Physical activity has been recognized as beneficial to children and adolescents with cystic fibrosis (CF) (3,7,14,17,19,23,27). However, enhanced physical activity has two potentially detrimental effects on these patients: arterial oxygen desaturation, occurring mostly when a patient with advanced disease performs high-intensity exercise (18), and a low tolerance to climatic heat stress. The latter has been shown to increase morbidity and mortality among CF patients (4,8,25).
Our group (1) and others (18,20,23) could not identify a specific malfunction of thermoregulatory ability among children with CF who exercised 1.5 to 3 h in a hot climate. However, unlike healthy people who usually increase their extracellular osmolality as a result of sweating, CF patients had a decline in serum NaCl and osmolality during exposures to the heat (1,20). This resulted from the much higher loss of NaCl in the sweat of exercising CF patients compared with that in healthy controls.
One of the triggers for thirst is an increase in extracellular osmolality which, in turn, stimulates hypothalamic osmoreceptors in animals (6,16,21) and possibly in humans (12,15). It is thus possible that patients with CF, whose sweating does not induce a normal increase in extracellular osmolality, would be deprived of this trigger for thirst. Indeed, children with CF, when allowed to drink water ad libitum during exposure to hot climate, drank half as much and dehydrated almost three times as much as healthy controls (1).
Voluntary dehydration (i.e., the inability to fully replenish fluid losses when a beverage is offered ad libitum) has been found in adults (22) and children (1,2). The main difference between the responses of children and adults was that, for a given level of dehydration (expressed as percent of initial body weight), the core temperature of children increased twice as much as in adults (2). This puts children at a greater risk of heat-related illness and is a further justification for the prevention of voluntary dehydration in children. The rationale is even stronger in children with CF because of their deficient thirst drive.
In healthy children voluntary dehydration can be attenuated by adding flavor and totally prevented by adding 18 mmol·L−1 NaCl and carbohydrates (2% sucrose and 4% fructose) to the water (24). The objective of the present study was therefore to determine whether the addition of NaCl and carbohydrate to water would also be effective in children with CF by enhancing their drinking volume and preventing voluntary dehydration. Because of the greater salt loss in the sweat of such patients, we used a higher concentration of NaCl (30 mmol·L−1) than the 18 mmol·L−1 given to the healthy children in the above study (24). In an extra session, some of the subjects in the current study were also given 50 mmol·L−1 NaCl.
Eleven children and adolescents with cystic fibrosis (5 boys and 6 girls, age 10.9-19.5 yr) took part. By clinical criteria, all subjects had mild to moderate disease. Children with O2 desaturation induced by moderate exercise were excluded. The study was approved by the Ethics Research Board of the Faculty of Health Sciences at McMaster University. A written informed consent was obtained from a parent (or the subject if ≥ 14 yr old), following verbal assent by the subject. In a preliminary visit, the general purpose and procedures were explained to parents and children, but the specific goal of the study was not disclosed. Subjects and parents were told only that we wanted to test responses to exercise in the heat.
There were three sessions (visits 1, 2, and 3), conducted 1 to 2 wk apart at the same time of the day. Chamber conditions were held stable throughout at 35 ± 1°C and 48-50% relative humidity. Exercise protocol consisted of four bouts of 20-min cycling at moderate intensity (heart rate 140-160 beats·min−1), interspersed with 25-min rest periods. Intensity was kept constant for each subject in all visits. Total chamber time was 180 min. One of the following beverages, kept at 8°C, was assigned in each session: unflavored water (W), flavored water (FW), or flavored water with 30 mmol·L−1 NaCl and 6% carbohydrates (2% glucose, 4% sucrose) (Na30). The sequence of the sessions was counterbalanced, using a Latin square principle, to prevent any order effect. Both the subjects and the investigators were blinded to the content of the flavored drinks, which had been prepared in an independent laboratory. Six of the CF patients agreed to perform an additional session (visit 4), in which they were given a flavored drink with 50 mmol·L−1 NaCl and 6% carbohydrate (Na50). The inclusion of 6% carbohydrates in both NaCl drinks was intended to prevent exercise-induced hypoglycemia. This concentration is found in commercially available sports drinks often used by CF patients.
To ensure euhydration, the children were instructed to drink two large glasses of fluid during the last hour before each visit. Before the first chamber session the subjects performed a taste test of four different flavors (lemon, orange, fruit punch, grape). The taste preference was determined by a category scale which ranged from "don't like at all" to "extremely good," as described by Meyer et al. (11). Each child's preferred flavor was then used for all subsequent chamber sessions. Likewise, the three flavored drinks (flavored water, Na30, Na50) were tested for taste perception, including overall palatability, sweetness, sourness, and saltiness.
Before each subject entered the chamber, a flexible rectal thermistor (YSI 400 series, Yellow Springs, OH) was inserted 10 cm beyond the anal sphincter. After measurement of height (Harpenden stadiometer 2109), body weight (Mott electro-scale, Brantford, Ontario, Model UMC-600, 20 g accuracy) and adiposity (bioelectrical impedance, BIA-101A RJL Systems, Clinton Twp, MN) the subject sat down quietly for 20 min, during which time an intravenous line was fixed on the back of the hand and 15 mL of blood was drawn. A polyethylene pouch (10 × 10 cm) was affixed on the lower back to collect sweat (5). The skin site was cleansed with distilled water and dab-dried with a sterile gauze. The pouch was then affixed with transparent surgical tape to prevent any leakage. Finally a heart rate monitor (Sporttester PE4000, Polar Electro, Kempele, Finland) was positioned around the chest. The clothes, shoes, and the heart rate monitor were weighed before and after the chamber session to correct for net changes in body weight using an Accuba scale (Model 1200, accuracy 0.2 g). Just before entering the chamber, the subjects emptied their bladder.
Upon entering the chamber, the subject was shown an opaque bottle containing the beverage, and was told: "This is your drink, you can use it any time you want." After that introduction, the investigator did not remind the subject about the drink so that drinking was solely guided by the subject's thirst. The bottle was placed within easy reach. Unbeknownst to the subject, drink intake was monitored throughout the session by weighing the bottle periodically outside the chamber. Subjects were told that the bottle was taken out to cool the drink.
Body weight, heart rate, rectal temperature, and drink intake were monitored before and following each exercise bout. Blood samples were drawn after the second and fourth bout. Sweat samples were collected with a small pipette at the end of the fourth exercise bout. Immediately after leaving the chamber, the subjects emptied their bladder. The final body weight was corrected for urine volume. Urine was collected also for electrolyte concentration and osmolality. The patients then sat down quietly for another 20 min and the last blood sample was drawn. Thirst perception was monitored before and after each exercise bout, using an analog scale which ranged from "not thirsty at all" to "very thirsty" (11).
Hydration level and drink intake were calculated as a percentage of initial body weight, corrected for urine output and the increase in weight of the clothes. Total sweat volume was calculated as net body weight changes plus drink intake minus urine output. Respiratory water losses and the small loss of caloric energy were considered negligible. Electrolyte balance was calculated by subtracting losses from urine and sweat from NaCl intake. Sweat from the lower back had been used previously to give a reasonable estimate of total body losses (10). The "gold standard" method of periodic total body rinsing was impractical for this study.
Blood samples were used to measure serum osmolality (freezing point depression, micro-osmometer Model 3 MO), sodium, potassium and chloride (ion-selective electrodes). Sweat samples were stored in 1.5 mL vials. Sweat and urine were analyzed for osmolality, sodium, potassium, and chloride. A two-way (drink, time) ANOVA with repeated measures was used to compare measurements among the sessions. A probability of less than 0.05 was taken as significant. Where indicated, we performed a Tukey's HSD post hoc test. Values are expressed as means ± SEM unless otherwise stated.
Mean body height of the 11 subjects was 157.6 cm (range 134.9-177.4). Body weight was 44.4 kg (32.5-67.2) and percent body fat 17.4% (9-31). Forced vital capacity ranged from 45.1 to 118.1% (mean 71.5%) of that predicted for gender and body height. This suggests that the subjects represented a wide variety of severity of CF. All 11 subjects completed the water, flavored water, and Na30 session, but only six of them agreed to take part in the subsequent Na50 session. Because there was no difference between responses of boys and girls, data for all subjects were pooled. Figure 1 shows the cumulative drink intake (top graph) and the body hydration status (bottom graph) in all the 11 subjects who performed the W, WF, and Na30 sessions. Voluntary drink intake was not different among the three beverages nor was the rate of progressive dehydration. On average subjects reached a similar level of hypohydration (approximately 1%BW) by the end of each session.
Figure 2 summarizes the same relationships, but only for the six subjects who completed the extra session (Na50). A significant drink by time interaction was found on drink intake and %BW changes (P = 0.04 and P = 0.03, respectively). Mean drink intake by the end of Na50 session was 56% higher than in the W session, but the difference was not significant (P = 0.10). While, as expected, the W regimen was accompanied by dehydration (P < 0.01 in the last h), the hydration status throughout the Na50 session was not significantly different from euhydration.
Fluid balance is summarized in Table 1. The top portion is related to the 11 subjects who attended sessions W, FW, and Na30. The bottom portion reflects the balance in the six who also completed session Na50. Intake, urine, and sweat volumes were practically identical in the W, FW, and Na30 sessions. However, there was a three-fold decrease in the negative fluid balance in session Na50 compared with session W (P < 0.08).
Once the study started, several children objected to having their blood taken. For ethical reasons we decided not to insist. This, plus technical difficulties with the venous line, yielded small numbers of adequate blood samples that could be compared across sessions. Likewise, we could harvest successfully only 19 out of possible 39 sweat samples. As a result, the highest number of subjects for whom we could obtain electrolyte balance was 6. In some sessions it was as low as 3. Such small samples did not allow for statistical analysis of intra- or intersession differences in electrolytes or osmolality. Mean values for serum electrolytes and osmolality were similar across sessions, and there was a trend for sodium, chloride, and osmolality to decrease over time in sessions W, FW, and Na30. The pooled data from these sessions showed significant decreases: sodium dropped from 143.1 ± 0.5 to 141.1 ± 0.7 mmol·L−1 (P = 0.01), chloride from 109.1 ± 0.5 to 107.5 ± 0.5 mmol·L−1 (P < 0.001), and osmolality from 290.6 ± 1.1 to 281.3 ± 1.2 mmol/kg (P < 0.0005). Serum potassium was not different before (4.41 ± 0.1 mmol·L−1) and after (4.39 ± 0.1 mmol·L−1) these sessions. The Na50 session (values available for three children) was the only one in which serum sodium and chloride did not decrease (for sodium 140.9 mmol·L−1 at the start of the session and 141.0 mmol·L−1 at its end; for chloride 105.9 mmol·L−1 at the start and 106.2 mmol·L−1 at the end). The pooled sweat values (Na+ 135 mmol·L−1, Cl− 125 mmol·L−1, Osm: 293 mmol/kg) were similar to, or even higher than, the serum levels. Table 2 summarizes the electrolyte balance in the four sessions. As stated above, we did not perform ANOVA for these small samples. However, the average Na+ deficit was highest in the W session and lowest in the Na50 session. The table further shows that sweat accounted for some 90-98% of the Na+ losses, 83-90% of the Cl− losses, but only 31-49% of the K+ losses.
The physiological heat strain was mild to moderate in all sessions, with an average increase of rectal temperature from 37.4-37.6 to 38.1-38.2°C and an average heart rate of 106-108 beats·min−1 at rest and 148-153 beats·min−1 during exercise. Thirst perception was not different among the drinks, nor over time. Taste, including sweetness, sourness, saltiness, and overall palatability, was identical for flavored water and the Na30 drink. However, the Na50 drink was perceived as significantly less tasty (P = 0.02) than the other two flavored drinks even though sweetness, saltiness, and sourness were not rated as different.
The main finding of this study is that children and adolescents with CF greatly underestimated their fluid intake and became dehydrated when exercising in the heat, even when flavor, carbohydrates, and 30 mmol·L−1 NaCl were added (Fig. 1). Yet, when given a 50 mmol·L−1-carbohydrate flavored solution, their fluid intake increased sufficiently to prevent dehydration (Fig. 2, Table 1).
Among healthy children voluntary dehydration, which occurs when water is given ad libitum(1,2,24), was reduced by flavoring the water and was prevented totally by further addition of 18 mmol·L−1 of NaCl and carbohydrates (24). As discussed in that study, the addition of NaCl to the drinking solution probably increased the stimulus to hypothalamic osmoreceptors which, in turn, triggered thirst. Such a mechanism has been suggested in earlier studies with healthy adults (12,13,15) and with children (24). Our decision to use with the CF patients 30 instead of 18 mmol·L−1 NaCl emanated from the documented high losses of NaCl in the sweat of children with CF during exercise in the heat (1,20). Indeed, the concentrations of Na+ and of Cl− in the sweat of our subjects (mean values of 135 and 125 mmol·L−1, respectively) were three to four times as high as those of healthy children and adolescents (10). We hypothesized that the 30 mmol·L−1 NaCl concentration of ingested drink would help to enhance their thirst. This hypothesis turned out to be incorrect as neither flavor nor 30 mmol·L−1 NaCl caused an increase in voluntary drinking volume (Fig. 1). As an addendum to the main study, we then administered a fourth session with a 50 mmol·L−1 NaCl drink. Its intent was to further compensate for the marked electrolyte loss in the sweat. Indeed, in that session fluid intake increased and, as a consequence, euhydration was maintained throughout the session (Fig. 2). Furthermore, the overall fluid balance became less negative (Table 1).
The low yield of blood samples in the various sessions limits our ability to discuss mechanisms for the increase in voluntary fluid intake with Na50.
The 3-h chamber exposures induced a hypo-osmolar state in sessions W, FW, and Na30 alike. This reflects the very high electrolyte losses in the sweat, as summarized in Table 2 (2.5-3.6 mmol/kg body weight for Na+ and 1.63-3.37 mmol·L−1 for Cl−), in addition to urinary losses. This pattern further suggests that these CF patients were deprived of an important trigger for thirst. The trend for a positive effect of the 50 mmol·L−1 NaCl drink on the electrolyte and fluid balance, as shown in Tables 1 and 2 is in line with this hypothesis. The Na+ deficit when the children drank unflavored water accounted for about 10% of the total exchangeable Na+ in the extracellular space (42 mmol·kg−1 body weight) (26), compared with 4% when they had the 50 mmol·L−1 NaCl drink. Altogether, the electrolyte deficit in our subjects was some 4 to 10 times higher than that described for healthy children who had been exposed to similar exercise-in-the-heat conditions for 120 min (9). It would have been useful to obtain serum levels of electrolytes and osmolality during the Na50 session. However, only three of the six subjects who consented to taking part in this extra session agreed to have further blood tests. In two of them there was indeed a smaller decrease in serum osmolality and in Na+ concentration.
A high salt content can make the drink less tasty. This indeed was the case with the 50 mmol·L−1 NaCl-carbohydrate drink, which was perceived as less palatable than the other drinks (P = 0.02). Despite its lower palatability, however, this drink induced the largest voluntary intake. This suggests that the trigger for enhanced thirst was physiological rather than perceptual. To discuss the nature of a physiological mechanism in our study, one would need to have a more complete set of data points for serum electrolytes and osmolality than was available to us. We suggest though that the beneficial effect of the high salt solution is in line with the previously postulated mechanism by which NaCl triggers thirst through hypothalamic osmoreceptors or other pathways (12,13,15,16,24).
In addition to its deleterious effect on thirst, the marked electrolyte loss may also lead to serum electrolyte aberrations such as hyponatremia. For ethical and safety reasons, we kept the sessions in this study to 3 h and the exercise-plus-rest conditions were rather mild. Even so, one of the boys had a drop of 11.6 mmol·L−1 (from 142.1 to 130.5 mmol·L−1) in his serum Na+ levels by the end of W session compared with only a 4 mmol·L−1 drop when he drank the 50 mmol·L−1 sodium solution.
In conclusion, this study suggests an approach for the prevention, or amelioration, of voluntary dehydration in children and adolescents with CF who exercise in the heat. They must be encouraged to drink above and beyond thirst. To stimulate their thirst, they should be given electrolyte solutions with a high NaCl content (preferably 50 mmol·L−1 or more) rather than water alone. It is possible that improvement in palatability of a high-sodium beverage would induce an even greater voluntary intake than shown in this study.
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