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FLUID REPLACEMENT AND HEAT STRESS Fluid Replacement and Heat Stress, 1993 Pp. 117-126. Washington, D.C. National Academy Press 10 Potassium Deficiency as the Result of Training in Hot Weather James P. Knochel1 INTRODUCTION It has been established by a number of investigators that potentially serious potassium deficiencies can occur in soldiers under conditions of intense, prolonged training in hot weather. Studies conducted during or after World War II (Conn, 1949; Streeten et al., 1960), and confirmed by others since that time (Gordon and Andrews, 1966; Knochel, 1977a; Knochel et al., 1972; Malhotra et al., 1976; Toor et al., 1967), have shown that men working in the heat for 8 to 12 hours on successive days can secrete up to 12 liters of sweat per day. Although measurements of the potassium concentration in sweat have shown values ranging between 2.5 and 21 mEq/liter (Robinson and Robinson, 1954), the majority of investigators have found that sweat produced under conditions of hard work generally ranges between 8 to 10 mEq/liter (Beller et al., 1975; Cage et al., 1970; Dobson and Abele, 1962; Drinkwater et al., 1982; Emrich et al., 1970; Furman and Beer, 1963; Grand et al., 1967; McConahay et al., 1964; Mor et al., 1985; Nose et al., 1988; Verde et al., 1982). This implies that sweat losses alone could explain the development of potassium deficiency during training in the heat. 1 James P. Knochel, Presbyterian Hospital, Walnut Hill Lane, Dallas, TX 75231
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FLUID REPLACEMENT AND HEAT STRESS Potassium deficiency under the conditions described above could also occur as a result of diffuse skeletal muscle injury secondary to intense exertion, especially when conducted during hot weather. Thus, realizing that muscle cell injury or rhabdomyolysis, as reflected by elevated muscle enzyme activity in the blood, invariably occurs when an untrained individual is subjected to severe muscular exercise in the heat (Demos et al., 1974), it would seem logical to assume that injured muscle cells could not retain sufficient ion transport activity or membrane integrity to maintain the normal distribution of sodium and potassium ions between the muscle cell and the plasma (Bilbrey et al., 1973). If this were so, potassium would leak from muscle cells and be excreted into the urine. A study was designed to examine these possibilities (Knochel et al., 1972). Healthy young Army recruits who were in good physical condition but untrained and poorly acclimatized to heat were studied during the summer and another group was studied during the winter. The two groups were studied while they were undergoing basic training conducted at Fort Sam Houston, Texas. Training activities were identical to those performed by recruits in basic training at other basic training facilities, with the exception that weapons training was replaced by field training for medical corpsmen activities. Training activities on many of these days were of 12 to 14 hours in duration. The caloric expenditure under such conditions probably exceeds that associated with weapons training. Each day the men consumed a constant diet containing 4,135 kcal that included 100 mEq of potassium, 149 g of protein, 158 g of fat, and 556 g of carbohydrate. Sodium chloride intake was 150 mEq/day in one group and 350 mEq/day in another. The men consumed their diets under the direct observation of a trained dietitian each day throughout the study. Total body potassium content was estimated by weekly determination of exchangeable 42K, which was then indexed as a function of lean body mass. Lean body mass was estimated from body density and from total body water. Each Thursday morning of the study body density was estimated by weighing the men underwater and measuring the total body volume after subtracting measured lung capacity. On the same morning, total body water was estimated by tritium dilution. Tritiated water was given by mouth. Tritiated aldosterone and NaS35O4, which were used to measure aldosterone secretory and excretory rates and extracellular fluid volume, were administered intravenously. Sampling for these determinations was conducted at appropriate intervals after measurement of total body volume. On the same day, a 24-h urine collection was obtained for measurements of creatine, creatinine, urea, calcium, phosphorus, electrolytes, and osmolality. Blood was obtained for measurements of the same biochemical parameters, and in addition, creatine kinase activity was measured as an index of muscle
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FLUID REPLACEMENT AND HEAT STRESS damage. Plasma renin activity was measured in the men before they arose in the morning and again before the noon meal. Table 10-1 shows average values for total body K+, urine K+, and K+ from clothing eluates for the subjects studied in both hot and cool weather. In the six subjects studied during training in hot weather, the potassium deficit measured on day 4 averaged 348 mEq, and on day 11 it averaged 463 mEq (Knochel, 1977a; Knochel et al., 1972). The maximum deficits ranged between 370 and 572 mEq. In two men, the maximum deficit appeared on day 4, and in one man it appeared on day 18; in the remainder of the men it occurred on day 11. The average maximum deficit was 510 mEq. Total body potassium as a function of lean body mass fell from 52.2 to 42.5 mEq/kg, thus suggesting a reduction of intracellular muscle potassium content. Thereafter, total body potassium rose during successive weeks, so Table 10-1 Potassium as Measured in Hot and Cool Weather Hot Weather Cool Weathera Total Body (mEq/d) Urine K (mEq) Clothing K Eluate (mEq) Total Body K (mEq) Urine K (mEq/d) Control 3252 66 29 3330 77 4 2904 57 38 3395 58 11 2789 61 19 3383 82 18 2995 77 24 - 68 25 3235 79 25 3586 62 32 3495b 49 14 3716 64 a In cool weather, 42K was not availabel for the 18 day study. b Average of 5 subjects only. that by week 5 the amount of potassium restored was about 200 mEq. The value of 42K per lean body mass was the same upon completion of training as it was during the first measurement. Potassium deficiency, defined as a reduction of 42Ke, did not occur during training in the winter. In the men who trained in the winter, total body potassium steadily increased from an initial value of 3,330 mEq to a final value of 3,716 mEq. When values for total body potassium over lean body mass were matched, there was a rise
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FLUID REPLACEMENT AND HEAT STRESS from 53.3 to 56.4 mEq/kg. This represented a significant change and suggested that there was an increase in the potassium concentration in skeletal muscle as a result of training. As is pointed out below, subsequent studies in dogs confirmed this notion. The fact that the men who trained in hot weather did not show an increase in potassium per kilogram of lean body mass indeed suggested that muscle injury might have prevented such a change. Although none of the subjects became frankly hypokalemic, most values were in the low normal range, that is, between 3.4 and 3.7 mEq/liter at the time of peak potassium deficiency. The absence of frank hypokalemia possibly indicates coincident muscle injury. Other studies showed that aldosterone was produced excessively in terms of sodium intake. However, when expressed as a function of sodium excretion, both secretory rates and excretory rates of aldosterone were perfectly appropriate. Renin activity measured before the men arose each day was often markedly elevated and became more elevated following maintenance of an upright posture during the morning hours, as would be expected. There also occurred a substantial rise in total body water, an expansion of extracellular fluid volume, and an increase of inulin clearance from an average value of 101 ml/min per 1.72 m2 of body surface area to a value of 123 ml/min (Knochel et al., 1974). Serum creatine kinase activity was within normal limits at the time of initial measurement. However, this value and the value for creatine excretion rose markedly by week 2 of training (Knochel et al., 1974), suggestive of muscle injury. Subsequently, both values fell to the normal range. Other indices suggestive of skeletal muscle injury that peaked on week 2 of training included a drop in the total serum calcium concentration that was not associated with changes in the serum protein concentration and an elevation of serum phosphorus. Frank hyperuricemia occurred in all of these individuals. In addition, uric acid excretion into the urine became abnormally high and was compatible with major muscle injury or rhabdomyolysis (Knochel and Carter; 1976; Knochel et al., 1974). These values also peaked during week 2 of training. At the time of peak potassium deficiency, average values for potassium excretion into the urine were 72 mEq/day. This is considered to be greatly in excess of that anticipated in potassium depletion and suggests either an obligatory loss as a result of muscle injury or that losses were the result of renal tubular sodium-potassium exchange mediated by aldosterone. The foregoing studies were interpreted to indicate that modestly severe potassium deficiency occurs as a result of intense training in hot weather. This did not occur under identical training conditions during cool weather. Although sweat cannot be collected accurately under such conditions, canteen counts confirmed water intakes of between 10 and 15 liters/day during hot weather. Since body weight did not change appreciably or fell,
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FLUID REPLACEMENT AND HEAT STRESS and since urine volumes were seldom over 1.5 liters/day, the assumption was made that the subjects produced huge quantities of sweat. Because of data suggesting that the sweat potassium concentration under such conditions averages 9 or 10 mEq/liter, it was assumed that the major factor responsible for potassium deficiency in these subjects was sweating. A net loss of only 42 mEq/day average total loss of 463 mEq divided by 11 days would have been necessary to result in the potassium deficiency observed at the end of the third measurement of 42K on day 11. The estimated loss in sweat was based upon a total intake of 100 mEq/day of potassium. On day 11, the average urinary excretion was 61 mEq. Allowing for an average unmeasured stool loss of 5 mEq/day, the unaccounted K loss was 100 − (61 + 5) + 42 or 76 mEq/day. This quantity of K+ could be lost by secreting an average of 8 or 9 liters of sweat volume per day. The brisk excretion of potassium into the urine, despite potassium deficiency, was compatible with an obligatory loss resulting from muscle cell injury or could have been mediated by renal tubular sodium-potassium exchange induced by aldosterone. The fact that potassium deficiency did not occur in men who trained in cool weather suggests that sweating was responsible for the bulk of potassium loss. Nevertheless, this does not completely exclude the possibility that skeletal muscle injury caused potassium loss, because it is known that training at such intensities results in much more severe skeletal muscle injury when conducted under hot rather than cool conditions. Costill has performed several studies in which he examined muscle potassium content (samples obtained by needle biopsy) or by measuring losses in sweat and urine. He reported that he was not able to demonstrate a significant potassium deficit occurring in healthy young men who cycled or walked on a treadmill for 1 1/2 to 2 hours per day. These studies were conducted in environmental chambers maintained at 40 ° or 30°C dry bulb temperature and 23.5% or 46% relative humidity respectively (Costill, 1975; 1986). However, in his subjects, the total sweat production per day amounted to about three liters and the amount of work performed by these individuals is by no means comparable to that encountered by a military recruit in basic training who works day after day in hot weather. Training exercises under such conditions are exhausting and commonly exceed twelve hours per day. The temperatures in our studies (Knochel et al., 1972) were also very high with a daytime outdoor maximum varying between 100 and 108°F on days 1 -5, and 96 to 100° between days 5 and 11. Thus, although the environmental temperatures were within the same range, on the basis of level of exercise performed I do not believe the studies are comparable. Additional studies were conducted in our laboratory using experimental animals to examine the possible effects of potassium deficiency on several important modalities including muscle glycogen metabolism, carbohydrate
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FLUID REPLACEMENT AND HEAT STRESS metabolism, glucose utilization, and muscle blood flow. A large body of evidence indicates that a normal concentration of potassium ions in skeletal muscle is a prerequisite for glycogen synthesis (Bergstrom and Hultman, 1966b; Gardner et al., 1950; Hastings, 1941; Knochel, 1977b; Losert, 1968; Torres et al., 1966). Our studies in dogs made potassium deficient by dietary deprivation in conjunction with administration of desoxycorticosterone, confirmed that muscle glycogen content falls to almost immeasurable values as a result of potassium deficiency (Knochel, 1987). Normal dogs also show the “supercompensation” phenomenon that was described by Bergstrom and Hultman in humans (Bergstrom and Hultman, 1966a). Thus, if a muscle is exercised to the point of exhaustion, glycogen stores become virtually zero. If glycogen content is then measured in that muscle daily for four or five days, the quantity increases to four or five times the original resting value. This is defined as glycogen supercompensation. The phenomenon is reproducible in the normal dog (Knochel, 1987). In contrast, stimulation of muscle contractions to the point of exhaustion by external electrodes followed by daily biopsy of the exercised muscle shows that the supercompensation phenomenon is eliminated by potassium deficiency (Knochel, 1987). Utilizing the isolated gracilis muscle preparation, we also showed that glucose utilization in potassium deficient muscle is perfectly normal (Knochel, 1987). However, electrical stimulation of the muscle shows reduced endurance that can be correlated exactly with reduction in muscle glycogen content. Finally, studies were conducted to measure the effect of potassium deficiency on skeletal muscle blood flow (Knochel, 1972). Stimulation of muscle cell contraction is associated with a release of potassium ions into the muscle interstitium at which site the local hyperkalemia acts as a vasodilator to trigger increased muscle blood flow with exercise. The hypothesis was made that in the presence of potassium deficiency, potassium would not be released adequately during contraction to increase muscle blood flow, and ischemic muscle damage would follow. Again, using the isolated gracilis muscle, we showed that electrically stimulated exercise of the normal muscle was associated with an increase of muscle K release from 0.4 to 32 µEq/100 g/min and, simultaneously, a rise of muscle blood flow from 6.2 ml/100 g/min to 24 ml/100 g/min. By contrast, K-deficient dogs showed a marked reduction in K release. During stimulated exercise, K-release rose from zero to only 2.1 µEq/100 g/min and blood flow from 6.0 to 7.8 ml/100 g/min (Knochel, 1972). If potassium were administered arterially to the contracting potassium deficient muscle, blood flow promptly increased. Finally, we showed that work conducted by potassium deficient muscle was initially equal to normal in terms of contractile strength but could not be sustained (Knochel, 1987). Following exercise to exhaustion, potassium deficient but not normal muscle becomes necrotic (Knochel,
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FLUID REPLACEMENT AND HEAT STRESS 1972). Observations in humans (Knochel, 1978; Knochel, 1982) have shown that potassium deficiency induced by a variety of mechanisms can be responsible for frank muscle necrosis. Thus, our finding that potentially serious potassium deficiency occurs during training in a hot climate infers that the associated muscle injury could be partially explained by potassium deficiency. Mention was made previously that men who trained in cool weather showed an increase of potassium per kilogram of lean body weight, suggesting an increase in the muscle potassium concentration. Since serum potassium values in highly trained endurance runners may be frankly hypokalemic in the absence of potassium deficiency, the possibility was suggested that muscle cells may become electrically hyperpolarized as a result of training. A biologic reason why this might happen would be to help forestall or dissipate exercise-induced hyperkalemia. This possibility was studied both in humans and animals. In dogs, endurance training on the treadmill caused a reduction of the serum potassium concentration, and with electrical hyperpolarization of muscle cells there was an increase of resting membrane potential measured by Ling electrodes from a control value of 92 ± 5 mV to a training value of 103 ± 5 mV. The muscle potassium concentration rose from 139 ± 7 to 148 ± 14 mEq/liter, and serum potassium fell from 4.2 ± 0.2 to 3.9 ± 0.3 mEq/liter. Measurements of magnesium-dependent Na, K ATPase activity in sarcoplasmic membranes from the trained dogs compared with that in normal dogs showed a marked increase in enzyme activity (Knochel et al., 1985). Direct measurements of resting membrane potential (anterior tibial muscle) on six highly trained long-distance competitive runners from Texas Christian University showed an average value of 98.8 mV compared with normal resting values of 91.5 mV in age-matched untrained men. While the actual implications of such studies are far from clear, at least preliminary studies in dogs indicated that the capacity to dissipate hyperkalemia and to withstand otherwise fatal infusions of potassium chloride were produced by exercise training. The foregoing data suggest that changes in potassium metabolism and balance play a critically important role in exercise and the ability to become trained. Potassium deficiency may occur as a result of intense training in hot weather. Comparable levels of potassium deficiency in experimental animals impair muscle blood flow during exercise and cause ischemic necrosis of skeletal muscle (rhabdomyolysis). Potassium deficiency also impairs energy storage by reducing glycogen synthesis in resting muscle or that which occurs in response to exercise. Finally, in proportion to reduced glycogen synthesis, exercise endurance is impaired. If physical training in the heat is of such intensity and duration to cause muscle injury, it would appear that potassium loss would be obligatory. At the present time, our understanding
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FLUID REPLACEMENT AND HEAT STRESS of exertional rhabdomyolysis is much more clear than it was prior to publication of our data in 1972 (Knochel et al., 1972). Clearly, the fact that the highest level of CK activity in serum, the highest levels of creatine excretion, the most pronounced hyperuricemia and uricosuria, the hyper-phosphatemia and hypocalcemia occurred simultaneously with peak potassium deficiency, strongly suggests that muscle cell injury was the primary factor responsible for a reduction of total body potassium (Knochel, 1982). It seems highly likely that if nitrogen balance and phosphorus balance would have been measured at the same time, these elements would have been similarly negative, confirming that a reduction of cellular mass had occurred as a result of injury. I suspect, but cannot prove from our data that potassium losses probably exceeded proportionate losses of phosphorus and nitrogen, primarily due to the fact that K losses in sweat were substantial and the possibility that brisk sodium excretion into the urine would favor disproportionate loss of potassium via the action of aldosterone. Whether potassium supplementation could overcome a deficit such as this is unlikely. Indeed, administration of a high potassium intake or potassium supplements to a person in whom skeletal muscle cells are temporarily injured and thus unable to take up potassium ions may be fraught with the hazard of hyperkalemia and potential cardiotoxicity. In this special case of training in hot weather, rather than toying with the idea of potassium supplementation, perhaps we should consider either reducing the intensity of training, or conducting such exercises in geographic areas that would not impose such levels of heat stress. REFERENCES Beller, G.A., J.T. Maher, L.H. Hartley, D.E. Bass, and W.E. Wacker. 1975 Changes in serum and sweat magnesium levels during work in the heat Aviat. Space Environ. Med. 46:709-712. Bergstrom, J., and E. Hultman. 1966a Muscle glycogen synthesis after exercise: an enhancing factor localized to the muscle cells in man. Nature 210:309-310. Bergstrom, J., and E. Hultman. 1966b The effect of thiazides, chlorthalidone and furosemide on muscle electrolytes and muscle glycogen in normal subjects. Acta Med. Scand. 180:363-376. Bilbrey, G.L., L. Herbin, N.W. Carter, and J.P. Knochel. 1973 Skeletal muscle resting membrane potential in potassium deficiency J. Clin. Invest. 52:3011-3018. Cage, G.W., S.M. Wolfe, R.H. Thompson, and R.S. Gordon, Jr. 1970 Effects of water intake on composition of thermal sweat in normal human volunteers. J. Appl. Physiol. 29:687-690. Conn, J.W. 1949 The mechanism of acclimatization to heat. Adv. Intern. Med. 3:373-393.
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FLUID REPLACEMENT AND HEAT STRESS Costill, D.L. 1975 Muscle water and electrolytes during acute and repeated bouts of dehydration. III International Symposium on Sportsmen Nutrition ( Warsaw, Poland) 123:143. Costill, D.L. 1986 Muscle metabolism and electrolyte balance during heart acclimatization Acta Physiologica Scand. 128 (Suppl. 556):111-118. Demos, M.A., E.L. Gitin, and L.J. Kagen. 1974 Exercise myoglobinemia and acute exertional rhabdomyolysis. Arch. Intern. Med. 134:669-673. Dobson, R.L., and D.C. Abele. 1962The correlation of structure and function in the human eccrine sweat gland. Pp. 54-75 in Advances in Biology of Skin, W. Montagna, ed. Pergamon, New York. Drinkwater, B.L., J.F. Bedi, A.B. Loucks, S. Roche, and S.M. Horvath. 1982 Sweating sensitivity and capacity of women in relation to age. J. Appl. Physiol. 53:671-676. Emrich, H.M., E. Stoll, and E. Rossi. 1970 Aldosteronwirkung auf die Natriumchlorid- und Kaliumausscheidung im Schweiss von Pandreasfibrose Patienten und Gesunden. Klin. Wochenschr. 48:966-972. Furman, K.I., and G. Beer. 1963 Dynamic changes in sweat electrolyte composition induced by heat stress as an indication of acclimatization and aldosterone activity Clin. Sci. 24:7-12. Gardner, L.I., N.B. Talbot, C.D. Cook, H. Berman, and C. Uribe. 1950 The effect of potassium deficiency on carbohydrate metabolism. J. Lab. Clin. Med. 35:592-602. Gordon, R.S., Jr., and H.L. Andrews. 1966 Potassium depletion under heat stress. Fed. Proc. 25:1372-01374. Grand, R.J., P.A. di Sant'Agnese, R.C. Talamo, and J.C. Pallavicini. 1967 The effects of exogenous aldosterone on sweat electrolytes. I. Normal subjects. J. Pediatr. 70:346-356. Hastings, A.B. 1941 Electrolytes of tissues and body fluids. Harvey Lectures 36:91-125. Knochel, J.P. 1977a Potassium deficiency during training in the heat. Ann. N.Y. Acad. Sci. 301:175-182. Knochel, J.P. 1977b Role of glucoregulatory hormones in potassium homeostasis. Kidney Intern. 11:443-452. Knochel, J.P. 1978 Rhabdomyolysis and effects of potassium deficiency on muscle structure and function. Cardiovasc. Med. 3:247-261. Knochel, J.P. 1982 Neuromuscular manifestations of electrolyte disorders. Am. J. Med. 72:521-535. Knochel, J.P. 1986 Clinical effects of potassium deficiency on skeletal muscle. Pp. 97-109 Potassium in Cardiovascular and Renal Medicine, P.K. Whelton, A. Whelton, and W.G. Walker, eds. Marcel Dekker, New York. Knochel, J.P. 1987 Metabolism and potassium. Pp. 383-400in Current Topics in Membranes and Transport. Potassium Transport: Physiology and Pathophysiology, G. Giebisch, ed. Academic Press, Orlando, Fla.
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FLUID REPLACEMENT AND HEAT STRESS Knochel, J.P., and N.W. Carter. 1976 The role of muscle cell injury in the pathogenesis of acute renal failure after exercise. Kidney Int. Suppl. 10:S58-S64. Knochel, J.P., L.N. Dotin, and R.J. Hamburger. 1972 Pathophysiology of intense physical conditioning in a hot climate J. Clin. Invest. 51:242-255. Knochel, J.P., L.N. Dotin, and R.J. Hamburger. 1974 Heat stress, exercise, and muscle injury: effects on urate metabolism and renal function. Ann. Intern. Med. 81:321-328. Knochel, J.P., J.D. Blachley, J.H. Johnson, and N.W. Carter. 1985 Muscle cell electrical hyperpolarization and reduced exercise hyperkalemia in physically conditioned dogs. J. Clin. Invest. 75:740-745. Losert, W. 1968 Relationships between electrolyte balance and carbohydrate metabolism Deutsch Sh. Med. Wschr. 93:1723-1731. Malhotra, M.S., K. Sridharan, and Y. Venkataswamy. 1976 Potassium losses in sweat under heat stress. Aviat. Space Environ. Med. 47:503-504. McConahay, T.P., S. Robinson, and J.L. Newton. 1964 D-Aldosterone and sweat electrolytes. J. Appl. Physiol. 19:575-579. Mor, A., L. Benzon, and M. Aladjem. 1985 Influence of digoxin and diuretic therapy on sweat fluid composition Miner. Electrolyte Metab. 11:155-157. Nose, H., G.W. Mack, X. Shi, and E.R. Nadel. 1988 Shift in body fluid compartments after dehydration on humans. J. Appl. Physiol. 65:318-324. Robinson, S., and A.H. Robinson. 1954 Chemical composition of sweat. Physiol. Rev. 34:202-220. Streeten, D.H., et al. 1960 Secondary aldosteronism: metabolic and adrenocortical responses of normal men to high environmental temperature. Metabolism 9:1071. Toor, M., J. Agmon, I. Zahavi, M. Wurzel, and J.B. Rosenfeld. 1967 Potassium depletion in permanent inhabitants of hot areas. Isr. J. Med. Sci. 3:149-150. Torres, H.N., L. Birnbaumer, M.D.C. Garcia-Fernandez, E. Bernard, and E. Belocopitow. 1966 Glycogen metabolism in muscle homogenates. I. The effect of potassium ions on glycogen synthesis. Arch. Biochem. Biophysics 116:59-68. Verde, T., R.J. Shephard, P. Corey, and R. Moore. 1982 Sweat composition in exercise and in heat. J. Appl. Physiol. 53:1540-1545.1
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