Physiologic basis for understanding quantitative dehydration assessment
Physiologic basis for understanding quantitative dehydration assessment1-4
Samuel N Cheuvront
Robert W Kenefick
Michael N Sawka
Dehydration (body water deficit) is a physiologic state that can have profound implications for human health and performance. Unfortunately, dehydration can be difficult to assess, and there is no single, universal gold standard for decision making. In this article, we review the physiologic basis for understanding quantitative dehydration assessment. We highlight how phenomenologic interpretations of dehydration depend critically on the type (dehydration compared with volume depletion) and magnitude (moderate compared with severe) of dehydration, which in turn influence the osmotic (plasma osmolality) and blood volume-dependent compensatory thresholds for antidiuretic and thirst responses. In particular, we review new findings regarding the biological variation in osmotic responses to dehydration and discuss how this variation can help provide a quantitative and clinically relevant link between the physiology and phenomenology of dehydration. Practical measures with empirical thresholds are provided as a starting point for improving the practice of dehydration assessment. Am J Clin Nutr 2013;97:455-62.
Dehydration (body water deficit) is a common physiologic state
that can have profound implications for human health (
). Although mild dehydration can be easily
corrected and is principally associated with impaired physical
), it may be linked with common public health
disorders if left chronically untreated (
). A greater severity of
dehydration can result in significant medical costs, morbidity, and
mortality across the life span (
). Although the physiology of
osmotic and vascular volume responses to dehydration in humans
have been well described (
), the phenomenology of
dehydration assessment has not. For example, there is no single,
universal gold standard method of dehydration assessment for
clinical decision making (
7, 15, 16
), which contributes greatly to
the difficulty that clinicians encounter when trying to accurately
assess dehydration in practice (
). This discordance between
the physiology and phenomenology of dehydration is a
recognized source of clinical confusion (17) for which clarity is needed
to improve the practice of dehydration assessment.
In this review, we highlight how phenomenologic
interpretations of dehydration depend critically on the type (dehydration
compared with volume depletion) and magnitude (moderate
compared with severe) of dehydration, which, in turn, influence
the plasma osmolality (Posm)5– and blood volume
(BV)–dependent compensatory thresholds for antidiuretic and thirst
responses. We also discuss the recent application of biological
variation analysis to osmotic responses during dehydration for
its novel potential as an adjunct (
) to clinical decision making.
Posm is the primary focus of this review because it is the key
regulated variable in fluid balance (
13, 14, 26–28
), and it is
commonly used to screen for dehydration and complement more
quantitative differential diagnoses of dysnatremias and other
3, 5, 28–30
). The osmolality of other body fluids
commonly used to assess dehydration (ie, urine and saliva) are
also mentioned as is the practical assessment of volume
depletion. Descriptions of other potential methods of dehydration
and volume-depletion assessment have been provided by other
7, 16, 19, 31, 32
). Complementary reviews (
similarly suggested for detailed information related to sodium
(natriuresis and appetite) and nonosmotic contributors (eg,
baroreceptors) to osmotic homeostasis.
FUNDAMENTALS OF OSMOTIC RESPONSES TO
DEHYDRATION IN HUMANS
In its simplest form, the net body water balance is generally the
zero sum of food (water and solute) and fluid intake minus
insensible and obligatory renal water losses (
). Fluid intakes,
1 From the US Army Research Institute of Environmental Medicine,
2 The opinions or assertions contained herein are the private views of the
authors and should not be construed as official or reflecting the views of the
Army the Department of Defense.
3 Supported by the United States Army Medical Research and Materiel
4 Address correspondence to SN Cheuvront, Thermal and Mountain
Medicine Division, US Army Research Institute of Environmental Medicine,
Kansas Street, Building 42, Natick, MA 01760-5007. E-mail: samuel.n.
5 Abbreviations used: AVP, arginine vasopressin; Bm, body mass; BV,
blood volume; Posm, plasma osmolality; PV, plasma volume; Sosm, saliva
osmolality; TBW, total body water; Uosm, urine osmolality.
Received June 5, 2012. Accepted for publication December 14, 2012.
First published online January 23, 2013; doi: 10.3945/ajcn.112.044172.
Am J Clin Nutr 2013;97:455–62. Printed in USA.
losses, and needs vary widely in free-living people and are
governed heavily by physical activity, environmental stress, and
cultural and habitual cues (
7, 8, 34–36
). Under conditions of
ordinary daily body water flux, osmotic constancy is maintained
by the secretion of the antidiuretic hormone arginine vasopressin
(AVP), which directly influences renal water excretion and
conservation in response to intravascular fluid shifts (that result
from thermal and positional changes) and ad libitum food and
fluid intakes (
14, 26, 37–39
). Thus, Posm remains stable as the
kidneys modify urine osmolal and water excretion in accordance
with ordinary living conditions. When a body water deficit in
excess of ordinary flux occurs (dehydration), threshold increases
in Posm (primary) and decreases in BV (secondary) produce
compensatory water-conservation (renal) and water-acquisition
(thirst) responses (
). As a result, the discriminatory power
of renal excretion measures for the detection of dehydration is
always secondary to changes in Posm (28).
AVP is synthesized in supraoptic and paraventricular nuclei
of the hypothalamus and is released from the posterior pituitary
). Basal AVP concentrations can fluctuate considerably
in response to ordinary postural and skin-temperature (skin blood
flow) shifts in BV (39). However, a threshold reduction in BV
.10% is required to elicit greater (compensatory) AVP
secretion, whereas smaller reductions in BV primarily act to enhance
the sensitivity of the AVP response to changes in Posm (
Osmotic homeostasis (,1–2% deviation in Posm) is also
maintained by basal AVP regulation, but compared to BV smaller
threshold increases in Posm (.2%) produce intracellular
dehydration and compensatory increases in AVP secretion, renal
water conservation, and thirst (
When the net balance between water intake and output
becomes negative (dehydration), renal water conservation is
insufficient to restore fluid balance. Obligatory renal water losses
persist, and fluid acquisition must occur, to restore the body water
). However, the Posm threshold for thirst is highly
variable in people (
27, 45, 46
), and thirst mechanisms are subject
to numerous influences unrelated to the body water balance
(47). In humans, fluid losses (because of sweating, vomiting, or
diarrhea) can easily outpace oral intakes. Peripheral
osmoreceptors (eg, gut) (
) and oropharyngeal cues trigger thirst
satiety well before volume is fully restored (
26, 48, 49
when dehydration is substantial (
). This transitory response
acts to buffer the presystemic impact of ingested fluids (
often leads to involuntary dehydration when water is consumed
without food (solute) (
TWO CRITICAL CAVEATS TO UNDERSTANDING
OSMOTIC RESPONSES TO DEHYDRATION
Caveat 1: a sufficient body water–deficit threshold must be reached before compensatory reactions become reliably engaged
Percentage reductions in body mass (Bm) that exceed typical
human variation are depicted in Figure 1, whereby a change in
Bm is equated with a change in total body water (TBW). The
change in Bm is used as the criterion value for practical
purposes but also because the random measurement error for
tracerdilution methods (the change in TBW) is larger than the same
for Bm (
). Typical human variation is defined as the
day-today CV in Bm, which is ,1.0% when fluid intake and activity
are tightly controlled (
). As a consequence, day-to-day
change in Bm must exceed 1% and approach 2% (ie, O2 3 1.65)
to be considered truly atypical (P , 0.05; 1-tailed test).
Therefore, day-to-day fluctuations in Bm ,1–2% cannot be
reliably associated with perturbations in body water beyond
ordinary (sinusoidal) physiologic and behavioral body water
regulation (55). Under these circumstances, renal water excretion
or conservation is a reflection of the flux produced by fluctuating
AVP concentrations in response to widely ranging dietary fluid
intakes, osmolar loads, and ordinary compartmental fluid shifts
without discernible changes in TBW, Posm, or, by extension,
intracellular hydration (
26, 37–39, 56
). Thus, day-to-day
fluctuations in Bm or TBW within this range should be interpreted
as euhydrated (the state of normal hydration).
Caveat 2: body water–deficit threshold for dehydration depends critically on the type and magnitude of the body water deficit incurred
A 2% increase in Posm (w5 mmol/kg) and a 10% decrease in
BV (w0.5 L) are commonly quoted physiologic thresholds for
compensatory water conservation and acquisition (Figure 1) (
). Posm increases to greater than w5 mmol/kg in response
to dehydration via sweat losses, fluid restriction, or osmotic
diarrhea (hypertonic hypovolemia) when those losses exceed
w2% of Bm (1.4 L at 70 kg) (
18, 54, 57–59
), which is a
threshold that is also consistent with negative physiologic
7, 8, 60
). The variation in sweat sodium losses in people
) or may not (
) add uncertainty to the magnitude of
the osmotic response to a given water deficit, depending on the
delicate balance between sweating rate and sweat sodium
Volume 3 concentration ¼ content
Similar considerations may be made of alterations in
extracellular volume [plasma volume (PV)], but on the basis of the
regression equations shown in Figure 2, the anticipated decrease
in PV is only w0.14 L at w2% dehydration (
) because of the
rapid osmotic redistribution of water from the intracellular to the
extracellular (interstitial and intravascular) fluid compartment
). Therefore, hypertonic hypovolemia results in a small
ratio of plasma-to-TBW losses (w1:10). Hypertonic
hypovolemia would not produce intravascular volume losses .10%
of BV until a 7% loss of Bm was achieved (Figure 2) (
This effect illustrates the primary influence of Posm as the
stimulus for early compensatory water-conservation and -acquisition
). Although the osmolalities of other body
fluids (eg, urine and saliva) also increase in parallel with Posm
and afford a good diagnostic accuracy for dehydration under ideal
), they remain secondary (
) and are inferior to
Posm for the detection of dehydration for additional reasons.
Isotonic hypovolemia can occur in response to diuretic use,
cold or altitude exposure, secretory diarrhea, and vomiting (
42, 44, 63, 65–68
). The ratio of PV-to-TBW loss is
approximately twice as large (w1:5) with isotonic hypovolemia than
with hypertonic hypovolemia (
63, 65, 68
). This type of body
water loss is often referred to as salt-depletion dehydration (
or volume depletion (
) because the added solute loss
produces little change in Posm but proportionally greater PV
reductions. When there are large losses of solute from the
extracellular space, there is a minimal or no osmotic gradient to
pull fluids from the larger intracellular space (
). As a
result, a smaller w4% loss of Bm (2.8 L at 70 kg; 0.56-L PV loss)
must be incurred to achieve the 10% BV threshold for
compensatory water conservation and acquisition with isotonic
hypovolemia (Figures 1 and 2).
Methods for the assessment of volume depletion vary widely,
with no single, standard approach advocated in the medical or
related literature (
). The use of a simple 20-beats/min
sit-tostand heart-rate response provides high specificity but low
sensitivity and only marginal diagnostic accuracy even when
dehydration is severe (
). BV losses .10% (w1.0 L),
whether measured directly (
) or by using lower body negative
pressure to simulate equivalent blood losses (
), are required
for an improved test sensitivity. The type of water loss with
a gastrointestinal illness can be unpredictable or mixed (
and thus, the presence of both types of dehydration probably
explains much of the difficulty associated with their interpretation
), in which neither Posm nor BV thresholds for compensatory
responses are reached (Figure 1). Under these circumstances, a more
heuristic assessment approach is needed (
19, 22, 24, 28
BIOLOGICAL AND METHODOLOGIC VARIATION
Human variation in osmotic responses to dehydration is
primarily biological, but the methodology used to study osmotic
responses can also contribute to variation. An understanding and
appreciation for these sources of variation can inform
probabilistic decision making related to the diagnosis of dehydration (
) and, likely, volume depletion as well (
Threshold and slope of AVP and thirst responses (biology)
It is common to refer to both the threshold and slope of the
Posm-AVP relation. The threshold Posm value is associated with
the initial increase in AVP secretion above baseline, whereas the
slope is the responsiveness (or sensitivity) of the AVP system for
any given increase in Posm above the threshold value. The
osmotic control of AVP, when defined by using slope and sensitivity
terms, is highly variable. For example, there appears to be a
polygenetic basis for the variation in the slope of the AVP-Posm
relation and Posm thresholds for AVP and thirst (
relations are highly correlated between monozygotic, but not
dizygotic, twin pairs (
). For a healthy and heterogeneous
population, the individual AVP-Posm slopes vary 10-fold in individuals
but are highly correlated within a subject (r = 0.94). The osmotic
threshold for AVP varies less in individuals (w8 mmol/kg) but
shows only a moderate correlation within subjects (r = 0.61).
The individual variation of Posm set points and thresholds
for both AVP release and unequivocal thirst relative to what has
been commonly reported in the literature for group means is
illustrated in Figure 3 (
). The variation contains the potential
influences of sex (
), but not age (
), on osmotic responses.
Posm thresholds for AVP release and unequivocal thirst differ
in subjects by w10 mmol/kg. The largest difference between
Posm thresholds for AVP release and unequivocal thirst within
an individual was 17 mmol/kg (subject 5). Also of importance
is the difference in the Posm set point relative to the Posm
threshold for AVP release and unequivocal thirst; for example,
subjects 7 and 15 fell on opposite extremes. Taken together, the
data in Figure 3 show that plasma osmotic responses (AVP and
thirst) vary considerably in people and have a strong genetic
component. These data may partly explain the 20-mmol/kg
range in Posm often reported for population reference intervals
(eg, 280–300 mmol/kg). Differences in health and hydration
states must also contribute to this range, but the volume of fluid
ingested and its proximity to measurement can also make an
important methodologic contribution (
), even in
wellcontrolled laboratory situations.
Threshold and slope of AVP and thirst responses (methodology)
Some of the variation in the Posm threshold for AVP and thirst
is methodologic rather than physiologic. In this context, moderate
water loading is one methodology used to standardize Posm and
suppress AVP secretion before imposing an intervention such as
saline infusion or water restriction (dehydration). However, this
approach produces low basal Posm values and results in threshold
and slope calculations dissimilar from studies in which ad libitum
water consumption was permitted before testing (
13, 43, 45, 76
Suppressed Posm thresholds for AVP release and thirst in studies
that used water-loading methodologies, although experimentally
sound, may be unrealistic for free-living people.
Interpreting osmotic responses after water loading should be
approached with caution. For example, the application of
regression equations for AVP-Posm and AVP–urine osmolality
(Uosm), which has been commonly adopted to explain the
physiology of osmotic responses, indicated that a near maximally
concentrated urine (w1100 mmol/kg) should occur at a Posm of
292 mmol/kg and AVP value of 4.6 pg/mL (
). This result
contrasts with everyday observations but is easily understood
from a starting Uosm:Posm ratio of approximately
187 : 282 ¼ 0:66
which can be back calculated from a starting AVP value of 1 pg/
mL in these experiments (
). If we assume unity between
plasma and urine electrolyte concentrations and accept that urea
contributes 40% to Uosm (
), any Uosm:Posm ratio #1.5 is
consistent with electrolyte-free renal water clearance and a
water-loaded state (
). In contrast, the change in Posm (12
mmol/kg) that is responsible for the 1100-mmol/kg Uosm is
entirely consistent with a hyperosmolal state:
DUosm ¼ 250 3 0:35 DPosm or D12 Posm
¼ D1050 Uosm ð27Þ
Therefore, both aspects of osmoregulation (ie, the variation
and basal set point) are very important considerations when Posm
is used to assess dehydration. When a person’s true Posm
baseline is not known, biological variation analysis can provide
confident probabilistic estimates of dehydration by using both
single and serial measures of Posm.
Biological variation of Posm (single measure)
Claude Bernard’s concept of the tightly regulated milieu
inte´rieur is commonly referenced by extension as a narrow 1–2%
variation in Posm. Surprisingly few studies have quantified the
intraindividual variation in Posm from day to day, but they have
been consistent with this concept and reported values that
ranged from 0.8% to 1.4% (2–4 mmol/kg), with the exclusion of
the analytic (measurement) variation (w0.5% or 1 mmol/kg)
54, 78, 79
). These studies (
54, 78, 79
) were not stratified and,
thus, included contributions to the variation because of sex (
and age (
). Although most measures of physiologic interest
have a larger interindividual variation than intraindividual
), the 2 measures are similar for Posm. This outcome
seems to contrast with wide population reference intervals until
it is considered that the variation between subjects shrinks when
measurement methodology and other preanalytic factors are
controlled for (
). The ratio of intraindividual to interindividual
variation (index of individuality) in Posm ranges from 0.9 to 1.4
54, 78, 79
). The index of individuality provides a statistical
framework to distinguish pathologic states such as dehydration
from a single measurement. Any atypical value for a given
individual, relative to the larger population of individuals, will go
unnoticed when the ratio is ,0.6 but will be captured when the
ratio is .1.4 (
). The probability of identifying an atypical
value increases rapidly as the ratio exceeds 0.60 and approaches
unity (1.00) (81).
The index of individuality concept for Posm is shown in
Figure 4 and includes Uosm and saliva osmolality (Sosm) for
). The interindividual variation is depicted
by the differences in means (dots), whereas the intraindividual
differences (typical day-to-day variation) in body fluid measures
are represented by the range (bars) that surrounds each
individual mean. “X” values in Figure 4 represent body fluid
measures in response to a –2.5-L loss of body water (–3%
dehydration). When graphed relative to the respective dehydration
thresholds determined empirically by receiver operating
characteristic curve analysis, probabilities of false-negative and
-positive findings become apparent. The index of individuality
for Posm was 0.90. For contrast, ratios for Uosm and Sosm were
0.49 and 0.27, respectively (54). As illustrated in Figure 4, an
atypical value for Posm (X, dehydrated) is more easily and
accurately detected than an atypical value for Uosm or Sosm,
despite the expected linear associations commonly reported
when the dehydration level against Sosm or Uosm is regressed.
The complete biological variation analysis (
) supports a Posm
threshold of 301 6 5 mmol/kg, which is mathematically identical
to the –0.568C depression in the freezing point proposed by
Olmstead et al (
) .50 y ago as a positive test for hypernatremia.
We recommend the inclusion of a variance term (65 mmol/kg) to
account for biological differences in basal set points (
) and note
its consistency to values (295–300 mmol/kg) reached by consensus
) as consistent with impending dehydration.
Biological variation of Posm (serial measures)
Reference change values (
) allow the observation of serial
changes in Posm to be interpreted in terms of diagnosing
). Reference change values can be calculated
(when the proper statistical assumptions are met) (
by using the sum of analytic and intraindividual variations in
). The probability that a measured change in Posm
is atypical can then be determined (
). As illustrated in
Figure 5, atypical changes in Posm begin above the daily
2–4mmol/kg constancy threshold and provide increasing predictive
certainty that dehydration has occurred in accordance with the
Probability = 1 2 e20.327x
where x is the measured change in Posm (
). As a result, the
probability that a change in Posm reflects the occurrence of
dehydration can be gauged in both quantitative and qualitative terms.
LIMITATIONS OF USE OF OSMOMETRY FOR
ASSESSMENT OF DEHYDRATION
It is clear that Posm is critical for body water regulation, and
plasma is a unique body fluid for use in the assessment of
dehydration. Although Uosm and Sosm have also been used
successfully for this purpose (
), human variation in these body
fluids seem to limit their potential utility (Figure 4). The greater
variation in Uosm and Sosm is not surprising. For example,
#40% of Uosm is attributable to urea (compared with only
w1% for Posm), and thus, the addition of solute in the form of
antecedent diet or catabolic byproducts of protein metabolism
associated with exercise or illness may increase Uosm by the
addition of solute (
). Similar limitations apply for
urinespecific gravity, whereas all urine-concentration measures are
subject to timing and uniformity concerns that manifest
empirically as differences between first morning, 24-h, and spot urine
) in addition to acute drinking and exercise behaviors
). The discriminatory power of renal excretion measures for
the detection of dehydration is clearly secondary to changes in
), but this does not, in any way, minimize the critical use
of Uosm (and its relation to Posm) in the measurement of renal
function related to the phenomenologic interpretation or
differential diagnosis of other disorders (
5, 28, 29
). With regard to
saliva, Sosm is subject to practical use issues related to simple
oral artifacts (
). Sosm may also be affected by anything that
affects salivation (salivary flow), which includes a multitude of
factors (85). Limitations of the use of Posm for the assessment of
dehydration must also be acknowledged.
Posm and plasma tonicity (effective osmolality) are very
similar quantities in health (
). However, substances in the blood
that raise osmolality but not tonicity (ineffective or penetrating
solutes) have the potential to confound dehydration assessment.
The calculation of the osmol gap will reveal contributions from
ineffective solutes, but the direct measurement of Posm is always
recommended for dehydration assessment because of the large
acceptable error in calculated osmolality (610 mmol/kg) (
Fluctuations in the volume of body fluid compartments will also
affect Posm. For example, consumption of a large meal can
increase Posm because of the osmolar shift of water out of the
vasculature and into the gut (
). In contrast, simple changes in
) and even low-intensity exercise (#40% maximal
oxygen uptake) (
) produce little effect, probably because
osmotic concordance is not disrupted by the 2-way fluid flow
between interstitial and intravascular spaces that share the same
osmotic pressures (
61, 64, 93
). Higher exercise intensities
increase Posm as a result of greater intravascular volume losses
and the presence of lactic acid, but recovery appears complete in
#20–30 min (
). Finally, as stated earlier, Posm is of no use for
the detection of volume depletion. When this distinction is
made, coupled with the importance of biological variation and
other issues discussed herein, criticisms for adopting Posm as
a gold standard for dehydration assessment (
CONCLUSIONS AND FUTURE DIRECTIONS
Dehydration is a common physiologic state with implications
for health and performance (
). Although the physiology of
dehydration is well described, it remains difficult to assess
accurately in practice. In this review, we highlighted how the
phenomenologic interpretation of dehydration depends critically
on the type and magnitude of dehydration, which directly affect
threshold osmotic and volume-dependent compensatory
antidiuretic and thirst responses. We also emphasized how
knowledge of biological variation improves our broader understanding
of the physiology that underpins the osmotic response to
dehydration in humans and affords important diagnostic insight for
dehydration assessment. To help improve the practice of
dehydration assessment, a single, atypical Posm threshold value
of 301 6 5 mmol/kg is suggested (54) as a starting point for
this purpose, along with a nomogram (
) for the estimation of
the probability of dehydration when serial changes in Posm are
measured as an adjunct to quantitative differential diagnostic
procedures. No standard method has been advocated for the
assessment of volume depletion (
), but a 20-beats/min
sitto-stand cutoff provides high test specificity for both
dehydration and volume depletion (
). Because Posm requires
the collection of blood and the preparation of plasma, future
efforts to identify or develop an acceptable noninvasive
surrogate for Posm would benefit clinical, sports, and military
medicine communities (
). A test with high diagnostic accuracy for
moderate volume depletion is also needed.
We thank Brett R Ely, Mary C Pardee, and Kristen R Heavens for technical
assistance with this manuscript.
The authors’ responsibilities were as follows—all authors: conception,
writing, and editing of the manuscript. None of the authors had a conflict
1. Adrogue´ HJ, Madias NE. Hypernatremia . N Engl J Med 2000 ; 342 : 1493 - 9 .
2. Campbell N. Dehydration: why is it still a problem? Nurs Times 2011 ; 107 : 12 - 5 .
3. Feig PU , McCurdy DK . The hypertonic state . N Engl J Med 1977 ; 297 : 1444 - 54 .
4. King CK , Glass R , Bresee JS , Duggan C . Managing acute gastroenteritis among children: oral rehydration, maintenance, and nutritional therapy . MMWR Recomm Rep 2003 ; 52 : 1 - 16 .
5. Nguyen MK , Kurtz I. A new quantitative approach to the treatment of the dysnatremias . Clin Exp Nephrol 2003 ; 7 : 125 - 37 .
6. Rose BD . Hyperosmolal states-hypernatremia . In: Burton DR, ed. Clinical physiology of acid-base and electrolyte disorders . New York, NY: McGrow-Hill , 1994 : 695 - 736 .
7. Institute of Medicine. Water. In: Dietary Reference Intakes. Washington, DC: National Academies Press, 2005 : 73 - 185 .
8. Sawka MN , Burke LM , Eichner ER , Maughan RJ , Montain SJ , Stachenfeld NS . American College of Sports Medicine position stand. Exercise and fluid replacement . Med Sci Sports Exerc 2007 ; 39 : 377 - 90 .
9. Stookey JD , Pieper CF , Cohen HJ . Hypertonic hyperglycemia progresses to diabetes faster than normotonic hyperglycemia . Eur J Epidemiol 2004 ; 19 : 935 - 44 .
10. Stookey JD , Barclay D , Arieff A , Popkin BM . The altered fluid distribution in obesity may reflect plasma hypertonicity . Eur J Clin Nutr 2007 ; 61 : 190 - 9 .
11. Black RE , Morris SS , Bryce J . Where and why are 10 million children dying every year ? Lancet 2003 ; 361 : 2226 - 34 .
12. Warren JL , Bacon WE , Harris T , McBean AM , Foley DJ , Phillips C. The burden and outcomes associated with dehydration among US elderly , 1991 . Am J Public Health 1994 ; 84 : 1265 - 9 .
13. Robertson GL . The regulation of vasopressin function in health and disease . Recent Prog Horm Res 1976 ; 33 : 333 - 85 .
14. Bourque CW . Central mechanisms of osmosensation and systemic osmoregulation . Natl Rev Neurosci 2008 ; 9 : 519 - 31 .
15. Armstrong LE . Assessing hydration status: the elusive gold standard . J Am Coll Nutr 2007 ; 26 ( 5 suppl) : 575S - 84S .
16. Peacock WF , Soto KM . Current techniques of fluid status assessment . Contrib Nephrol 2010 ; 164 : 128 - 42 .
17. Crecelius C. Dehydration: myth and reality . J Am Med Dir Assoc 2008 ; 9 : 287 - 8 .
18. Hayajneh WA , Jdaitawi H , Al SA , Hayajneh YA . Comparison of clinical associations and laboratory abnormalities in children with moderate and severe dehydration . J Pediatr Gastroenterol Nutr 2010 ; 50 : 290 - 4 .
19. McGee S , Abernethy WB III, Simel DL . The rational clinical examination . Is this patient hypovolemic? JAMA 1999 ; 281 : 1022 - 9 .
20. Robinson BE , Weber H . Dehydration despite drinking: beyond the BUN/Creatinine ratio . J Am Med Dir Assoc 2004 ; 5 : S67 - 71 .
21. Roland D , Clarke C , Borland ML , Pascoe EM . Does a standardised scoring system of clinical signs reduce variability between doctors' assessments of the potentially dehydrated child ? J Paediatr Child Health 2010 ; 46 : 103 - 7 .
22. Steiner MJ , DeWalt DA , Byerley JS . Is this child dehydrated ? JAMA 2004 ; 291 : 2746 - 54 .
23. Steiner MJ , Nager AL , Wang VJ . Urine specific gravity and other urinary indices: inaccurate tests for dehydration . Pediatr Emerg Care 2007 ; 23 : 298 - 303 .
24. Thomas DR , Cote TR , Lawhorne L , Levenson SA , Rubenstein LZ , Smith DA , Stefanacci RG , Tangalos EG , Morley JE . Understanding clinical dehydration and its treatment . J Am Med Dir Assoc 2008 ; 9 : 292 - 301 .
25. Vivanti A , Harvey K , Ash S , Battistutta D. Clinical assessment of dehydration in older people admitted to hospital: what are the strongest indicators? Arch Gerontol Geriatr 2008 ; 47 : 340 - 55 .
26. Reeves WB , Bichet DG , Andreoli TE . Posterior pituitary and water metabolism . In: Wilson JD, Foster DW , Kronenberg HM , Larsen PR , eds. Williams textbook of endocrinology. 9th ed. Philadelphia, PA: WB Saunders Co , 1998 : 341 - 87 .
27. Robertson GL , Shelton RL , Athar S. The osmoregulation of vasopressin . Kidney Int 1976 ; 10 : 25 - 37 .
28. Shoker AS . Application of the clearance concept to hyponatremic and hypernatremic disorders: a phenomenological analysis . Clin Chem 1994 ; 40 : 1220 - 7 .
29. Haraway AW Jr, Becker EL . Clinical application of cryoscopy . JAMA 1968 ; 205 : 506 - 12 .
30. Mange K , Matsuura D , Cizman B , Soto H , Ziyadeh FN , Goldfarb S , Neilson EG . Language guiding therapy: the case of dehydration versus volume depletion . Ann Intern Med 1997 ; 127 : 848 - 53 .
31. Armstrong LE . Hydration assessment techniques . Nutr Rev 2005 ; 63 : S40 - 54 .
32. Oppliger RA , Bartok C . Hydration testing of athletes . Sports Med 2002 ; 32 : 959 - 71 .
33. Antunes-Rodrigues J , de Castro M , Elias LLK , Valenc¸a MM, McCann SM . Neuroendocrine control of body fluid metabolism . Physiol Rev 2004 ; 84 : 169 - 208 .
34. Gonzalez RR , Cheuvront SN , Montain SJ , Goodman DA , Blanchard LA , Berglund LG , Sawka MN . Expanded prediction equations of human sweat loss and water needs . J Appl Physiol 2009 ; 107 : 379 - 88 .
35. Sawka MN , Cheuvront SN , Carter R III. Human water needs . Nutr Rev 2005 ; 63 : S30 - 9 .
36. de Castro JM . A microregulatory analysis of spontaneous fluid intake by humans: evidence that the amount of liquid ingested and its timing is mainly governed by feeding . Physiol Behav 1988 ; 43 : 705 - 14 .
37. Shore AC , Markandu ND , Sagnella GA , Singer DR , Forsling ML , Buckley MG , Sugden AL , MacGregor GA . Endocrine and renal response to water loading and water restriction in normal man . Clin Sci (Lond ) 1988 ; 75 : 171 - 7 .
38. Phillips PA , Rolls BJ , Ledingham JG , Morton JJ . Body fluid changes, thirst and drinking in man during free access to water . Physiol Behav 1984 ; 33 : 357 - 63 .
39. Segar WE , Moore WW . The regulation of antidiuretic hormone release in man . J Clin Invest 1968 ; 47 : 2143 - 51 .
40. Dunn FL , Brennan TJ , Nelson AE , Robertson GL . The role of blood osmolality and volume in regulating vasopressin secretion in the rat . J Clin Invest 1973 ; 52 : 3212 - 9 .
41. Robertson GL , Athar S. The interaction of blood osmolality and blood volume in regulating plasma vasopressin in man . J Clin Endocrinol Metab 1976 ; 42 : 613 - 20 .
42. Kimura T , Minai K , Matsui K , Mouri T , Sato T . Effect of various states of hydration on plasma ADH and renin in man . J Clin Endocrinol Metab 1976 ; 42 : 79 - 87 .
43. Robertson GL , Mahr EA , Athar S , Sinha T . Development and clinical application of a new method for the radioimmunoassay of arginine vasopressin in human plasma . J Clin Invest 1973 ; 52 : 2340 - 52 .
44. Nadal JW , Pedersen S , Maddock WG . A comparison between dehydration from salt loss and from water deprivation . J Clin Invest 1941 ; 20 : 691 - 703 .
45. Baylis PH , Robertson GL . Plasma vasopressin response to hypertonic saline infusion to assess posterior pituitary function . J R Soc Med 1980 ; 73 : 255 - 60 .
46. Zerbe RL , Miller JZ , Robertson GL . The reproducibility and heritability of individual differences in osmoregulatory function in normal human subjects . J Lab Clin Med 1991 ; 117 : 51 - 9 .
47. Greenleaf JE , Morimoto T. Mechanisms controlling fluid ingestion: thirst and drinking . In: Buskirk ER , Puhl SM , eds. Body fluid balance: exercise and sport . Boca Raton, FL: CRC Press, 1996 : 3 - 17 .
48. Geelen G , Keil LC , Kravik SE , Wade CE , Thrasher TN , Barnes PR , Pyka G , Nesvig C , Greenleaf JE . Inhibition of plasma vasopressin after drinking in dehydrated humans . Am J Physiol 1984 ; 247 : R968 - 71 .
49. Denton D , Shade R , Zamarippa F , Egan G , Blair-West J , McKinley M , Fox P . Correlation of regional cerebral blood flow and change of plasma sodium concentration during genesis and satiation of thirst . Proc Natl Acad Sci USA 1999 ; 96 : 2532 - 7 .
50. Greenleaf JE , Sargent F . Voluntary dehydration in man . J Appl Physiol 1965 ; 20 : 719 - 24 .
51. Rothstein A , Adolph EF , Wills JH . Voluntary dehydration . In: Visscher MB , Bronk DW , Landis EM , Ivy AC , eds. Physiology of man in the desert. Rochester , NY: Interscience Publishers Inc, 1947 : 254 - 77 .
52. Gudivaka R , Schoeller DA , Kushner RF , Bolt MJ . Single- and multifrequency models for bioelectrical impedance analysis of body water compartments . J Appl Physiol 1999 ; 87 : 1087 - 96 .
53. Cheuvront SN , Carter R III, Montain SJ , Sawka MN . Daily body mass variability and stability in active men undergoing exercise-heat stress . Int J Sport Nutr Exerc Metab 2004 ; 14 : 532 - 40 .
54. Cheuvront SN , Ely BR , Kenefick RW , Sawka MN . Biological variation and diagnostic accuracy of dehydration assessment markers . Am J Clin Nutr 2010 ; 92 : 565 - 73 .
55. Greenleaf JE . Problem: thirst, drinking behavior, and involuntary dehydration . Med Sci Sports Exerc 1992 ; 24 : 645 - 56 .
56. Johnson RE . Water and osmotic economy on survival rations . J Am Diet Assoc 1964 ; 45 : 124 - 9 .
57. Bartok C , Schoeller DA , Sullivan JC , Clark RR , Landry GL . Hydration testing in collegiate wrestlers undergoing hypertonic dehydration . Med Sci Sports Exerc 2004 ; 36 : 510 - 7 .
58. Cheuvront SN , Fraser CG , Kenefick RW , Ely BR , Sawka MN . Reference change values for monitoring dehydration . Clin Chem Lab Med 2011 ; 49 : 1033 - 7 .
59. Popowski LA , Oppliger RA , Patrick LG , Johnson RF , Kim JA , Gisolf CV . Blood and urinary measures of hydration status during progressive acute dehydration . Med Sci Sports Exerc 2001 ; 33 : 747 - 53 .
60. Carter R III , Cheuvront SN , Vernieuw CR , Sawka MN . Hypohydration and prior heat stress exacerbates decreases in cerebral blood flow velocity during standing . J Appl Physiol 2006 ; 101 : 1744 - 50 .
61. Nose H , Mack GW , Shi XR , Nadel ER . Shift in body fluid compartments after dehydration in humans . J Appl Physiol 1988 ; 65 : 318 - 24 .
62. Sawka MN , Toner MM , Francesconi RP , Pandolf KB . Hypohydration and exercise: effects of heat acclimation, gender, and environment . J Appl Physiol 1983 ; 55 : 1147 - 53 .
63. Cheuvront SN , Kenefick RW , Montain SJ , Sawka MN . Mechanisms of aerobic performance impairment with heat stress and dehydration . J Appl Physiol 2010 ; 109 : 1989 - 95 .
64. Coleman TG , Norman RA , Manning RD . Equilibrium between extracellular and intracellular fluid . In: Guyton AC , Taylor AE , Granger HJ , eds. Circulatory physiology II: dynamics and control of the body fluids . Philadelphia, PA: WB Sanders Company, 1975 : 225 - 42 .
65. Cheuvront SN , Ely BR , Kenefick RW , Buller MJ , Charkoudian N , Sawka MN . Hydration assessment using the cardiovascular response to standing . Eur J Appl Physiol 2012 : 112 : 4081 - 9 .
66. Hoyt RW , Honig A . Body fluid and energy metabolism at high altitude . In: Fregley MJ , Blatteis CM , eds. Handbook of physiology. Vol 2 , Sect 4. New York, NY: Oxford University Press, 1996 : 1277 - 89 .
67. Lennquist S. Cold-induced diuresis. A study with special reference to electrolyte excretion, osmolal balance and hormonal changes . Scand J Urol Nephrol 1972 ; 9 ( suppl 9): 1 - 142 .
68. O 'Brien C , Young AJ , Sawka MN . Hypohydration and thermoregulation in cold air . J Appl Physiol 1998 ; 84 : 185 - 9 .
69. Witting MD , Gallagher K. Unique cutpoints for sitting-to standing orthostatic vital signs . Am J Emerg Med 2003 ; 21 : 45 - 7 .
70. Knopp R , Claypool R , Leonardi D . Use of the tilt test in measuring acute blood loss . Ann Emerg Med 1980 ; 9 : 72 - 5 .
71. Cooke WH , Ryan KL , Convertino VA . Lower body negative pressure as a model to study progression to acute hemorrhagic shock in humans . J Appl Physiol 2004 ; 96 : 1249 - 61 .
72. Fortes MB , Diment BC , Di FU , Gunn AE , Kendall JL , Esmaeelpour M , Walsh NP . Tear fluid osmolarity as a potential marker of hydration status . Med Sci Sports Exerc 2011 ; 43 : 1590 - 7 .
73. Stachenfeld NS , Splenser AE , Calzone WL , Taylor MP , Keefe DL . Sex differences in osmotic regulation of AVP and renal sodium handling . J Appl Physiol 2001 ; 91 : 1893 - 901 .
74. Kenney WL , Chiu P . Influence of age on thirst and fluid intake . Med Sci Sports Exerc 2001 ; 33 : 1524 - 32 .
75. Sollanek KJ , Kenefick RW , Cheuvront SN , Axtell RS . Potential impact of a 500-mL water bolus and body mass on plasma osmolality dilution . Eur J Appl Physiol 2011 ; 111 : 1999 - 2004 .
76. Zerbe RL , Robertson GL . Osmoregulation of thirst and vasopressin secretion in human subjects: effect of various solutes . Am J Physiol 1983 ; 244 : E607 - 14 .
77. Shimizu K , Kurosawa T , Sanjo T , Hoshino M , Nonaka T . Solute-free versus electrolyte-free water clearance in the analysis of osmoregulation . Nephron 2002 ; 91 : 51 - 7 .
78. Fraser CG , Cummings ST , Wilkinson SP , Neville RG , Knox JD , Ho O , MacWalter RS . Biological variability of 26 clinical chemistry analytes in elderly people . Clin Chem 1989 ; 35 : 783 - 6 .
79. Jahan A , Browning MC , Fraser CG. Desirable performance standards for assays of serum water and osmolality . Clin Chem 1988 ; 34 : 995 .
80. Fraser CG . Biological variation: from principles to practice . Washington, DC: American Association of Clinical Chemistry Press, 2001 .
81. Harris EK . Effects of intra- and interindividual variation on the appropriate use of normal ranges . Clin Chem 1974 ; 20 : 1535 - 42 .
82. Olmstead EG , Roth DA . The use of serum freezing point depressions in evaluating salt and water balance in preoperative and postoperative states . Surg Gynecol Obstet 1958 ; 106 : 41 - 8 .
83. Harris EK , Brown SS . Temporal changes in the concentrations of serum constituents in healthy men. Distributions of within-person variances and their relevance to the interpretation of differences between successive measurements . Ann Clin Biochem 1979 ; 16 : 169 - 76 .
84. Shirreffs SM , Maughan RJ . Urine osmolality and conductivity as indices of hydration status in athletes in the heat . Med Sci Sports Exerc 1998 ; 30 : 1598 - 602 .
85. 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 - 54 .
86. Meroney WH , Rubini ME , Blythe WB . The effect of antecendent diet on urine concentrating ability . Ann Intern Med 1958 ; 48 : 562 - 73 .
87. Pepper OH . Studies on the specific gravity of the urine . J Clin Invest 1924 ; 1 : 13 - 9 .
88. Gowans EM , Fraser CG . Despite correlation, random spot and 24-h urine specimens are not interchangeable . Clin Chem 1987 ; 33 : 1080 - 1 .
89. Ely BR , Cheuvront SN , Kenefick RW , Sawka MN . Limitations of salivary osmolality as a marker of hydration status . Med Sci Sports Exerc 2011 ; 43 : 1080 - 4 .
90. Kruse JA , Cadnapaphornchai P. The serum osmole gap . J Crit Care 1994 ; 9 : 185 - 97 .
91. Gill GV , Baylis PH , Flear CT , Lawson JY . Changes in plasma solutes after food . J R Soc Med 1985 ; 78 : 1009 - 13 .
92. Shirreffs SM , Maughan RJ . The effect of posture change on blood volume, serum potassium and whole body electrical impedance . Eur J Appl Physiol Occup Physiol 1994 ; 69 : 461 - 3 .
93. Greenleaf JE , Van BW , Brock PJ , Morse JT , Mangseth GR . Plasma volume and electrolyte shifts with heavy exercise in sitting and supine positions . Am J Physiol 1979 ; 236 : R206 - 14 .
94. Montain SJ , Laird JE , Latzka WA , Sawka MN . Aldosterone and vasopressin responses in the heat: hydration level and exercise intensity effects . Med Sci Sports Exerc 1997 ; 29 : 661 - 8 .
95. Francesconi RP , Hubbard RW , Szlyk PC , Schnakenberg D , Carlson D , Leva N , Sils I , Hubbard L , Pease V , Young J , et al. Urinary and hematologic indexes of hypohydration . J Appl Physiol 1987 ; 62 : 1271 - 6 .
96. Hackney AC , Coyne JT , Pozos R , Feith S , Seale J . Validity of urineblood hydrational measures to assess total body water changes during mountaineering in the sub-Arctic . Arctic Med Res 1995 ; 54 : 69 - 77 .
97. Perrier E , Vergne S , Klein A , Poupin M , Rondeau P , Le Bellego L , Armstrong LE , Lang F , Stookey J , Tack I. Hydration biomarkers in free-living adults with different levels of habitual fluid consumption . Br J Nutr 2012 ; Aug 31 (Epub ahead of print).