . 2010;20:145–153. [PubMed]
Thomas DR Tariq SH Makhdomm S Haddad R Moinuddin A. Physician misdiagnosis of dehydration in older adults. J Am Med Dir Assoc . 2004;5:S30–S34. [CrossRef] [PubMed]
Bhagat CI Garcia-Webb P Fletcher E Beilby JP. Calculated vs measured plasma osmolalities revisited. Clin Chem . 1984;30:1703–1705. [PubMed]
Stookey JD Burg M Sellmeyer DE A proposed method for assessing plasma hypertonicity in vivo. Eur J Clin Nutr . 2007;61:143–146. [CrossRef] [PubMed]
Troiano P Monaco G. Effect of hypotonic 0.4% hyaluronic acid drops in dry eye patients: a cross-over study. Cornea . 2008;27:1126–1130. [CrossRef] [PubMed]
Footnotes
 Disclosure: N.P. Walsh, None; M.B. Fortes, None; P. Raymond-Barker, None; C. Bishop, None; J. Owen, None; E. Tye, None; M. Esmaeelpour, None; C. Purslow, None; S. Elghenzai, None
Figure 1. 
 
Whole-body hydration status assessed using plasma osmolality in participants classified as DE using Tosm after removal of participants on known ocular drying medications. Data for plasma osmolality shown in panel A use a single Tosm cutoff of 316 mOsm/L (DE >316, CON ≤316 mOsm/L), and panel B where DE Tosm >324 mOsm/L and CON <308 mOsm/L. Data are mean ± SD. Cohen's d effect sizes were 0.83 and 0.94 for (A) and (B) indicating “large” effects. Panel A: DE N = 26 and CON N = 15. Panel B: DE N = 20 and CON N = 10.
Figure 1. 
 
Whole-body hydration status assessed using plasma osmolality in participants classified as DE using Tosm after removal of participants on known ocular drying medications. Data for plasma osmolality shown in panel A use a single Tosm cutoff of 316 mOsm/L (DE >316, CON ≤316 mOsm/L), and panel B where DE Tosm >324 mOsm/L and CON <308 mOsm/L. Data are mean ± SD. Cohen's d effect sizes were 0.83 and 0.94 for (A) and (B) indicating “large” effects. Panel A: DE N = 26 and CON N = 15. Panel B: DE N = 20 and CON N = 10.
Figure 2. 
 
Whole-body hydration status assessed using plasma osmolality in participants classified as DE using composite DE assessments after removal of participants on known ocular drying medications. Data for plasma osmolality are shown in panel A where DE Tosm >324 mOsm/L and DEQ-5 ≥6 and CON Tosm <308 mOsm/L and DEQ-5 <6. Data shown in panel B where DE Tosm >324 mOsm/L and NITBUT <10 seconds and CON where Tosm <308 mOsm/L and NITBUT ≥10 seconds. Data are mean ± SD. Cohen's d effect sizes were 1.07 and 1.08 for (A) and (B) indicating “large” effects. Panel A: DE N = 8 and CON N = 6. Panel B: DE N = 12 and CON N = 6.
Figure 2. 
 
Whole-body hydration status assessed using plasma osmolality in participants classified as DE using composite DE assessments after removal of participants on known ocular drying medications. Data for plasma osmolality are shown in panel A where DE Tosm >324 mOsm/L and DEQ-5 ≥6 and CON Tosm <308 mOsm/L and DEQ-5 <6. Data shown in panel B where DE Tosm >324 mOsm/L and NITBUT <10 seconds and CON where Tosm <308 mOsm/L and NITBUT ≥10 seconds. Data are mean ± SD. Cohen's d effect sizes were 1.07 and 1.08 for (A) and (B) indicating “large” effects. Panel A: DE N = 8 and CON N = 6. Panel B: DE N = 12 and CON N = 6.
Figure 3. 
 
Whole-body hydration status assessed using plasma osmolality in all participants classified as DE where the VAS reading for eye dryness was ≥6 cm and DEQ-5 was ≥6 (N = 12) and CON where VAS <6 cm and DEQ-5 <6 (N = 57). Data are mean ± SD. Cohen's d effect size = 0.58 indicates a “medium” effect.
Figure 3. 
 
Whole-body hydration status assessed using plasma osmolality in all participants classified as DE where the VAS reading for eye dryness was ≥6 cm and DEQ-5 was ≥6 (N = 12) and CON where VAS <6 cm and DEQ-5 <6 (N = 57). Data are mean ± SD. Cohen's d effect size = 0.58 indicates a “medium” effect.
Table 1. 
 
Ocular Characteristics for DE and CON Groupings
Table 1. 
 
Ocular Characteristics for DE and CON Groupings
Tosm, DE >316† Tosm, DE >324‡ Tosm and DEQ-5§ Tosm and NITBUT||
Tosm, mOsm/L Tosm, mOsm/L Tosm, mOsm/L DEQ-5 Tosm, mOsm/L NITBUT, s
No medications
 DE 346 ± 28* 354 ± 27* 356 ± 30* 10.1 ± 3.9* 361 ± 31* 6.2 ± 2.0*
 CON 297 ± 14 291 ± 12 286 ± 11 2.0 ± 2.4 292 ± 13 15.8 ± 5.3
All participants
 DE 347 ± 28* 356 ± 27* 356 ± 28* 8.9 ± 3.2* 357 ± 27* 6.8 ± 2.2*
 CON 300 ± 13 293 ± 11 290 ± 10 2.1 ± 2.0 294 ± 11 21.1 ± 10.9
Table 2. 
 
Whole-Body Hydration Status Measured by Posm in All Participants (Including Those Taking Medication) for DE and Non-DE CON Groups
Table 2. 
 
Whole-Body Hydration Status Measured by Posm in All Participants (Including Those Taking Medication) for DE and Non-DE CON Groups
Tosm Alone, 316 Cutoff Tosm Alone, >324 and <308 Cutoff Tosm and DEQ-5§ Tosm and NITBUT||
Plasma osmolality, mOsm/kg
 DE (N) 288 ± 11* (54) 288 ± 10* (31) 288 ± 12* (17) 287 ± 10 (22)
 CON (N) 284 ± 10 (45) 284 ± 11 (28) 279 ± 13 (14) 283 ± 10 (17)
 Cohen's d 0.36 0.42 0.70 0.44
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