0195-91atie212406-065?$3.00r0
`MEDICINE AND SCIENCE tN SPORTS AND EXERCSSE
`Copyright c 1992 by the American College at Sports Medicine
`
`Vol. 24, No. 6
`Printed in USA.
`
`Physiological consequences of
`hypohydration: exercise performance and
`thermoregulation
`
`MICHAEL N. SAWKA
`
`(1.5. Army Research Institute ofEnvironmenral Medicine,
`Natick, MA 01760-5007
`
`ABSTRACT
`SAWKA, M. N. Physiological consequences of hypohydration: exer-
`cise performance and thermoregulation. Med. Sci. Sports Erato, Vol.
`24, No. 6, pp. 657-670, 19%. During exercise in the heat, sweat
`output often exceeds water intake, which results in a body water
`deficit or hypohydration. This water deficit occurs from both the
`intracellular and extracellular fluid compartments, and causes a hy-
`pertonic-hypovolcmia of the blood. Aerobic exercise tasks are likely
`to be adversely affected by hypohydration: and the warmer the
`environment the greater the potential for performance decrements.
`Hypohydration causes greater heat storage and reduces one‘s ability
`to tolerate heat strain. The greater heat storage is mediated by reduced
`sweating rate (evaporative heat loss) and reduced skin blood flow (dry
`heat loss) for a given core temperature. Reductions of sweating rate
`and skin blood flow are most tightly coupled to blood hypertonicity
`and hypovolcmia, respectively. In addition, hypovolcmia and the
`displacement of blood to the skin make it difficult to maintain central
`venous pressure and thus an adequate cardiac output to simultane-
`ously support metaboiistn and thermoregulation during exercise-heat
`stress.
`
`BLOOD VOLUME, CORE TEMPERATURE, DEHYDRATION,
`HEAT STRESS, HYPEROSMOLALITY, HYPOVOLEMIA, SKIN
`BLOOD FLOW, SWEATING, TONICITY
`
`Adolph and associates (1) were the first to effectively
`communicate the devastating effects that body water
`loss can have on physiological strain and exercise per-
`formance in the heat. During exercise-heat exposure,
`body water is primarily lost through sweat output,
`which results in increased plasma tonicity (osmolality)
`with decreased blood volume (hyperosmotic—hypovo-
`lemia). The fact that either hypertonicity or hypovole-
`mia can adversely affect temperature regulation and
`exercise performance was established during the 19305
`through the 19505 (see Table I; 1,25,49,64,86) and has
`been confirmed by subsequent investigators. Exercise/
`environmental physiologists, however, have generally
`emphasized the role of hypovolemia and have often
`ignored the role of hypertonicity on degrading ther-
`moregulation and exercise performance (63).
`This paper describes the genesis of current concepts
`
`Submitted for publication September l‘J9 1.
`Accepted for publication December 199l.
`
`concerning the effects of body water loss on fluid redis-
`tribution, exercise performance, and temperature reg-
`ulation. Particular attention is directed to delineating
`the relative importance of hypertonicity and hypovo-
`lemia on human thermoregulation and exercise per~
`formance. Throughout this paper, the term “euhydra—
`tion” refers to “normal” body water content, whereas
`“hypohydration” refers to body water deficit. The more
`common term “dehydration” denotes the dynamic loss
`of body water or the transition from euhydratiOn to
`hypohydration.
`
`BODY WATER LOSS AND REDISTRIBUTION
`
`Physical exercise increases total body metabolic rate
`to provide energy for skeletal muscle contraction. De-
`pending on the type of exercise, between 70% and 100%
`of metabolism is released as heat and needs to be
`
`dissipated in order to achieve body heat balance. De-
`pending on the environmental temperature, the relative
`contributions of evaporative and dry heat exchange to
`the total heat loss vary, and the hotter the environment
`the greater the dependence on evaporatiVe heat loss,
`and thus on sweating (80). Therefore, in hot environ«
`ments, a considerable amount of body water is lost via
`eccrine sweat gland secretion to enable evaporative
`cooling of the body (128).
`For athletes, the highest sweating rates occur during
`prolonged high intensity exercise in the heat. Figure 1
`provides approximate hourly sweating rates, and there-
`fore water requirements, for runners based upon mct~
`abolic rate data from several laboratories (105). The
`amount of body fluid lost as sweat can vary greatly,
`and sweating rates of 1 Lb" are common. The highest
`sweating rate reported in the literature was 3.? Lb”,
`which was measured for Alberto Salazar during the
`1984 Olympic Marathon (5). The upper limits for fluid
`replacement during exercise-heat stress are set by the
`maximal gastric emptying rates, which approximate
`1.0-1.5 lth" for an average adult male (67,70). The
`
`657
`
`InnoPharma Exhibit 1108.0001
`
`

`

`658
`
`Official Journal of the American College of Sports Medicine
`
`MEDICINE AND SCIENCE IN SPORTS AND EXERCISE
`
`TABLE 1. Early observations on the role of blood volume and tonicity on
`temperature regulation in dehydrated humans.
`Blood Volume
`Lee and Mulder
`Protein content increased
`suggesting plasma vol-
`ume decreased
`
`1939
`
`Plasma Tonlcity
`Dontas
`Sardine eating de-
`layed sweating
`
`1935
`
`1937
`
`1942
`
`Harvard Fatigue Laboratory
`Boulder City. NV
`Blood volume decreased
`
`Desert Laboratory Unit
`Colorado Desert. CA
`Blood volume decreased
`and lead to circulatory
`failure
`
`1942
`
`1956
`
`Desert Laboratory Unit
`Colorado Desert, CA
`Serum chloride in-
`creased
`
`Pearcy et al.
`Serum chloride alters
`sweat rate during
`exercise
`
`swnnna
`
`‘.I
`
`1.0
`
`RATEu-n“)
`
`RUNNING SPEED (m: min“)
`l_l_._;l__—I____._L_
`1
`o
`10
`I
`B
`5
`MINUTES PER MILE RUN
`
`Figure l—An approximation of hourly sweating rates for runners
`(105).
`
`gastric emptying rates are reported to decreased during
`high intensity (>75% Ozmax) exercise (22,75), hypoh-
`ydration (76,93) and heat strain (76,85).
`It is difficult to balance the volume of fluid consumed
`
`to the volume of sweat output during exercise-heat
`exposure. Investigators report (1,29) that thirst provides
`a poor index of body water requirements and that ad
`libitum drinking results in incomplete fluid replace-
`mentor “involuntary dehydration” (8,52,87). Humans
`will commonly dehydrate by 2—8% of their body weight
`during exercise-heat stress (1,5,10,92). In one study (29)
`of hypohydrated humans, the multiple regression anal-
`yses indicated that the consumed volume of rehydration
`fluid was related to plasma hyperosmolality (r2 = 0.58),
`with only small amounts of additional variance ac-
`counted for by hypovolemia (r2 = 0.07) and subjective
`thirst indices (r2 = 0.13) after exercise-heat exposure.
`Water is the largest component of the human body
`and represents 45—70% of body weight. The average
`male (75 kg) contains about 45 l of water, which cor-
`responds to about 60% of body weight. Since adipose
`tissue is about 10% water and muscle tissue is about
`
`75% water, a person’s total body water depends upon
`their body composition (98). In addition, muscle water
`
`will vary with glycogen content because of the osmotic
`pressure exerted by glycogen granules within the mus-
`cle’s sarcoplasm (74). As a result, trained athletes have
`a relatively greater total body water, than their seden-
`tary counterparts, by virtue of a larger muscle mass and
`a higher skeletal muscle glycogen concentration.
`The water contained in body tissues is distributed
`between the intracellular and extracellular fluid com-
`
`is
`fluid compartment
`partments. The intracellular
`larger and contains about 30 l of water, whereas the
`extracellular fluid compartment contains about 15 1 of
`water for the average 75-kg male. Sweating reduces
`total body water if adequate amounts of fluid are not
`consumed. As a consequence of free fluid exchange,
`hypohydration should affect the water content of each
`fluid compartment. Figure 2 illustrates the findings of
`two studies (20,27) on the redistribution of water be-
`tween fluid compartments when hypohydrated (98).
`Costill et al. (20) dehydrated subjects by using a com-
`bination of cycle ergometer exercise and heat exposure.
`Shortly after completing cycle ergometer exercise, blood
`and skeletal muscle samples were obtained from their
`subjects. Durkot et al. (27) dehydrated rats by using a
`passive heat exposure for up to 11 h. The intent of
`Figure 2 is to present data trends and not to imply that
`a given percent decrease of total body water is similar
`between man and rat. At low volumes of body water
`loss, the water deficit primarily comes from the extra-
`cellular compartment; as the body water loss increases,
`a proportionately greater percentage of the water deficit
`comes from the intracellular compartment.
`Nose and colleagues (83) determined the distribution
`of body water loss among the fluid spaces as well as
`among different body organs. These investigators ther-
`mally dehydrated rats by 10% of body weight, and after
`the animals regained their normal core temperature,
`the body water measurements were obtained. The water
`deficit was apportioned between the intracellular (41%)
`and extracellular (59%) compartments; and among the
`organs, 40% from muscle, 30% from skin, 14% from
`
`EPLASMA INTERSTITIAL INTHACELLULAR
`11%
`
`40 L Durkotetal. 1986
`
`(mi) NO
` WATER
`
`WATERDEFICIT
`DEFICIT(r)
`
`PERCENT DECREASE IN TOTAL BODY WATER
`
`Figure 2—The findings of two studies (22,27) concerning the parti-
`tioning of water deficit between fluid compartments during resting
`conditions (98).
`
`InnoPharma Exhibit 1108.0002
`
`

`

`PHYSIOLOGICAL CONSEQUENCES OF HYPOHYDRATION
`
`Official Journal of the American College of Sports Medicine
`
`659
`
`. EUHYDRATED
`03%
`Am HYPOHYDRATED XtSE
`Am
`zone
`31D 40%":
`
`|—__ 49°C, any h ._—.{
`“'
`
`l l l l l
`
`l
`
`0,,»o———--0----—
`A
`
`/
`
`/
`
`EXERCISE
`EXERCISE
`EXERCISE
`__l_1______—
`-1O
`0
`10
`35 45
`70 80
`105
`
`is O
`
`280
`
`3.4
`
`3.2
`
`so
`'
`
`2.8
`
`
`
`OSMOLALITY(mosmollkg)
`
`$3in
`s
`
`3 2
`
`“
`U!
`2
`5
`o-
`
`TIME (min)
`
`Figure 3—Plasma osmolality and plasma volume values (:SE) at
`rest and exercise when euhydrated (0%) and hypohydrated by per-
`centage of body weight (110).
`
`with sweat are primarily found in the extracellular fluid
`(98). The amount of electrolytes lost in sweat are mod-
`ified by the individual’s state of heat acclimation (2,55).
`For example, Kirby and Convertino (55) report that
`over the course of heat acclimation the sweat sodium
`
`concentration decreases; thus, despite a 12% increase
`of sweating rate, the sodium losses decreased by 59%.
`Therefore, for a given sweating rate the heat acclimated
`individual loses less solute from the plasma. It seems
`logical that for a given amount of body fluid loss via
`sweat, the greater amount of sodium retained in heat
`acclimated individual would cause more fluid to move
`
`from the intracellular to the extracellular compartment
`(as compared with an unacclimated individual) and
`perhaps cause a better defense of blood (plasma) vol-
`ume when hypohydrated.
`In the early 19305, investigators from the Harvard
`Fatigue Laboratory found that for a given loss of body
`water, via sweating, the blood volume decreased more
`in winter than in summer (49). This observation was
`made on one subject who voluntarily dehydrated over
`an extended period by performing physical exercise in
`the desert. Figure 4 presents recent data (98,106) show—
`ing the magnitude of hypovolemia associated with hy-
`pohydration of 5% of body weight both before and after
`a 10-d heat acclimation program. These data were
`
`InnoPharma Exhibit 1108.0003
`
`viscera, and 14% from bone. Neither the brain nor liver
`lost significant water content. Those investigators con—
`cluded that hypohydration results in water redistribu-
`tion largely from the intra- and extracellular compart-
`ments of muscle and skin in order to maintain blood
`volume.
`
`The method of dehydration might affect the parti-
`tioning of the remaining water between the body fluid
`spaces (60). For example, it is estimated that 3—-4 g of
`water are associated with each gram of glycogen (84),
`although this relationship is variable (115). Several
`papers (21—23) report a substantial decrease of intracel-
`lular water content in skeletal muscle following 1.5—2.5
`h of exercise dehydration. These investigators suggest
`that the loss of intracellular water may be the result of
`water released with the breakdown of muscle glycogen.
`Thus, exercise-induced hypohydration may result in a
`greater intracellular water loss than thermally induced
`hypohydration. Kozlowski and Saltin (60) have re-
`ported data to support this view, but Costill and Saltin
`(22) found no difference between exercise and thermal
`dehydration for the partitioning of water between the
`fluid compartments. Therefore, whether exercise and
`thermally induced hypohydration cause a difference in
`the redistribution of water between fluid compartments
`remains unresolved.
`The redistribution of water between the intracellular
`
`and the extracellular compartment is dependent upon
`the osmotic gradient between these spaces. Cell mem-
`branes are freely permeable to water but only selectively
`permeable to various solutes. As a result,
`transient
`alterations in the solute concentration cause water re-
`distribution across the cell membrane until the two
`
`fluid spaces are in equilibrium with respect to osmotic
`pressure. Therefore, if the methods used to attain hy-
`pohydration lead to differences in the intracellular and/
`or extracellular solute losses, the partitioning of water
`loss between the fluid compartments will vary accord-
`ingly.
`It is known that exercise or heat-induced hypohydra-
`tion will increase the osmotic pressure in the plasma
`(98,114). Eccrine sweat is ordinarily hypotonic relative
`to plasma (55); therefore, the plasma becomes hyper-
`tonic when dehydration is induced by sweat output
`(61,112). For humans, plasma osmolality can increase
`from about 283 mosmol-kg‘l when euhydrated to val-
`ues exceeding 300 rnosmol-kg‘l when hypohydrated
`(see Fig. 3) (110). Sodium, potassium, and their prin-
`cipal anion (chloride), are primarily responsible for the
`elevated
`plasma
`tonicity
`during
`hypohydration
`(61,112). As recently reemphasized by Nose et a]. (81),
`it is the plasma hypertonicity that mobilizes fluid from
`the intracellular to the extracellular compartments to
`enable the defense of the blood (plasma) volume in
`hypohydrated subjects.
`The electrolytes, sodium and chloride, that are lost
`
`

`

`660
`
`Official Journal of the American College of Sports Medicine
`
`MEDICINE AND SCIENCE IN SPORTS AND EXERCISE
`
`0 PREACCLIMATION }
`. POSTACCLIMATION
`
`XI
`
`:50
`
`12:
`5:
`
`5
`6 RM“
`
`10
`
`01
`
`o
`
`I
`
`.. o
`
`
`
`PERCENTCHANGEINPLASMAVOLUMEAFTER5%REDUCTIONINBODYWEIGHTLImU!
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`l
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`NO
`
`_._____.l_.._L._1_I__.L_gI_l_I_I_I__I_
`123456789101112
`SUBJECT
`
`Figure 4—Magnitude of plasma volume reduction, while at rest,
`associated with a hypohydration of 5% body weight both before and
`after a heat acclimation program (data from ref. 106 as presented in
`ref. 98).
`
`obtained while the individuals were resting; hypohydra-
`tion was achieved by voluntary food and fluid denial
`combined with exercise in a hot environment. Subjects
`rested 15 h in a comfortable environment (while hy-
`pohydrated) prior to the measurements. An identical
`program of exercise-heat stress, but with full fluid re-
`placement, was completed on the day prior to the
`euhydration measurements (dotted line). After the sub-
`jects were heat acclimated, there was a smaller plasma
`volume reduction for a given body water loss. It can be
`theorized that, since hypohydration was induced by
`exercise-heat stress, a more hypotonic sweat secretion
`in heat acclimated subjects resulted in a greater amount
`of solute remaining in the plasma that enabled redistri-
`bution of fluid from the intracellular compartment.
`Therefore, an individual’s state of heat acclimation
`probably alters the magnitude of hypovolemia associ-
`ated with hypohydration.
`Figure 3 presents plasma volume responses for heat
`acclimated subjects when euhydrated and hypohy-
`drated by 3%, 5%, and 7% of their body weight during
`rest and exercise (1 10). Note that plasma volumes were
`generally reduced with increased hypohydration, al-
`though there was some evidence of a plasma volume
`defense during the 7% hypohydration. The most im-
`portant point from this figure is that the hypohydration
`mediated plasma volume reduction that occurs at rest
`continues throughout
`the subsequent
`light
`intensity
`(25% Ozmax) exercise. In fact, the differences between
`the euhydration and hypohydration plasma volume
`values are greater during exercise than rest because of
`the small exercise hemodiiution that occurs when sub-
`
`I I I I I I l i I | I I 1 I I I I I
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`
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`
`jects are euhydrated but not when hypohydrated
`(99,109,110).
`There is evidence that plasma volume can be partially
`defended despite a progressive dehydration during in-
`tense (65—75% Ozmax) running exercise (36,50,104).
`For example, Sawka and colleagues (104) showed that
`during 100 min of treadmill running, the plasma vol-
`ume remained stable despite a 4% reduction in body
`weight. Likewise, Kolka et a1. (58) reported that during
`a competitive marathon race the plasma volume re-
`mained stable despite a 7% reduction in body weight.
`Reasons for the stable plasma volume during intense
`exercise, despite progressive dehydration, might include
`the release of water from glycogen breakdown, meta-
`bolic water (90), and the redistribution of water from
`inactive skeletal muscle (98). The higher the exercise
`intensity, the greater the use of muscle glycogen as a
`metabolic substrate (16) and therefore the greater the
`water release from glycogen breakdown. Also,
`the
`greater amount of substrate oxidation,
`including fat,
`will result
`in a greater amount of metabolic water
`release.
`
`Convertino (17) has speculated that the endocrine
`system could contribute to the redistribution of water
`into the intravascular space during intense exercise.
`The plasma concentration of angiotensin and vasopres-
`sin are increased in relation to the exercise intensity
`(18,19) and the magnitude of water deficit (9,34,35).
`Both of these hormones are potent vasoconstrictors,
`and their increased circulating concentrations causes
`vasoconstriction in inactive tissues. Vasoconstriction
`
`increases the ratio of pre— to post-capillary resistance,
`and favors fluid absorption from the inactive tissues
`(98). Therefore, during high-intensity exercise while
`hypohydrated, the elevated circulating concentration of
`these hormones favors additional fluid absorption from
`the inactive tissues. Regardless of the physiological
`mechanisms, exercise intensity may influence the avail-
`ability of water for redistribution to the intravascular
`space.
`
`Some athletes may use diuretics to reduce their body
`weight. Diuretics are drugs that increase the rate of
`urine formation and generally result
`in the loss of
`solutes (127). The commonly used thiazide (e.g.,
`Diuril), carbonic anhydrase inhibitors (e.g., Diamox),
`and furosemide (e.g., Lasix) result in natriuresis. Di-
`uretic-induced hypohydration generally results in an
`iso-osmotic hypovolemia, with a much greater ratio of
`plasma loss to body water loss than either exercise or
`heat induced hypohydration (51). As a result, with a
`diuretic—mediated loss of body water, there is not a
`solute excess in the plasma to exert an osmotic pressure
`for the redistribution of body water. Therefore, diuretic-
`induced hypohydration results in a relatively greater
`loss of extracellular and thus plasma water than sweat—
`induced hypohydration.
`
`InnoPharma Exhibit 1108.0004
`
`

`

`PHYSIOLOGICAL CONSEQUENCES 0F HYPOHYDRATION
`
`Official Journal of the American College of Sports Medicine
`
`661
`
`EXERClSE PERFORMANCE
`
`Generally, body water deficits adversely influence
`exercise performance (105). The critical water deficit
`and magnitude of performance decrement are related
`to the environmental temperature and exercise task;
`the warmer the environment the greater the potential
`for exercise performance decrements (105). Prolonged
`aerobic exercise tasks are more likely to be adversely
`influenced by hypohydration than short-term anaerobic
`exercise tasks (105). In addition, the thermoregulatory
`advantages conferred by high aerobic fitness and heat
`acclimation are negated by hypohydration during ex—
`ercise in the heat (11,12,106). Cognitive performance
`is also adversely influenced by body water deficits
`(1,38,62). For many complex athletic and industrial
`tasks, both the mental decision making and physiolog»
`ical function are closely related. As a result, hypohydra-
`tion probably has a more profound effects of real-life
`tasks than on solely physiological performance meas-
`ures.
`
`Table 2 presents a summary of investigations con-
`cerning the influence of hypohydration on maximal
`aerobic power and physical work capacity (4,11,13,
`24,46,50,88,96,126). In a temperate environment, a
`body water deficit of less than 3% body weight did not
`alter maximal aerobic power. Maximal aerobic power
`was decreased (11,13,126) in three of the five studies
`when hypohydration equaled or exceeded 3% body
`weight. Therefore, a critical water deficit (3% body
`weight) might exist before hypohydration reduces max-
`imal aerobic power in a temperate environment. In a
`hot environment, Craig and Cummings (24) demon-
`strated that small (2% body weight) to moderate (4%
`body weight) water deficits resulted in large reduction
`of maximal aerobic power. Likewise, their data indicate
`a disproportionately larger decrease in maximal aerobic
`power with an increased magnitude of body water
`deficit. It seems that environmental heat stress has a
`
`The physical work capacity for progressive intensity
`aerobic exercise was decreased during hypohydration
`in all of the studies presented in Table 2. Physical work
`capacity was decreased by marginal (l-2% body weight) .
`water deficits that did not alter maximal aerobic power
`(4,13). The more pronounced the water deficit, the
`larger the reduction in physical work capacity. Clearly,
`hypohydration resulted in much larger decrements of
`physical work capacity in hot as compared with tem-
`perate environments (24,88). It appears that the ther-
`moregulatory system, perhaps via increased body tem-
`peratures, has an important role in the reduced exercise
`performance mediated by a body water deficit.
`A reduced maximal cardiac output might be the
`physiological mechanism by which hypohydration de-
`creases an individual’s maximal aerobic power and
`physical work capacity. Remember, hypohydration is
`associated with a decreased blood (plasma) volume
`during both rest and exercise. A decreased volume can
`increase blood viscosity (125) as well as possibly reduce
`venous return. During maximal exercise, a viscosity-
`mediated increased resistance and a reduced cardiac
`
`filling could decrease both stroke volume and cardiac
`output. Several investigators (3,119) have reported a
`tendency for reduced cardiac output for hypohydrated
`subjects during short-term moderate intensity exercise
`in temperate environments.
`It is not surprising that environmental heat stress
`potentiates the hypohydration mediated reduction in
`maximal aerobic power. For euhydrated individuals,
`environmental heat stress alone decreases maximal
`
`aerobic power by ~7% (l08). In the heat, the superficial
`skin veins reflexiver dilate to increase the cutaneous
`blood flow and volume. The redirection of blood flow
`to the cutaneous vasculature could decrease maximal
`
`aerobic power by: (a) reducing the portion of cardiac
`output perfusing the contracting musculature or, (b)
`decreasing the effective central blood volume, central
`venous pressure, and thus reduce venous return and
`cardiac output. A hypchydrated person performing ex-
`potentiating effect on the reduction of maximal aerobic
`ercise in the heat would be hypovolemic and still have
`power elicited by hypohydration.
`
`TABLE 2. Hypchydratlon effects on maxlmal aerobic power and physical work capacity.
`
` Test Exercise Maximal Physical Work
`
`
`Dehydration
`Envlronment
`Mode
`Aerollc Power
`Capacity
`Procedure
`Diuretics
`Exercise.
`diuretics,
`sauna
`Sauna. heal. exercise.
`diuretics
`Fluid restriction
`
`Study
`Armstrong et al.
`Caldwell at al.
`
`Saltln
`
`fiction et at.
`
`Year
`1985
`1984
`
`1964
`
`1988
`
`Craig and Cummings
`
`Busklrk et al.
`Webster el al.
`Herbert and filbisl
`Houston at al.
`
`1966
`
`1958
`1988
`1971
`1981
`
`Heat
`
`Exercise. heat
`Exercise in heat, sauna
`?
`Fluid restriction
`
`AWT
`—1°/o
`—2%
`—-3°/o
`—4%
`—4%
`
`—1 “re
`-2%
`—3%
`4%
`—4%
`—5%
`-5%
`-5%
`—8%
`
`Neutral
`Neutral
`Neutral
`Neutral
`Neutral
`
`Hot
`Hot
`Hot
`Hot
`Hot
`Neutral
`Neutral
`Neutral
`Neutral
`
`TM
`CY
`CY
`CY
`CY
`
`CY
`CY
`CY
`TM
`TM
`TM
`TM
`CY
`TM
`
`ND
`ND
`\( (8%)
`( (4%)
`ND
`
`-
`—
`-
`l (16%}
`1 (27%)
`( (0.22 l. min")
`l (7%)
`—~
`ND
`
`l (6%)
`1 (7 W)
`l (21 W)
`l (23 W)
`1 (.7)
`
`((6%)
`(18%}
`t 20%)
`gave}
`l (48%)
`——
`l (12%)
`1 (17%)
`—
`
`InnoPharma Exhibit 1108.0005
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`

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`662
`
`Official Journal of the American College of Sports Medicine
`
`MEDICINE AND SCIENCE IN SPORTS AND EXERCISE
`
`to simultaneously perfuse the cutaneous vasculature
`and contracting skeletal muscles. In addition, a sub-
`stantial volume of blood would be redirected to the
`
`skin, and therefore removed from the effective central
`circulation and not available to perfuse the skeletal
`muscles (94). As a result, both hypohydration and
`environmental heat stress would independently act to
`limit cardiac output and therefore oxygen delivery dur-
`ing maximal exercise.
`Surprisingly few investigators have documented the
`effects of dehydration on human tolerance to submax—
`imal exercise in the heat. Adolph and associates (1)
`performed experiments in the California deserts during
`1942 and 1943.
`In those experiments, subjects at—
`tempted endurance (2—23 h) walks (at 4—6.5 km-h")
`in the desert (Ta ~38°C) and were either allowed to
`drink water ad libitum or refrained from drinking.
`Adolph and associates (1) reported that 1 l of 70 soldiers
`(16%) and only one of 59 (2%) soldiers suffered ex-
`haustion from heat strain during a desert walk when
`they did not drink and did drink, respectively. In sub-
`sequent experiments, they reported that 15 of 70 sub-
`jects (21%) and one of 59 subjects (2%) suffered ex-
`haustion from heat strain during an attempted 8—h
`desert walk when they did not drink and did drink,
`respectively. The magnitude of dehydration suffered by
`the subjects was not provided in either set of experi-
`ments. Ladell (62) had subjects attempt l40—min walks
`in a hot (Ta = 38°C) environment while drinking dif—
`ferent amounts of water. They reported that exhaustion
`from heat strain occurred in nine of 12 (75%) experi-
`ments when not receiving water and three of 41 (7%)
`experiments when receiving water. Clearly, dehydration
`increases the incidence of exhaustion from heat strain.
`
`Sawka and colleagues (110) had eight subjects at-
`tempt treadmill walks (~25% Ozmax for 140 min) in a
`hot-dry (Ta = 49°C, rh = 20%) environment when
`euhydrated and when hypohydrated by 3%, 5%, and
`7% of their body weight. All eight subjects completed
`the euhydration and 3% hypohydration experiments,
`and seven subjects completed the 5% hypohydration
`experiments. For the 7% hypohydration experiments,
`six subjects discontinued after completing only (mean)
`64 min. Recently, those investigators (111) reported
`experiments where subjects walked to exhaustion from
`heat strain when either euhydrated or hypohydrated
`(8% of total body water). The experiments were de-
`signed so that the combined environment (Ta = 49°C,
`rh = 20%) and exercise intensity (46% Ozmax) would
`not allow thermal equilibrium and exhaustion from
`heat strain would eventually occur. Hypohydration re-
`duced tolerance time (1 14 to 48 min), but more impor-
`tantly, hypohydration reduced the body temperature
`level that an individual could tolerate. Exhaustion from
`
`heat strain occurred after mean body temperature in-
`creases of 1.8°C in the euhydration experiments, but of
`only l.3°C in the hypohydration experiments.
`
`One investigation has examined the effects of a body
`water deficit on competitive distance running perform-
`ance. Armstrong and colleagues (4) had athletes com-
`pete in 1,500, 5,000, and 10,000 m races when euhy-
`drated and when hypohydrated. Hypohydration was
`achieved by administration of a diuretic (furosemide)
`that decreased body weight by 2% and plasma volume
`by 1 1%. Remember, diuretics result in a disproportion-
`ately larger loss of plasma water relative to total body
`water loss than either exercise or thermally mediated
`hypohydration. Those investigators found that running
`performance was degraded by hypohydration to a
`greater extent in longer races (~5% for the 5,000 and
`10,000 m) than in shorter race (3% for 1,500 m). They
`speculated that hyperthermia might have provided the
`physiological mechanism that caused greater perform-
`ance decrements during the longer races when hypoh-
`ydrated.
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`TEMPERATURE REGULATION
`
`Prolonged aerobic exercise is adversely affected by
`hypohydration via impairments of the thermoregula-
`tory and cardiovascular systems (105). In comparison
`to euhydration, hypohydration results in an increased
`core
`temperature during exercise
`in
`temperate
`(12,39,76,104) as well as in hot(15,86,89,102,112,117)
`environments. The critical water deficit of 1% body
`weight elevates core temperature during exercise (28).
`As the magnitude of water deficit increases, there is a
`concomitant graded elevation of core temperature dur-
`ing exercise.
`Two studies examined core temperature response to
`exercise while hypohydration levels were varied during
`independent tests in the same subjects. Strydom and
`Holdsworth (121) studied two miners at two hypohy-
`dration levels (low, 3—5%, and high, 5—8% weight loss)
`and found higher core temperatures at the greater hy-
`pohydration level. Sawka et al. (110) reported that
`hypohydration linearly increased the core temperature
`by 0.15°C during exercise in the heat for each percent
`decrease in body weight. Other investigators, reporting
`a gradation of elevated core temperature with increased
`water deficits, have interpolated from a single hypohy-
`dration level (41) and/or employed prolonged exercise—
`heat exposure to elicit a progressive dehydration (1,3,7).
`Reanalyzing the data of Adolph and associates (1), it
`was found that their subjects had an elevated core
`temperature of 020°C for each percent decrease in body
`weight. Their data represent progressive dehydration
`under a variety of field and laboratory conditions.
`Greenleaf and Castle (41) reported that core tempera—
`ture was elevated 010°C for each percent decrease in
`body weight during exercise (49% Ozmax) in a temper-
`ate environment. This relationship was based on inter-
`polation from a single hypohydration (5% body weight
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`InnoPharma Exhibit 11080006
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`

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`PHYSIOLOGICAL CONSEQUENCES OF HYPOHYDRATION
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`Official Journal of the American College of Sports Medicine
`
`668
`
`loss) level. Gisolii and Copping (37) reported that core
`temperature was elevated by 040°C for each percent
`decrease in body weight after a weight loss of greater
`than 2% during intense exercise (74% Ogmax) in a hot
`environment. Figure 5 presents the relationships be—
`tween hypohydration and the elevation in core temper-
`ature (above euhydration levels) during exercise (105).
`When hypohydrated, the increased heat storage could
`result from either a disproportionate increase in
`metabolic heat production or a disproportionate de-
`crease in heat loss. Hypohydration probably does not
`influence metabolic rate during submaximal exercise
`(41,9?,103,106,110) and therefore a reduction of heat
`dissipation is responsible for the hypohydration-me-
`diated greater heat storage during exercise. The relative
`contributions of evaporative and dry heat exchange
`during exercise depend on the specific environmental
`conditions, but both avenues of heat toss are adversely
`affected by hypohydration (100).
`Hypohydration is associated with both reduced
`(69,112,121) and unchanged (15,122,123) sweating
`rates during exercise at a given metabolic rate. How—
`ever, investigators reporting no change in sweating rate
`usually
`observed
`an
`elevated
`core
`temperature
`(15,100,123). Therefore, the sweating rate is lower for
`a given core temperature, and the potential for heat
`dissipation via evaporation is reduced when hypohy-
`drated. Figure 6 shows with increased hypohydration
`levels there is a systematic reduction in total body
`sweating rate for a given core temperature during ex-
`ercise in the heat (1 10). Likewise, Figure 7 (lefl) presents
`data showing a reduced local sweating rate with hypoh-
`ydration (5% body weight) during exercise in the heat
`(101). These figures suggest that hypohydration delays
`the onset of sweating during exercise-heat stress.
`The physiological mechanisms mediating the re—
`duced sweating rate during hypohydration are not
`clearly defined. Both the singular and combined effects
`of plasma hypertonicity (l4,45,66,113) and hypovole—
`mia (31,32,47,68) have been sugge