Fluid Replacement and Heat Stress, 1993

Pp. 169-193. Washington, D.C.

National Academy Press

14

Solute Model or Cellular Energy Model? Practical and Theoretical Aspects of Thirst During Exercise

Roger W. Hubbard1, Patricia C. Szlyk, and Lawrence E. Armstrong

INTRODUCTION

Most physiologists would agree that repaying the water debt incurred through evaporative cooling is part of the physiological cost of work in the heat. Pitts et al. (1944) emphasized that during work in the heat, men never voluntarily drink as much water as they lose and usually replace only two-thirds of the net water loss. Rothstein et al. (1947) observed that this occurred even when water was availabel and called this phenomenon voluntary dehydration. Some physiologists feel that voluntary dehydration occurs because “. thirst is an inadequate stimulus to drinking” (Ladell, 1965, p. 253). On the other hand, Vokes (1987) contends that “. one of the best examples of a perfectly functioning homeostatic system is water balance” (Vokes, 1987, p. 383). One of our goals is to reconcile the fact that under certain conditions both of these statements are correct. We will also try to switch the reader's interest from water to salt for, although man may drink, “. water cannot be held until the missing osmoles are made good”

1  

Roger W. Hubbard, Department of the Army, U.S. Army Research Institute of Environmental Medicine, Natick, MA 01760-5007



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FLUID REPLACEMENT AND HEAT STRESS Fluid Replacement and Heat Stress, 1993 Pp. 169-193. Washington, D.C. National Academy Press 14 Solute Model or Cellular Energy Model? Practical and Theoretical Aspects of Thirst During Exercise Roger W. Hubbard1 , Patricia C. Szlyk, and Lawrence E. Armstrong INTRODUCTION Most physiologists would agree that repaying the water debt incurred through evaporative cooling is part of the physiological cost of work in the heat. Pitts et al. (1944) emphasized that during work in the heat, men never voluntarily drink as much water as they lose and usually replace only two-thirds of the net water loss. Rothstein et al. (1947) observed that this occurred even when water was availabel and called this phenomenon voluntary dehydration. Some physiologists feel that voluntary dehydration occurs because “. thirst is an inadequate stimulus to drinking” (Ladell, 1965, p. 253). On the other hand, Vokes (1987) contends that “. one of the best examples of a perfectly functioning homeostatic system is water balance” (Vokes, 1987, p. 383). One of our goals is to reconcile the fact that under certain conditions both of these statements are correct. We will also try to switch the reader's interest from water to salt for, although man may drink, “. water cannot be held until the missing osmoles are made good” 1   Roger W. Hubbard, Department of the Army, U.S. Army Research Institute of Environmental Medicine, Natick, MA 01760-5007

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FLUID REPLACEMENT AND HEAT STRESS (Ladell, 1965, p. 284). This may be seen as at least one explanation of why thirst is inadequate, and there are others. Common sense would dictate that it is quite useless to estimate a “normal” fluid intake because we are dealing with a homeostatic system designed to equate water requirements with the various losses (respiratory, urinary, skin, and sweat). Let us look briefly at these as a partial inventory of our water demand. Under normal conditions, respiratory water loss is about 200 ml/day, but it can be around 350 ml/day for men working in a dry climate and can approach 1,500 ml/day for men working at high altitudes in cold air (Ladell, 1965). The insensible perspiration may be as low as 500 ml in a moist climate, and with a minimum urine volume (<300 ml/day), a person can barely meet obligate losses on 1,000 ml of water per day. The obligate urine volume varies with the diet and is high on a high-protein diet and low on a carbohydrate diet. A more reasonable figure for urine volume represents a maximum of 1.4 osmol of metabolic end products (mostly urea and surplus electrolyte) per liter of urine on a mixed European-style diet. Thus, the greatest rate of water loss, by far, is represented in a healthy individual by eccrine sweating, which most physiologists would agree can be sustained at something over 1 liter/h. This makes sense, because the maximum rate of gastric emptying has been estimated between 15 and 20 ml/min or 900 to 1,200 ml/h (Davenport, 1982). According to Ladell, “. thirst is primarily a sensation, which often serves as a drive to drink, but the drive and the sensations are not necessarily identical ” (Ladell, 1965, p. 271). Ladell (1965) has further introduced a concept of free circulating water, equivalent to some 2 liters, which does not appear to participate in the osmotic balance of the body. This suggests that the drive to drink would not come into play until this free circulating water is expended. This interesting notion actually delivers two important ideas: (1) There is an inherent delay in the onset or drive of thirst. If this could be explained, it would then be more accurate to describe thirst as delayed rather than inadequate. (2) The delay is a manifestation of the body's osmotic control. HYPERTONICITY, ANTIDIURETIC HORMONE RELEASE, AND THIRST Although the solute composition of the extracellular compartment is markedly different from that of the intracellular space, the total osmolalities (solute concentration, not content) (Conway and McCormack, 1953) are very similar. This is because most cell membranes are freely permeable to water. Thus, one can approximate intracellular fluid osmolality by measuring the

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FLUID REPLACEMENT AND HEAT STRESS plasma osmolality (Feig and McCurdy, 1977). The major intracellular osmotic solutes are potassium, magnesium, organic phosphates, and protein. The major osmotic solutes in extracellular fluid are normally sodium and its anions, chloride, and bicarbonate. They are referred to as impermeant but are kept on the proper side of the membrane by molecular size, electrical charge, or active pumps. Net movement of water is determined by the osmolalities of the intra- and extracellular compartments (Peters, 1944). The osmolal concentration or osmolality (usually in milliosmoles per kilogram of water) is an indiscriminating summation of all the particles, ions, and molecules present in a solution. It is usually measured by freezing point depression or change in vapor pressure. Measured osmolality should be differentiated from effective osmolality (i.e., the concentration of solutes that will create an osmotic force in vivo). For example, sodium is the major determinant of the effective osmolality of the extracellular fluid because its concentration is high and it acts as if it is restricted from entering cells (Guyton, 1986). In contrast, urea permeates cells freely and does not exert an osmotic force if it is elevated in either compartment. The addition of an impermeant solute to the extracellular space causes a net intracellular fluid volume depletion and creates, by definition, a hypertonic state (Feig and McCurdy, 1977). Freezing point depression does not distinguish between permeant and impermeant solutes by measuring osmolality. Thus, an elevated plasma osmolality must be checked by calculation of tonicity before it is interpreted as hypertonicity. For example, 2 × plasma sodium (meq/liter) + plasma glucose (mg/dl/18) = approximate tonicity. Normally, intracellular fluid contains about two-thirds of the total body solute, and one-third is in the extracellular fluid. Since water distributes according to the amount of impermeant solute in each compartment, the intracellular fluid contains two-thirds of total body water (TBW) and extracellular fluid contains about one-third of TBW. Assume, for ease of calculation, that the average 70-kg adult is 60% water (TBW = 42 liters) and two-thirds (28 liters) is intracellular and one-third (14 liters) is extracellular (3.5 liters of plasma and 10.5 liters of interstitial fluid). Note by calculation (Feig and McCurdy, 1977) that the intravascular or plasma volume is equivalent to one-twelfth of the total body water (3.5:42 as 1:12) and that the plasma volume is one-fourth the extracellular volume (3.5:14 as 1:4). Thus, by definition, if a pure water loss occurs (no salt loss), two-thirds comes from the intracellular water, one-third comes from the extracellular water, and one-twelfth comes from the intravascular water. In practice, less than one-twelfth of the water loss usually comes from the plasma space because of increased plasma protein oncotic pressure (Feig and McCurdy, 1977). It also follows that if the extracellular space loses 4 liters

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FLUID REPLACEMENT AND HEAT STRESS of isotonic saline, three-fourths would come from the interstitial fluid and one-fourth would come from the plasma fluid. Gilman (1937) demonstrated that intravenous infusions of hyperosmotic sodium chloride elicited drinking but that equally hyperosmotic solutions of urea stimulated thirst poorly. Since urea could diffuse into cells but sodium would produce shrinkage, an osmotic basis for thirst was established. Other solutes that cause the withdrawal of water from cells, such as sucrose and sorbitol, were equally effective in producing thirst when infused intravenously (Holmes and Gregersen, 1950a,b). These observations reinforced the important role of cellular dehydration in triggering thirst and drinking behavior. The classic work of Verney (1947) demonstrated that water diuresis in dogs could be inhibited by intracarotid infusions of hypertonic sodium chloride and, therefore, that both thirst and antidiuresis were linked to the osmotic withdrawal of water from cells. Verney (1947) deduced that the inhibition of water diuresis resulted from neurohypophyseal secretion of vasopressin, which was later confirmed (Wade et al., 1982). According to Andersson (1978), the most potent stimulators of antidiuretic hormone (ADH) release and thirst are absolute and relative dehydration. Although ADH is released as a function of the body osmolality (Robertson and Athar, 1976; Robertson and Mahr, 1972), it is equally well correlated with plasma sodium (Olsson et al., 1978). Andersson (1978) suggested that sodium itself is the crucial factor in the osmotic control of water balance and proposed that the centrally located osmoreceptors are responding to specific changes in the cerebrospinal fluid (CSF) sodium concentration subsequent to perturbations in the extracellular fluid osmolality. This was supported by the observation that hypertonic sucrose did not stimulate thirst and ADH when infused into the third ventricle (Olsson, 1969). Intracerebral infusions of hypertonic sucrose can inhibit ADH release by dilution-reduction of the CSF sodium concentration, which argues against a receptor location outside the blood-brain barrier. Andersson (1978) recognized that there is the possibility that both elevated sodium and cellular dehydration trigger a biochemical process involved in the receptor-excitation mechanism. Andersson (1978) further suggested that angiotensin II might be an activator of a cationic transporting enzyme. Angiotensin II (Gutman et al., 1972), L-norepinephrine (Desaiah and Ho, 1977), and prostaglandin PGE1 (Limas and Cohn, 1974) interact with sodium, possibly at the level of Na-K-adenosine triphosphatase (ATPase), in stimulating ADH and thirst. The ADH of humans and most other mammals is arginine vasopressin, which is produced by the neurohypophysis. Under physiological conditions, ADH release is apparently controlled primarily by plasma osmolality, but the osmoregulatory system appears to display large individual (Robertson, 1977;

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FLUID REPLACEMENT AND HEAT STRESS Robertson et al., 1976) differences (biological variability?) in both sensitivity and threshold. However, this could be analogous to the apparent differences in the onset of sweating, which depends on an acclimatization response to repeated exposures. Within any one individual, the plasma vasopressin response (ADH release) is linearly related to plasma osmolality across the same range within which thirst is stimulated (Robertson et al., 1976). Generally, the range of body fluid osmolality in a person in good health is between 280 and 295 mosmol/kg of water or 287 ± 2% (Feig and McCurdy, 1977). At a plasma osmolality of 280 mosmol/kg of water, ADH release is completely inhibited (Feig and McCurdy, 1977) and the urine osmolality is minimal (< 100 mosmol/kg of water). According to Robertson and Berl (1985), the full range of urinary concentrations can be achieved by changing the plasma ADH concentration to between 0.5 and 5.0 pg/ml. The most important action of ADH is to conserve body water by increasing the renal reabsorption of solute-free water, which increases the urine concentration and decreases the urine flow. Although there is wide variation in individual thirst threshold, Vokes (1987) estimated its average value at 295 mosmol/kg of water. Thus, at the thirst threshold (the highest plasma osmolality that occurs normally), the increased ADH concentration elicits maximum urinary concentration [urine osmolality (Uosmol)> 800-1000 mosmol/kg of water]. According to Feig and McCurdy (1977), the mathematical relationship between variables across this physiologic range can be expressed by the following equations: 0.34 × change in plasmaosmol (Posmol) = change in plasma ADH (in pg/ml), change Uosmol = 95 × change in Posmol. Thus, a 1-mosmol plasma change increases urine osmolality by almost 100 mosmol, and at the thirst threshold (295 mosmol/kg of water), urine volume is reduced 10- to 20-fold. Therefore, it can be appreciated that ADH and thirst play key roles in maintaining the water balance, primarily by regulating the plasma osmolality over a very narrow range (Vokes and Robertson, 1985) bounded on the lower end by the osmotic threshold for ADH releases (280 mosmol/kg) and on the upper end by the osmotic threshold for thirst (295 mosmol/kg). This lack of complete parity between an increase in osmolality and the behavior of thirst--(1) seeking water, (2) drinking water, (3) ceasing to drink, and (4) absorption and distribution (Adolph et al., 1954)--could represent an importation adaptation which frees people and animals from the necessity to irritate themselves repeatedly in response to minor increases in osmolality (Stricker and Verbalis, 1980,

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FLUID REPLACEMENT AND HEAT STRESS p. 261). Thus, thirst does not become prominent until the osmotic dehydration exceeds the renal capacity to deal with it physiologically. EXAMPLE 1: FREE CIRCULATING WATER Ladell (1965) has introduced the idea of free circulating water that is equivalent to some 2 liters of TBW but does not appear to participate in the body's osmotic balance. Let us examine this in light of the current mechanism for thirst stimulation. If we assume that a pure water deficit does not alter the total body solute, then hypertonicity will be proportional to the volume of water lost (Feig and McCurdy, 1977): (normal TBW) × (normal Posmol) = present TBW) × (present Posmol). We also assume parity between a liter and a kilogram of water: If a man begins to lose pure water at the lowest normal plasma osmolality (Feig and McCurdy, 1977) of 280 mosmol/kg of water (fully hydrated), we can calculate about how much water will be lost before the average threshold (Vokes, 1987) for thirst is reached at 295 mosmol/kg water: (normal TBW) × (normal Posmol) = (thirst TBW) × (thirst Posmol), (42 liters) × (280 mosmol/kg) = liters x (295 mosmol/kg) (11,760 mosmol/295 mosmol/kg) = liters = 39.9 liters = TBW at the thirst threshold, (42 liters-39.9 liters) = 2.1 liters = TBW deficit. This calculation suggests that, on average, 2.1 liters of water would be lost before reaching the thirst threshold. This assumes that a person begins losing water when that person is fully hydrated, which is more common practice in research than in other activities. This figure appears to confirm the prior observation by Ladell (1965) that there is free circulating water equivalent to some 2 liters that does not appear to participate in the osmotic balance of the body. This calculation provides futher support to the two arguments (1) that thirst is delayed rather than inadequate and (2) that the delay is a manifestation of the body's osmotic control. EXAMPLE 2: PURE WATER DEFICIT IN THE HYDRATED STATE: IMPACT ON REHYDRATION Let us examine the impact of the thirst threshold on rehydration in a common situation (TBW loss = 6% of body weight or 4.2 liters; begin from fully hydrated state).

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FLUID REPLACEMENT AND HEAT STRESS Dehydration First, let us calculate how high the plasma osmolality would be driven without fluid intake. (normal TBW) × (normal Posmol) = (dehydrated TBW) × (dehydrated Posmol), (42 liters) × (280 mosmol/kg) = (42 liters − 4.2 liters) × (? mosmol/kg) (11,760 mosmol/37.8 liters) = 311.1 mosmol/kg = dehydrated Posmol. Rehydration (dehydrated TBW) × (dehydrated Posmol) = (thirst TBW) × (thirst Posmol) (37.8 liters) x (311.1 mosmol/kg) = (295 mosmol/kg) x (? liters) (11,760 mosmol/295 mosmol/kg) = 39.9 liters = rehydrated TBW. Thus, at the thirst threshold (a plasma osmolality of 295 mosmol/kg), a TBW of 39.9 liters is theoretically achieved. Since the prior, dehydrated TBW was 37.8 liters, there was a net gain in TBW of 2.1 liters (39.9 liters − 37.8 liters). This suggests that only 50% (2.1 liters × 100/4.2 liters) of the fluid deficit would be rehydrated before the thirst threshold is reached. Under these conditions, thirst is not inadequate. The rehydration deficit is an inherent feature of the offset between the thirst set point relative to the renal diuresis set point in the fully hydrated condition. For example, it is not uncommon to assess a fully hydrated condition by having test subjects consume water until urine specific gravity declines to some target end point. Thus, fully hydrated test subjects before dehydration will almost certainly never fully rehydrate after dehydration. This calculation appears to confirm the early assertion of Pitts et al. (1944) that subjects rarely consume sufficient water to replace the deficit. Since only one-twelfth or less of this deficit (2.1 liters/12 = 175 ml) comes from plasma (3.5 liters:42 liter as 1:12), given its high oncotic pressure, there is very little impact on cardiovascular performance.

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FLUID REPLACEMENT AND HEAT STRESS EXAMPLE 3: PURE WATER DEFICIT PRODUCING CLINICAL SHOCK Clinical shock from pure water loss generally requires a sodium above 170 meq/liter (Feig and McCurdy, 1977). This water deficit can be calculated by the following formula equation *(Yarbrough and Hubbard, 1989): Water deficit (liters) = TBW or (0.6 × wt in kg) − [TBWX desired (Na)/measured (Na)], water deficit = 42 liters − [(42 liters) × (140 meq/liters)/(170 meq/liters)] = 42 liters − 34.6 liters = 7.4 liters Thus, in a pure water deficit sufficient to produce shock, one might estimate a minimum loss of some 7.4 liters. Since one-twelfth of this deficit is coming from the plasma (7,400 ml/12 = 616 ml), there is a decline in plasma volume of about 18% (616 ml × 100/3,500 ml). One rarely sees a pure water deficit since salt is usually lost as well. The percent body weight loss in this example is 10.6% (7.4 liters × 100/70 kg). EXAMPLE 4: PURE WATER DEFICIT IN THE HYPOHYDRATED STATE: IMPACT ON REHYDRATION If the subjects losing water are hypohydrated at the thirst threshold with a thirst plasma osmolality of 295 mosmol/kg of water (thirst TBW = 39.9 liters) and then lose 4.2 liters (6% of initial body weight), their plasma osmolality could rise to: (thirst TBW) × (thirst Posmol) = (dehydrated TBW) × (dehydrated Posmol), (295 mosmol/kg) × (39.9 liters) = (39.9 liters − 4.2 liters) × (? mosmol/kg), (11,770 mosmol/35.7 liters) = 330 mosmol/kg water. The dehydrated plasma osmolality could be 330 mosmol/kg and the dehydrated TBW could be 35.7 liters. If they drink until the starting thirst threshold is reached (rehydrate), they should consume: (dehydrated TBW) × (dehydrated Posmol) = (thirst TBW) × (thirst Posmol), (35.7 liters) × (330 mosmol/kg) = (? liters) × (295 mosmol/kg), (11,781 mosmol/295 mosmol/kg) = 39.9 liters (thirst TBW).

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FLUID REPLACEMENT AND HEAT STRESS Thus, at the thirst threshold (a plasma osmolality of 295 mosmol/kg), a TBW of 39.9 liters would be achieved. Since the dehydrated TBW was 35.7 liters, an intake of 4.2 liters was required to reach the thirst threshold. This suggests that, by beginning the dehydration in the hypohydrated state at the thirst threshold, a nearly 100% rehydration of the dehydration deficit but only 66.7% of the total deficit (6.3 liters) could be expected. Therefore, rehydration results will depend on whether test subjects show up hydrated (50% rehydration) or hypohydrated (100% rehydration) for an experiment producing a 6% loss in body weight as body water. EXAMPLE 5: HYPOTONIC WATER DEFICIT IN THE HYDRATED, NON-HEAT-ACCLIMATIZED STATE Assume that the subject is unacclimatized to heat and produces a hypotonic sweat (0.43% NaCl = 1/2 isotonic saline) as the source of body water deficit. He begins work in the heat in a fully hydrated, normal condition (plasma osmolality = 280 mosmol/kg of water) and then loses 6% of body weight (4.2 liters) as sweat. Solute Deficit We first compute the impact of the solute loss (sweat NaCl) on the total solute content of the body. The total of 11,760 mosmol (280 mosmol/kg × 42 liters) is reduced by an amount equivalent to the solute content of the lost sweat. Assume that 1/2 isotonic saline is equivalent to an osmolality of 140 mosmol/kg (0.5 × 280 mosmol/kg), then: (140 mosmol/kg of sweat) × (4.2 liters) = 588 mosmol of lost solute. The new salt-depleted total solute content is 11,172 mosmol (11,760 mosmol − 588 mosmol). Dehydration The new salt-depleted TBW will be 37.8 liters (42.0 liters − 4.2 liters). The new salt-depleted, dehydrated plasma osmolality will be 295.6 mosmol/kg (11,172 mosmol/37.8 liters). Assume that one-half of the fluid loss is pure water (2.1 liters) and the other half is isotonic saline. The plasma would contribute one-twelfth of the pure water deficit, or 175 ml. The extracellular space would lose 2.1 liters of isotonic saline, of which the

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FLUID REPLACEMENT AND HEAT STRESS plasma contributes (3.5:14 as 1:4) 2,100 ml × 1/4 = 525 ml. If we add the 175 ml from the pure water portion (525 ml + 175 ml = 700 ml), we see that the plasma has lost 20% of its volume (700 ml × 100/3,500 ml) which, as seen above, is close to the shock threshold. Thus, a 4.2 liter sweat loss has theoretically as much impact on the plasma (volume −20%) as a much greater volume (7.4 liters) of pure water loss (−18%). Rehydration If the subject drank pure water until the plasma osmolality reached the thirst threshold (295 mosmol/kg), he or she would reach a thirst TBW of: (dehydrated TBW) × (dehydrated Posmol) = (thirst TBW) × (thirst Posmol). Assume the dehydrated condition to be a TBW of 37.8 liters and a salt-depleted, dehydrated plasma osmolality of 295.6 mosmol/kg of water. Assume the plasma osmolality to be 295 mosmol/kg at the thirst threshold. (37.8 liters) × (295.6 mosmol/kg) = (? liters) × (295 mosmol/kg), (11,172 mosmol/295 mosmol/kg) = 37.88 liters of TBW. The subject would increase his or her TBW by only 80 ml (37.88 liters – 37.8 liters) before the thirst threshold was reached. This is equivalent to only 1.9% of the initial water deficit (80 ml x 100/4,200 ml). In contrast to a similar volume of pure water loss from a hydrated starting point, a hypotonic deficit reduces the expected percent rehydration from 50% to 1.9%. This example serves to indicate the impact of solute loss on rehydration. Under these conditions, thirst is not inadequate. The problem is the missing solute. Any fluid intake under these conditions would probably be stimulated by the volume deficit. EXAMPLE 6: HYPOTONIC WATER DEFICIT IN THE HYDRATED, HEAT-ACCLIMATIZED STATE Assume that a subject was producing a sweat of minimum sodium concentration (a very hypotonic sweat; 0.17% NaCl = 0.2 isotonic saline) due to heat acclimation and a low-salt diet (high aldosterone levels). He subsequently loses 6% of his body weight (4.2 liters) after beginning work in the heat, fully hydrated.

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FLUID REPLACEMENT AND HEAT STRESS Solute Deficit His solute content would be 280 mosmol/kg × 42 liters = 11,760 mosmol, and his solute loss would be equivalent to the sweat solute concentration (280 mosmol/kg × 0.2 = 56 mos/kg) × sweat volume (4.2 liters) = 235 mosmol. His salt-depleted total solute content would be 11,760 mosmol − 235 mosmol = 11,525 mosmol. Dehydration His salt-depleted, dehydrated TBW would be 37.8 liters; therefore, the plasma osmolality would be: 11,525 mosmol/37.8 liters = 305 mosmol/kg of water. This deficit is equivalent to 839 ml (1,000 ml × 235/280) of isotonic saline or 0.84 liters of saline. The plasma contributes 25% or 210 ml of this deficit (839 ml/4). The remaining deficit is pure water (4,200 ml – 839 ml = 3,361 ml), of which the plasma contributes one-twelfth or 280 ml. The total plasma deficit is 490 ml (280 ml + 210 ml) or 14% (490 ml × 3,500 ml) of the plasma volume. Rehydration If the subject drank until the plasma osmolality reached the thirst threshold, then: (dehydrated TBW) × (dehydrated Posmol) = (thirst TBW) × (thirst Posmol), (37.8 liters) × (305 mosmol/kg) = (? liters) × (295 mosmol/kg), (11,525 mosmol/295 mosmol/kg) = 39.07 liters. The subject would consume 1.27 liters (39.0 liters – 37.8 liters) in reaching the thirst threshold. This represents 30.2% replacement of the total deficit (1.27 liters × 100/4.2 liters). Approximately 100 ml of this 1.27 liters would be returned to the plasma (1.27/12) and would reduce its deficit to 11%, 490 ml – 100 ml or 390/3,500 ml. Thus, heat acclimation could be expected to improve cardiovascular stability by reducing the solute loss, thereby preserving some plasma volume (390 ml versus 750 ml deficits). Moreover, it should have a pronounced impact on rehydration (30.2% versus 1.9%).

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FLUID REPLACEMENT AND HEAT STRESS Voluntary dehydration, nonacclimated, euhydrated (example 7) 6.3L 9.0% 235/ 118 668ml 2.66L −19% 323 3.39L 54% ~4 h of work in heat

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FLUID REPLACEMENT AND HEAT STRESS Following is a list of the hypothetical characteristics of such a site. Common feature of all cells, especially nerves and muscles Temperature sensitive Related to cell volume changes Functionally related to the acclimatization response Functionally related to tolerance and fatigue Ability to generate heat Potential for inducing irreversible change The key factors in this list all relate in some way to the sodium pump, a change in membrane permeability to sodium, a stimulation of metabolism and especially glycolysis, and a resultant energy drain upon the cell. For example, consider those factors in the following list that tend to increase intracellular sodium and to drive the sodium pump in a hyperthermic person. Active transport hydrolyzes one ATP per three Na ions translocated for two K ions Heat increases kinetic energy and ion diffusion stimulating Na permeability Heat increases intracellular acidity and a Na-H exchange Heat storage results in hypohydration and increased extracellular Na Increased extracellular Na increases Na permeability Hypohydration increases basal metabolism Heat increases the neural stimulation frequency required to maintain force Each molecule of acetylcholine stimulates a 50,000 cation flux at the receptor Increased neural stimulation increases Na flux in nerves and muscles Heat and exercise produce regional ischemia Regional ischemia induces regional acidosis and increased Na flux A doubling of cellular Na results in an eight fold increase in ATP hydrolysis Thus, all these factors that stimulate the influx of sodium into the cell increase ATP utilization, heat production, and lactate formation and produce an energy drain on the cell. We refer to this concept as the energy depletion model of heat stroke pathophysiology (Hubbard et al., 1987). Therefore, if these mechanisms produce an intracellular glucopenia, this could account for part of the increased ADH release and thirst associated with hyperthermia and could account for the generalized increase in

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FLUID REPLACEMENT AND HEAT STRESS hormone release. In this regard, it is also interesting to note that Andersson (1978) suggested that the thirst receptors are also sensitive to temperature and that local warming of the preoptic region elicits drinking in water-fed goats, whereas preoptic cooling inhibits it. This is exactly the behavior we would expect from a sodium pump-mediated process. For example, membrane leakage of sodium and potassium ions and the resultant active transport may account for nearly half of the basal metabolism of the brain (Astrup, 1982; Whittam, 1962). Hypothermia provides clinical protection from circulatory arrest by thermally restricting Na channels, delaying energy depletion, delaying potassium efflux, and stabilizing the cell membrane (Astrup et al., 1981). If extracellular fluid osmolality decreases, water must enter cells and the cellular volume increases; conversely, if extracellular fluid osmolality increases, because of the addition of solutes that penetrate cell membranes poorly, water must leave the cells and the cellular volume decreases. Thus, the basic physiological mechanisms that control the osmolality of the extracellular fluid affect cell volume. The maintenance of cellular volume also depends on the energy metabolism of the cell (Robertson, 1953). Tissues incubated in a medium similar to extracellular fluid maintained a normal volume while respiring but swelled when metabolism was inhibited (MacKnight and Leaf, 1977). Swelling was associated not only with the uptake of water but with extracellular solutes as well (Mudge, 1951). Thus, two factors can cause or contribute to an increase in cellular volume: a decrease in extracellular osmolality or a decrease in the energy metabolism of the cell. These two factors must be borne in mind when interpreting factors that elicit thirst or appear to inhibit it. Water itself appears to cross cell membranes very rapidly. This process could be considerably slower in vivo than in vitro experiments would suggest. The gain in water and solute when metabolism is depressed is expected from a Gibbs-Donnan system with the presence of nonpermanent polyvalent macromolecules restricted to one side of the membrane (MacKnight and Leaf, 1977). Calculations show that there is an excess of osmotic pressure in that compartment contributed by the polyvalent macromolecule itself and its associated counterions. Only if the excess osmotic pressure is counterbalanced by some additional solute restricted to the opposite compartment will a steady state be achieved. It is the active extrusion of sodium in metabolizing tissues that allows stabilization of cellular volume. Since this transport of sodium out of the cell takes place against an electrochemical gradient, work or active transport is required. The energy comes from the metabolism of the cell, and any inhibition of metabolism will result in the accumulation of sodium in cells like those in the kidney (Leaf, 1956; MacKnight and Leaf, 1977; Mudge, 1951), the liver (Elshove and Van Rossum, 1963; Heckmann

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FLUID REPLACEMENT AND HEAT STRESS and Parsons, 1959), skeletal muscle (Kleinzeller and Knotkova, 1964; Rixon and Stevenson, 1956), cardiac muscle (Page et al., 1964), and brain (Bourke and Tower, 1966; Franck et al., 1968). As discussed by MacKnight and Leaf (1977), a central question confronting physiologists in the mid-1950s was not why did cells swell when their metabolism was inhibited, but was restated (Manery, 1954) as why cells did not swell given their high content of intracellular proteins and other macromolecules that exert an osmotic pressure? As recognized by Leaf (1956) and as explained by MacKnight and Leaf (1977, p. 520) “. so long as the rate at which a substance crossed the membrane from the extracellular fluid into the cell was equaled by the rate at which it was passed from cell to the extracellular fluid, that substance in effect would be held in the extracellular compartment and could offset the intracellular swelling force.” These authors postulated that the active extrusion of sodium from the cells allowed stabilization of cellular volume in metabolizing tissues. It follows from this that sodium is leaking into cells at all times and therefore accounts for a substantial amount of the cells' basal metabolic rate (Astrup, 1982; Siesjo and Wieloch, 1985; Whittam, 1962; Whittam and Willis, 1963). It also follows that if the thirst receptor were a sodium receptor, then it could interpret an increase in the sodium concentration and leak rate as an increase in energy demand. This would add significance to the observation that thirst can be induced by brain heating and can be inhibited by brain cooling. If this were true, it would lead to further insight; that is, thirst could be sensing energy demand and, therefore, could be intimately related to metabolism and hunger! For example, Gutman (1963) injected hydrochlorothiazide (an inhibitor of active Na+ transport) in nephrectomized rats and observed reduced drinking in response to a load of hypertonic saline. Injections of ouabain had a similar effect (Bergman et al., 1967; Gutman et al., 1971). Ouabain apparently inhibits ADH release (Gutman et al., 1971). It was also very interesting to note that glycerol (Albers and Koval, 1972) and deuterium oxide (D2O) (Ahmed and Foster, 1974) are two weaker inhibitors of Na-K-ATPase. D2O had the same inhibitory effects when it was used as the solvent for hypertonic saline in goats (Leksell et al., 1976; Rundgren et al., 1977). Infusions of glycerol (Olsson et al., 1976, 1978) were found to suppress dehydrative thirst and ADH secretion much more effectively than corresponding glucose infusions. This could suggest that thirst is more easily attenuated by inhibiting the activity of the Na-K-ATPase than by raising the glucose levels within the cell. For example, if sodium were leaking into the cell at a higher rate, there would be a greater turnover of availabel ATP producing more ADP and Pi to stimulate metabolism, possibly glycolysis in the vicinity of the cell

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FLUID REPLACEMENT AND HEAT STRESS membrane. Inhibiting the Na-K-ATPase would likely reduce this source of metabolic stimulation, and ATP demand would fall and concentrations would increase. Thus, low thirst would correlate with low pump activity and higher energy (ATP) levels within the cell (high thirst would correlate with high rates of sodium entrance, high rates of ATP hydrolysis, lower ATP levels, higher ADP and Pi levels, and stimulated glycolysis). In this model, high thirst correlates with high pump activity and lower steady-state ATP levels. If the cellular trigger for thirst were related to lower ATP levels (energy depletion), then this might explain the analogous condition of high ADH release (Baylis and Robertson, 1980; Baylis et al., 1981) with either intracellular glucopenia or 2-deoxyglucose (2dG). If glucose were either unavailabel (glucopenia) or unable (2-DG) to fuel glycolysis, then steady-state ATP levels would fall (energy depletion), thereby stimulating ADH release and thirst. Depending upon the situation (glucose concentration, insulin, etc.), elevated glucose levels might elevate the ATP levels and inhibit thirst, but even higher levels might deplete ATP levels by producing excess hexose phosphates. This difficult concept is summarized in Table 14-2. Table 14-2 Effect of Cellular Energy Levels on Thirst and ADH Release High Thirst; High ADH Release Low Thirst; Low ADH Release Increased metabolic demand Elevated plasma Na, increased Na leaks, hyperthermia Increased pumping Lower ATP levels Increased glycolysis/lactate Low or normal metabolic demand Low plasma Na, low leaks, cold Decreased pumping Elevated ATP levels Elevated glucose Inhibited metabolism Intracellular glucopenia, 2dG Lower ATP levels Reduced blood volume/flow Reduced substrate/oxygen availability Inhibited Na-K-ATPase Ouabain, hydrochlorothiazide Glycerol, deuterium elevated ATP level Table 14-2 provides logic that thirst and ADH release can both be defined or regulated in terms of energy balance rather than the more common approach using water deficits and elevated osmolalities. This concept is relatively sophisticated and useful because it unifies a number of observations that on the surface are either unrelated or difficult to interpret

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FLUID REPLACEMENT AND HEAT STRESS with the existing model (hyperosmolality). Table 14-2 also provides an interesting perspective on the potential for unravelling physiological regulation by stimulating metabolic demand or by reducing the substrate availability fueling it. Selective inhibition studies then tend to identify key enzymes or regulators in the system, or at switching points. For example, reducing the activity of the pump enzymes with ouabain might make more ATP availabel for other uses such as muscular contractility. Therefore, this model would predict that a reduction of blood volume and flow and attendant reductions in substrate availability and use would stimulate thirst. This explains the apparently inappropriate thirst found in those with salt depletion that tends to confound the hyperosmolality model. Other recent experiments (Thrasher et al., 1980) infused equally hyperosmotic solutions of sodium, sucrose, urea, and glucose intravenously. All solutions appeared to raise CSF osmolality and sodium concentrations, but only saline and sucrose stimulated thirst. These results appear to question the specificity of the receptor for sodium but are compatible with centrally located osmoreceptors, since urea and glucose do not cause cellular dehydration. These results, however, do not rule out the possibility that either glucose or urea are interfering with some biochemical event in the receptor-response pathway, nor is it clear, if a proper equilibrium had been established, why they should raise CSF sodium in the first place. It is likely that this debate will continue. ACKNOWLEDGEMENTS The authors gratefully acknowledge the skilled technical assistance of Jo-Ann DeLuca, Ingrid Sils, and Diane Danielski in the preparation and typing of this manuscript. The views, opinions, and findings contained in this report are those of the authors and should not be construed as an official Department of the Army position. REFERENCES Adolph, E.F., J.P. Barker, and P.A. Hoy. 1954 Multiple factors in thirst. Am. J. Physiol. 178:538-562. Ahmed, K., and D. Foster. 1974 Studies on effects of 2H2O on Na-K-ATPase. Ann. N.Y. Acad. Sci. 242-280-292. Albers, R.W. and G.J. Koval. 1972 Sodium-potassium-activated adenosine triphosphate. J. Biol. Chem. 247:3088-3902.

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FLUID REPLACEMENT AND HEAT STRESS Andersson, B. 1978 Regulation of water intake. Physiol. Rev. 58:582-603. Astrup, J. 1982Energy-requiring cell functions in the ischemic brain: their critical supply and possible inhibition in protective therapy. J. Neurosurg. 56:482-487. Astrup, J., P. M. Sorensen, and H. R. Sorensen. 1981 Oxygen and glucose consumption related to Na-K transport in the canine brain. Stroke 12:726-730. Baylis, P.H., and G.L. Robertson. 1980 Rat vasopressin response to insulin-induced hypoglycemia. Endocrinology 107:1975-1979. Baylis, P.H., R.L. Zerbe, and G.L. Robertson. 1981 Arginine vasopressin response to insulin-induced hypoglycemia in man. J. Clin. Endocrinol. Metab. 53:935-940. Bergman, F., M. Chaimovitz, A. Costin, Y. Gutman, and Y. Ginath. 1967 Water intake of rats after implantation of ouabain into the hypothalamus Am. J. Physiol. 213:328-332. Bourke, R.S., and D.B. Tower. 1966 Fluid compartmentation and electrolytes of cat cerebral cortex in vitro. I. Swelling and solute distribution in mature cerebral cortex J. Neurochem. 13:1071-1097. Burch, G.E. 1945 Rate of water and heat loss from respiratory tract of normal subjects in subtropical climate. Arch. Intern. Med. 76:315-327. Conway, E.J., and J.I. McCormack. 1953 The total intracellular concentration of mammalian tissues compared with that of the extracellular fluid. J. Physiol. 120:1-14. Davenport, H.W. 1982 Physiology of the Digestive Tract, 5th ed. Yearbook Medical Publishers, Chicago. Desaiah, D., and I.K. Ho. 1977 Kinetics of catecholamine sensitive Na-K-ATPase activity in mouse brain synaptosomes. Biochem. Pharmacol. 26:2029-2035. Elshove, A., and G.D.V. Van Rossum. 1963 Net movements of sodium and potassium, and their relation to respiration, in slices of rat liver incubated in vitro. J. Physiol. London 168:531-553. Feig, P.U., and D.K. McCurdy. 1977 The hypertonic state. N. Engl. J. Med. 297:1444-1454. Franck, G., M. Cornette, and E. Schoffeniels 1968 cationic composition of incubated cerebral cortex slices J.Neurochem. 15:843-857. Gilman, A. 1937 The relation between blood osmotic pressure, fluid distribution and voluntary water intake. Am. J. Physiol. 120:323-328. Gutman, J. 1963 An extrarenal effect of hydrochlorothiazide. Experientia 19:544-545.

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FLUID REPLACEMENT AND HEAT STRESS Gutman, Y., F. Bergmann, and A. Zerachia. 1971 Influence of hypothalamic deposits of antidipsic drugs on renal excretion Eur. J. Pharmacol. 13:326-329. Gutman, Y., D. Shamir, D. Glushevitzky, and S. Hochman. 1972 Angiotensin increases microsomal (Na-K)-ATPase activity in several tissues. Biochim. Biophys. Acta 273:401-405. Guyton, A.C. 1986 Pp. 382-392 in Textbook of Medical Physiology, 7th ed. A.C. Guyton, ed. The W.B. Saunders Co., Philadelphia. Heckmann, K.D., and D.S. Parsons. 1959 Changes in the water and electrolyte content of rat-liver slices in vitro. Biochim. Biophys. Acta 36:203-213. Holmes, J.H., and M.I. Gregersen. 1950a Role of sodium and chloride in thirst. Am. J. Physiol. 162:338-347. Holmes, J.H. and M.I. Gregersen. 1950b Observations on drinking induced by hypertonic solutions. Hubbard, R.W., C.B. Matthew, M.J. Durkot, and R.P. Francesconi. 1987 Novel approaches to the pathophysiology of heatstroke: the energy depletion model. Ann. Emerg. Med. 16:1066-1075. Kleinzeller, A., and A. Knotkova. 1964 Electrolyte transport in rat diaphragm. Physiol. Bohemoslov. 13>:31-326. Ladell, W.S.S. 1965 Water and salt (sodium chloride) intakes. Pp. 235-299 in The Physiology of Human Survival, O. Edholm and A. Bacharach, eds. Academic Press, New York. Leaf, A. 1956 On the mechanism of fluid exchange of tissues in vitro. Biochem. J. 62:241-248. Leksell, L.G., F. Lishajko, and M. Rundgren. 1976 Negative water balance induced by intracerebroventricular infusion of deuterium. Acta Physiol. Scand. 97:142-144. Limas, C.J., and J.N. Cohn. 1974 Stimulation of vascular smooth muscle Na-K-ATPase by vasodilators Circ. Res. 35:601-607. MacKnight, A.D.C. and A. Leaf. 1977 Regulation of cellular volume. Physiolo. Rev. 57:510-573, 1977. Manery, J.F. 1954 Water and electrolyte metabolism. Physiol. Rev. 34:334-417. McCutchan, J.W., and G.L. Taylor. 1951 Respiratory heat exchange with varying temperature and humidity of inspired air. J. Appl. Physiol. 4:121-135. Mudge, G.H. 1951 Studies on potassium accumulation by rabbit kidney slices: effect on metabolic activity. Am. J. Physiol. 164:113-127. Olsson, K. 1969 Studies on central regulation of secretion of antidiuretic hormone (ADH) in the goat. Acta Physiol. Scand. 77:465-474. Olsson, K., B. Larsson, and E. Liljekvist. 1976 Intracerebroventricular glycerol: a potent inhibitor of ADH-release and thirst. Acta Physiol. Scand. 98:470-477.

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FLUID REPLACEMENT AND HEAT STRESS Olsson, K., F. Fyhrquist, B. Larsson, and L. Eriksson. 1978 Inhibition of vasopressin-release during developing hypernatremia and plasma hyperosmolality: an effect of intracerebroventricular glycerol. Acta Physiol.Scand. 102:399-409. Osborne, W.A. 1913 Water in expired air. J. Physiol. 47:12. Page, E.R., J. Goerke, and S.R. Storm. 1964 Cat heart muscle in vitro. IV. Inhibition of transport in quiescent muscles. J. Gen. Physiol. 47:531-543. Peters, J.P. 1944 Water exchange. Physiol. Rev. 24:491-531. Pitts, G.C., R.E. Johnson, and F.C. Consolazio. 1944 Work in the heat as affected by intake of water, salt and glucose Am. J. Physiol. 142:253-259. Rixon, R.H., and J.A.F. Stevenson. 1956 The water and electrolyte metabolism of rat diaphragm in vitro. Can. J. Biochem. Physiol. 34:1069-1083. Robertson, G.L. 1977 The regulation of vasopressin function in health and disease. Rec. Prog. Horm. Res. 33:333-385. Robertson, G.L., and S. Athar. 1976 The interaction of blood osmolality and blood volume in regulating plasma vasopressin in man. J. Clin. Endocrinol. Metab. 42:613-620. Robertson, G.L., and T. Berl. 1985 Water metabolism. Pp. 385-432 in The Kidney, 3rd ed., B.M. Brenner and F.C. Rector, eds. The W.B. Saunders Co., Philadelphia. Robertson, G.L., and E.A. Mahr. 1972 The importance of plasma osmolality in regulating antidiuretic hormone in man. J. Clin. Invest. 51:79 (abstract). Robertson, G.L., R.L. Shelton, and S. Athar. 1976 The osmoregulation of vasopressin. Kidney Int. 10:25-37. Robertson, J.R. 1953 The active transport of water in living systems. Biol. Rev. 28:158:194 Rothstein, A., E.F. Adolph, and J.H. Wills. 1947 Voluntary dehydration. Pp. 254-270 in Physiology of Man in the Desert, E.F. Adolph and Associates, eds. Interscience Publishers, New York. Rundgren, M., L.G. Leksell, F. Lishajko, and B. Anderson. 1977 Deuterium-induced extinction of ADH release in response to intracerebroventricular infusions of hypertonic NaCl and angiotensin. Acta Physiol. Scand. 100:45-50. Siesjo, B.K., and T. Wieloch. 1985 Cerebral metabolism in ischemia: Neurochemical basis for therapy. Br. J. Anesthesiol. 57:47-62. Stricker, E.M., and J.G. Verbalis. 1980 Hormones and behavior: The biology of thirst and sodium appetite. Am. Sci. 75:261-267. Thrasher, T.N., C.J. Brown, L.C. Keil, and D.J. Ramsay. 1980 Thirst and vasopressin release in the dog: an osmoreceptor or sodium receptor mechanism? Am. J. Physiol. 238:R333-R339.

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FLUID REPLACEMENT AND HEAT STRESS Verney, E.B. 1947 The antidiuretic hormone and factors which determine its release. Proc. R. Soc. London Ser. B. 135:25-106. Vokes, T. 1987 Water homeostasis. Annu. Rev. Nutr. 7:383-406. Vokes, T., and G.L. Robertson. 1985 Clinical effects of altered vasopressin secretion. Pp. 1-41 in Neuroendocrine Perspectives, E.E. Muller, R.M. MacLeod, and A. Frohmann, eds. Vol. 4. Elsevier Science, Amsterdam. Vokes, T., and G.L. Robertson. 1986 Physiology and secretion of vasopressin. Front. Horm. Res. 13:127-155. Wade, C.E., P. Bie, L.C. Keil, and D.J. Ramsay. 1982 Effect of hypertonic intracarotid infusions on plasma vasopressin concentration. Am. J. Physiol. 243(Endocrinol. Metab. 6):E522-E526. Whittam, R. 1962 The dependence of the respiration of brain cortex on active cation transport. Biochem. J. 82:205-212. Whittam, R., and J.S. Willis. 1963 Ion movements and oxygen consumption in kidney cortex slices. J. Physiol. London 168:158-177. Yarbrough, B.E., and R.W. Hubbard. 1989 Heat-related illness. Pp. 119-143 in Management of Wilderness and Environmental Emergencies. C.V. Mosby, St. Louis.

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