Abstract
Decreased salivary flow rate causes xerostomia (symptoms of oral dryness) in patients who undergo hemodialysis (HD); however, whether it thus contributes to thirst and excess interdialytic weight gain (IDWG) remains undetermined. In the observational study, 3 mo of data of 90 stable HD patients were collected, and sensations of thirst and xerostomia were assessed by 100-mm visual analog scales (VAS). Multivariate analyses revealed that the VAS oral dryness score was an independent determinant for thirst, daily IDWG, and IDWG%. Unstimulated whole salivary flow rate (UWS) was measured in 45 participants and was negatively correlated with VAS oral dryness score (r = −0.690, P ≤ 0.001), daily IDWG (r = −0.361, P = 0.016), and daily IDWG% (r = −0.302, P = 0.045). In the interventional trial, the test drug was 5 mg of oral pilocarpine solution or placebo. Sixty hyperdipsic HD patients (IDWG% > 2%/d) were randomly assigned to either the sequence pilocarpine (2 wk)–washout (3 wk)–placebo (2 wk)–washout (2 mo)–placebo (3 mo) or placebo (2 wk)–washout (3 wk)–pilocarpine (2 wk)–washout (2 mo)–pilocarpine (3 mo) with 35 participants completing the trial. During the 2-wk crossover period (the first to seventh weeks), pilocarpine increased UWS and decreased xerostomia and thirst. The IDWG2d decreased (by approximately 0.2 kg; P = 0.013) but not IDWG3d. During the 3-mo interventional period, pilocarpine increased UWS but decreased both IDWG2d (by 0.76 kg; P = 0.021) and IDWG3d (by 1.07 kg; P = 0.007). It also modestly increased serum albumin and decreased mean BP. Pilocarpine-related adverse effects were generally mild. In conclusion, decreased salivary flow is a dipsogenic factor in HD patients, and pilocarpine can alleviate it.
Failure to restrict fluid is the rule rather than the exception in patients who undergo long-term hemodialysis (HD), despite frequent exhortations from staff, including warning about the complications of fluid overload (1–5). Three types of interventions for reducing thirst (the urge to drink) and interdialytic weight gain (IDWG) are identified in the literature: dialysis protocol related (increasing frequency and varying sodium concentration) (6–9), pharmaceutical (angiotensin-converting enzyme inhibitors [ACEI]) (10–13), and dietetic interventions (10,14). However, no definite effectiveness could be shown (5), which might be explained by the fact that many of the underlying mechanisms for thirst and drinking behavior remain unknown.
Known dipsogenic factors (factors that cause thirst and high fluid intake) in HD patients include high sodium intake, potassium depletion, increased blood urea, sugar and angiotensin II (Ang II) levels, and psychologic factors (2,3,5,10–16). Another potential dipsogenic factor is the reduction of salivary flow rate. Recently, Brunstrom et al. (17) demonstrated that healthy volunteers consume more water and drink more frequently in the xerostomic state, which is induced by decreasing saliva in the oral cavity. Because xerostomia (symptoms of oral dryness), which is caused by the reduction of salivary flow, is prevalent among HD patients (18–23), it is conceivable that the decreased salivary flow leads to thirst and excess IDWG. Some observational studies (24,25) have described an association between xerostomia and IDWG in HD patients; however, other known dipsogenic factors (e.g., blood urea, Ang II, sugar level) were not controlled in those studies. In addition, no interventional trial in the literature indexed by Medline has demonstrated the impact of the decreased salivary flow on IDWG. Therefore, whether the decreased salivary flow influences fluid intake in HD patients remains undetermined.
We conducted a 3-mo prospective observational study followed by a trial of pilocarpine—a parasympathomimetic agent that has been shown effectively to increase salivary flow in radiation-induced xerostomia or Sjögren syndrome (26–29)—to determine whether the reduction of salivary flow contributes to exaggerated thirst and excess IDWG in HD patients and whether pilocarpine can alleviate it.
Materials and Methods
The study protocol was approved by ethics committees of National Cheng Kung University Hospital and Kuo’s General Hospital, Tainan, Taiwan, and adhered to the Declaration of Helsinki. Informed consent was obtained from each participant.
In the observational study, we collected prospective data from December 2002 to February 2003 on 90 participants who were recruited from a pool of 217 patients who were undergoing HD at the outpatient dialysis unit of the Kuo’s General Hospital. Inclusion criteria were age older than 18 yr, HD three times weekly for at least 6 mo, daily urine output <200 ml, and stable clinical conditions including stable dry weight and hematocrit. Exclusion criteria were hemodynamic instability preventing sufficient ultrafiltration, hospitalization within the preceding 3 mo, dementia or terminal diseases, logistic impossibility of investigation, anxiety or depression (which cause xerostomia possibly as a result of the dysfunction of both brain and salivary glands), use of xerogenic medications (including anticholinergics, antidepressants, antipsychotics, antihistamines, antiparkinsonian agents, and diuretics), and unwillingness to participate in this study.
The inclusion and exclusion criteria for the interventional trial (March to October 2003) were the same as those in the observational study except that only hyperdipsic patients (IDWG% >2%/d [10]) were included, and patients who were using the xerogenic medications were included when these drugs could be stopped at least 14 d before entering and throughout the trial.
Assessment of IDWG
The body weight was determined using an Electronic Chair Scale (American Scale Co., New York, NY), and participants were weighed before and after each dialysis session. All patients were routinely asked to disrobe (except for their underwear), remove their shoes, and put on a clean gown before entering the dialysis unit. The patient was offered two options: to finish his or her meal before starting dialysis or to eat his or her meal within 1 h after starting dialysis. After choosing an option, the patient was asked to continue with it throughout the study periods. If the patient chose to eat after starting dialysis, then the meal would be weighed to guide the setting of the ultrafiltration rate. IDWG is defined as the difference between the predialysis weight and the weight at the end of the previous dialysis session, and IDWG% is obtained by dividing IDWG by the patient’s target dry weight. The IDWG was expressed as daily IDWG, daily IDWG%, IDWG2d, and IDWG3d as indicated. The target dry weight was determined according to standard clinical criteria (30) and was reviewed continuously by nephrologists. To allow better assessment of the changes of IDWG, we set the ultrafiltration rate according to the IDWG in each dialysis session and corrected the postdialysis body weight to the target dry weight. Because we recruited patients with stable dry weight and excluded patients with hemodynamic instability preventing sufficient ultrafiltration, the target dry weights did not change, and the postdialysis body weights of the participants were comparable with target dry weights throughout the study.
Assessment of Xerostomia, Thirst, and Stress of Fluid Restriction
Participants first were asked to respond to two-point categorical questions (yes or no) on sensations of xerostomia and thirst during each study period and then to questions about their sensations of five xerostomic items (oral dryness, oral comfort, requirement to sip liquid to speak, sleep, and chew and swallow), thirst, and stress of fluid restriction by 100-mm self-rating visual analog scales (VAS) with the negative and the positive on the left and right, respectively (e.g., 100 mm = extremely dry). VAS scores of speak, sleep, chew, and swallow were estimates of the requirement to sip liquid to speak, sleep, chew, and swallow. These VAS questions for xerostomia were identical to those in two previous Phase III trials that led to the Food and Drug Administration approval of pilocarpine for treatment of radiation-induced xerostomia (26,31) and in a multicenter clinical trial of pilocarpine in patients with Sjögren syndrome (32). A trained investigator, blind to the clinical data, administered all questionnaires.
Saliva Collection
The unstimulated salivary flow rate (UWS) and test drug–stimulated (by pilocarpine or placebo) whole salivary flow rates were determined before commencement of HD unless otherwise specified. Participants were instructed not to eat, drink, smoke, chew gum, or perform oral hygiene for at least 60 min before the collection. Whole saliva was collected for 10 min using an established spitting technique (33,34). Test drug–stimulated whole saliva was collected at 30, 60, and 90 min after stimulation as indicated. The collection volumes were determined gravimetrically (assuming specific gravity of 1.0), with saliva flow rates expressed in milliliters per minute. The salivary collection was performed by a trained investigator who was blind to all clinical data.
Study Medications
As pilocarpine tablets were not licensed in Taiwan during the study period, 5 mg of pilocarpine OPD solution (1% pilocarpine ophthalmic solution; Shionogi Co. Taipei, Taiwan) was used, a dose that is recommended as safe and effective for Sjögren syndrome (27). The placebo was a 3:7 mixture of normal saline and Milli-Q water. The sodium concentration of the two solutions was identical, with both administered in fixed doses (10 drops four times/d, 30 min before each meal and at bedtime). Ten drops of pilocarpine OPD solution is equivalent to 5 mg of pilocarpine.
Study Protocol
Observational Study.
Age, gender, underlying diseases, HD duration, and the use of ACEI or Ang II receptor antagonists (AIIA) were recorded. Mean values of Kt/V, normalized protein catabolic rate (nPCR), daily IDWG, daily IDWG%, hematocrit, and biochemistry values were calculated from monthly predialytic data. VAS scores of xerostomia and thirst and UWS were assessed twice in the study period (middle and end), and the mean values were used for analyses. Plasma Ang II and atrial natriuretic peptide (ANP) levels were determined at the end of the observational period.
Pilot Study before Clinical Trial.
No previous study has documented the effect of pilocarpine on salivary flow in HD patients with hyposalivation (UWS < 0.150 ml/min [34]); therefore, we performed a pilot study to evaluate whether pilocarpine could increase salivary flow and the time course of its effect in this population. Fifteen patients were randomly selected from 60 eligible candidates (who were hyperdipsic and were expected to have hyposalivation) of the interventional trial, and 15 healthy control subjects were enrolled. The UWS and test drug–stimulated (by pilocarpine or placebo) whole salivary flow rates were compared.
Interventional Clinical Trial.
Short-Term, Single-Blind, Placebo-Controlled, Crossover Clinical Trial Period.
After a run-in period, 60 participants were randomized to either protocol pilocarpine (2 wk)–washout (3 wk)–placebo (2 wk) or placebo (2 wk)–washout (3 wk)–pilocarpine (2 wk) (Figure 1) on the basis of a balanced block randomization list technique by numbered containers. A third party that was not involved in the conduct of the study generated the allocation sequence, assigned participants to their groups, and maintained the test drugs. The sequence was concealed until interventions were assigned. Pilocarpine and placebo solutions had identical appearance and packaging, and the participants were blinded as to the test drug. Before entering and at the end of each treatment and washout period, laboratory and UWS measurements were conducted under fasting state, and VAS scores of xerostomia, thirst, and stress of fluid restriction were obtained. The mean IDWG2d and IDWG3d during each study period were calculated, and each participant was queried about possible adverse events.
Flow diagram of the progression through the phases of the pilocarpine interventional trial.
Long-Term, Single-Blind, Placebo-Controlled Clinical Trial Period.
Fifteen participants who had completed the short-term pilocarpine (2 wk)–washout (3 wk)–placebo (2 wk) protocol received the placebo treatment, and 20 who had completed the placebo (2 wk)–washout (3 wk)–pilocarpine (2 wk) protocol received pilocarpine treatment (Figure 1). Each treatment lasted for 3 mo, and clinical data and laboratory measurements were made before and after each treatment. The UWS and VAS scores of xerostomia, thirst, and stress of fluid restriction of each patient were assessed. The mean IDWG2d and IDWG3d were calculated in the last study month.
Withdrawal, Outcome Measures, and Sample Size in the Interventional Trial.
Patients were withdrawn when they missed >30% of the doses of either regimen, experienced severe adverse effects or acute illness requiring hospitalization, or were unwilling to continue. An adverse event was defined as any clinically significant change in physical signs or symptoms or a significant change in laboratory test results.
The primary outcomes were changes in the VAS scores of xerostomia, thirst, and stress of fluid restriction; UWS; and mean IDWG2d and IDWG3d in each intervention period. The secondary outcomes were changes in mean BP, adverse events, and blood test results.
Under the scenario of a two-sided significance level of 0.05 and a power of 0.8 (a β error of 0.2), a sample size of 52 (26 in each group) was found to be sufficient for a t test to detect a standardized effect size of 0.80. We added four more participants in each group to accommodate possible dropouts.
Statistical Analyses
In the observational study, data were expressed as mean ± SD, and Spearman correlation coefficient was used to assess the correlations between continuous variables. Predictors that showed the significance level of 0.15 in the correlation analyses and the known dipsogenic factors (2,3,10) were included in the multiple linear regressions with stepwise selections and thereby to identify factors that were independently associated with VAS thirst score, daily IDWG, and daily IDWG%. The multivariate analyses were repeated forcing all variables left in the stepwise selection model, together with gender, the presence of diabetes, use of ACEI or AIIA, nPCR, sodium, potassium, and Ang II levels into the final regression model. In the interventional trial, data were expressed as mean ± SEM, and Mann-Whitney U and Wilcoxon signed-rank tests were applied to evaluate differences in unpaired and paired continuous variables respectively. χ2, Fisher exact, and McNemar tests were applied to evaluate differences in categorical variables. The ANOVA with baseline and washout measurement model were applied to evaluate the efficacy and carryover effect of drugs. All statistical analyses were conducted using the statistical software SAS at the two-tailed significance level of 0.05.
Results
Observational Study
Ninety patients (42 men and 48 women) were enrolled in the observational study. The mean age was 57.1 ± 14.3 yr, and patients were on HD for 51.3 ± 43.6 mo. Causes of the ESRD included chronic glomerulonephritis (26.6%), diabetes (23.3%), hypertension (13.3%), tubulointerstitial nephritis (11.1%), lupus nephritis (3.3%), adult polycystic kidney disease (2.2%), and unknown (20%). The salient characteristics and predialytic biochemical data of the 90 participants are presented in Table 1. Sixty-two (68.9%) patients reported abnormal sensation of xerostomia. The VAS oral dryness score in the 90 participants was 49.2 ± 25.2 mm, and the mean daily IDWG and IDWG% were 1.4 ± 0.4 kg and 2.3 ± 0.6%, respectively. The VAS thirst score was 47.1 ± 24.5 mm, which was significantly correlated with daily IDWG (r = 0.842, P ≤ 0.001) and IDWG% (r = 0.542, P ≤ 0.001).
Clinical data of 90 HD participants in the observational studya
The correlation coefficients between various predictors and VAS of thirst, daily IDWG, and daily IDWG% are shown in Table 2. We omitted time on HD, post-HD systolic and diastolic BP, alanine aminotransferase, serum creatinine, fasting blood sugar, lipid profiles (fasting triglycerides and cholesterol), and plasma osmolality and ANP levels in the table because none of the correlation coefficients had a P < 0.15, and none was left or forced into the final model of multiple linear regressions with stepwise selections. The VAS xerostomia scores seemed to be correlated with VAS of thirst, daily IDWG, and IDWG%. In multiple regression analyses (Table 3), daily IDWG was independently associated with the nPCR, VAS oral dryness score, and blood urea nitrogen and hematocrit levels. Daily IDWG% was independently associated with age, VAS oral dryness score, and blood urea nitrogen level. This indicates that xerostomia is an independent determinant for IDWG in HD patients.
Correlates of VAS thirst score, mean daily IDWG, and daily IDWG% in the observational study
Multiple linear regression analyses for thirst, daily IDWG, and daily IDWG% in the observation period (final models)a
The UWS was measured in 45 of the 90 participants, and the demographic data of these 45 participants did not differ from those of the other participants (data not shown). The UWS was normal (0.250 to 0.500 ml/min [35]) in 13 (29%) participants, and the overall mean was 0.162 ± 0.107 ml/min. Twenty (44%) participants had hyposalivation (UWS <0.150 ml/min [34]), and 4 (8%) had no measurable saliva. The UWS was significantly correlated with VAS scores for oral dryness (r = −0.690, P ≤ 0.001; Figure 2A), oral comfort (r = −0.523, P = 0.035), speaking (r = −0.452, P = 0.043), and sleeping (r = −0.391, P = 0.048) but not the VAS chew and swallow score (r = −0.257, P = 0.084). The UWS was modestly correlated with IDWG (r = −0.361, P = 0.016; Figure 2B) and IDWG% (r = −0.302, P = 0.045). These data demonstrated that the xerostomia in our participants was correlated with the decreased UWS, which might be a target of intervention for reducing IDWG.
The unstimulated salivary flow rate (UWS) in 45 hemodialysis (HD) patients. (A) The UWS was significantly correlated with visual analog scales (VAS) score of oral dryness (r = −0.69, P ≤ 0.001). (B) The UWS was modestly correlated with mean daily interdialytic weight gain (IDWG; r = −0.361, P = 0.016).
Pilot Study before Clinical Trial
Fifteen hyperdipsic HD patients (age 52.3 ± 5.1 yr; duration of HD 38.4 ± 8.2 mo; mean daily IDWG% 2.8 ± 0.9%/d) and 15 age-matched healthy control subjects (age 54.9 ± 5.1 yr) were enrolled for pilocarpine and placebo treatment (Figure 3). Although pilocarpine treatment increased the salivary flow rate, the rate did not increase to the baseline level of healthy control subjects. The time course of the pilocarpine’s effect on the whole salivary flow rate in HD patients was comparable to that in healthy control subjects, and no effect on salivary flow rate was noted with the placebo treatment. In addition, the predialysis UWS and pilocarpine-stimulated whole salivary flow rates were significantly greater than those of postdialysis at each time point. This demonstrated that the hydration status could affect the salivary flow rate in HD patients.
Effect of pilocarpine and placebo on whole salivary flow rate of hyperdipsic (IDWG% > 2%/d) HD patients (n = 15) and healthy control subjects (n = 15) in the pilot study. aP < 0.001 as compared with the baseline level of healthy control subjects; bP < 0.01 as compared with the pre-HD baseline levels of HD patients; cP < 0.05 as compared with the pre-HD baseline levels of HD patients; dP < 0.05 as compared with baseline levels in each group; eP < 0.01 as compared with baseline levels in each group. Error bars = SE.
Interventional Clinical Trial
Short-Term, Single-Blind, Placebo-Controlled, Crossover Study Period.
Sixty hyperdipsic patients were enrolled and randomly assigned to one of the two treatments (Figure 1), and 35 participants who completed this study period were included in the analyses. After the pilocarpine treatment, we demonstrated a significant improvement in UWS and the VAS scores of oral dryness, oral comfort, and speaking, with overall improvements in thirst and stress of fluid restriction. A modest but statistically significant decrease in IDWG2d (approximately 0.2 kg; P = 0.013) was also observed, but no significant change was found in IDWG3d or blood test results (Table 4). A total of 25 patients withdrew during this study period, and the reasons for withdrawals and adverse effects in the remaining 35 participants are presented in Table 5.
Results of short-term (2 wk), single-blind, placebo-controlled, crossover intervention perioda
Withdrawal and adverse effects in short-term (2 wk) intervention period (60 hyperdipsic patients)
Long-Term, Single-Blind, Placebo-Controlled Study Period.
Thirty-five participants completed this study period, among whom 20 received placebo treatment and 15 received pilocarpine treatment. There was no significant between-group difference in age, gender, time on HD, and underlying diseases that caused ESRD. After 3 mo of pilocarpine treatment, significant improvements were observed in three of the five xerostomia-related items (oral dryness, oral comfort, and speaking), VAS scores for thirst and stress of fluid restriction, UWS, IDWG2d (2.95 ± 0.31 versus 3.71 ± 0.32; P = 0.021), and IDWG3d (3.31 ± 0.45 versus 4.38 ± 0.22; P = 0.007; Table 6). Pilocarpine treatment was also associated with decreased BP, increased serum albumin, and a near-significant increase in serum sodium. No such effects were observed in the placebo treatment group. Adverse effects were generally of mild or occasionally moderate severity and mostly appeared within the first several days of drug administration and improved within 2 wk. The most frequent side effect was sweating (in nine participants [45%] in the pilocarpine treatment group), and other adverse effects included anorexia, dizziness, headache, dyspepsia, and diarrhea. There was no withdrawal in this study period.
Results of long-term (3 mo), single-blind, placebo-controlled intervention perioda
Discussion
To our knowledge, this study is the first report to document the impact of decreased salivary flow rate on the thirst and IDWG in HD patients on the basis of both observational and interventional data. These findings have an important implication for the care of HD patients because thirst and fluid overload are unsolved stressors in the daily life of many patients (1–5). We demonstrated that pilocarpine treatment increased UWS and reduced both the subjective feeling of thirst and the objective IDWG. It also led to a modest decrease in the mean arterial BP and an increase in the serum albumin level.
Taiwan has the highest incidence and the second highest prevalence of dialysis in the world (36). A nationwide survey at the end of 2001 showed that the mean patient age was 56.1 ± 9.8 yr and that the causes of ESRD include chronic glomerulonephritis (32%), diabetic nephropathy (29%), and hypertension (6%) (37). The demographic data of our participants (Table 1) were comparable to that survey. Xerostomia was reported by 68.9% of the 90 participants in our observational study, which also agreed with other studies (19,25). Measurement of UWS is the most reliable method for quantifying the salivary function (38), and the mean UWS (0.162 ± 0.107 ml/min) of our patients was significantly lower than the normal reference value of 0.25 to 0.5 ml/min (35). We also found that hyperdipsic patients had extremely low baseline UWS (0.09 ml/min in the pilot study [Figure 3]; 0.11 and 0.09 ml/min in each group, respectively, in the interventional trial [Tables 4 and 6]), which was comparable with that of patients who received radiotherapy for head and neck tumors (0.113 ml/min) (39). Such low flow rates indicate massive salivary gland damage (approximate 75% of total salivary glandular tissue) (40). The results suggest a high prevalence of severe salivary gland dysfunction in HD patients, especially in hyperdipsic ones.
The multivariate analyses in our study revealed that VAS oral dryness score (a xerostomic score) was an independent determinant of thirst, IDWG, and IDWG% in HD patients (Table 3). We also demonstrated that the UWS was correlated with several VAS scores for xerostomia, daily IDWG, and IDWG%, especially oral dryness score (Figure 2), suggesting that xerostomia in our participants was caused by the decreased UWS, which is in agreement with other studies showing that uremic xerostomic symptoms are associated with salivary gland dysfunction (18–20). These observational data strongly suggested that decreased salivary flow might contribute to IDWG, and the subsequent pilocarpine interventional trial further confirmed the dipsogenic effect of decreased saliva flow. Whereas pilocarpine has a weak central dipsogenic effect (17,41), it is unlikely that pilocarpine reduces IDWG by directly inhibiting the thirst center. The results of this study agree with previous physiologic researches (17,42,43), suggesting an oropharyngeal factor that influences drinking. Ramsay et al. (42) found that dehydrated dogs drank water rapidly but stopped well before normal blood osmolality was restored. This early inhibition of thirst (and vasopressin secretion) occurred even when the water was drained from the stomach through a gastric fistula to prevent rehydration. These observations suggest neural inputs from the oropharynx to the brain that allowed dogs to regulate their drinking volume (42). This phenomenon has been confirmed in humans by Figaro et al. (43). Brunstrom et al. (17) induced a xerostomic state by placing two absorbent rolls in each cheek to reduce salivary flow and confirm that decreased salivary flow may cause more fluid intake in healthy volunteers. Our study further demonstrated that the magnitude of decreased salivary flow rate was sufficient to cause exaggerated thirst and large IDWG in hyperdipsic HD patients.
The mechanism of salivary gland dysfunction in HD patients is unknown; however, some researchers (18,19) have proposed that it is caused by dehydration and direct uremic injury. In normal individuals, there is a relationship between the salivary flow rate and body hydration, and the UWS is larger in well-hydrated status than that in dehydrated status (33–35). This relationship is maintained in dialysis patients and can be demonstrated by Figure 3, which shows that the predialysis UWS and pilocarpine-stimulated whole salivary flow rates were significantly greater—but modest—than those of the postdialysis period in each corresponding time point. In HD patients with persistent large IDWG, it is possible that large IDWG increases UWS initially; however, large IDWG also leads to large ultrafiltration in dialysis session; it thus compromises the tissue perfusion and causes damage of salivary glands. In such a condition, the UWS will decrease with time, and the effect of hydration to increase UWS may be attenuated subsequently. Because low UWS further increases fluid intake, the hyperdipsic HD patients will have lower UWS eventually. In addition, Bots et al. (25) argued that salivary glands maintain their secretory capacity because they observed a remarkable difference between UWS and chewing-stimulated whole salivary flow. In our trial, however, pilocarpine treatment only modestly increased the salivary flow rate. Noteworthy, any mechanical stimulation would increase the fluid from a nonsalivary gland source, such as gingival crevicular fluid, and might interfere with the interpretation of salivary function tests (18,44). Recent studies (20,45) demonstrated that the uremic salivary dysfunction is associated with glandular atrophy, fibrosis, and accumulation of fibrillar components, which suggest that uremic salivary dysfunction is not only a functional disturbance but also an organic change.
Pilocarpine exerts its effect through cholinergic stimulation of saliva from residual salivary gland tissues, and an increase of a relatively modest amount of saliva seems to be sufficient to overcome the xerostomia (40). Although pilocarpine alleviated the subjective feeling of xerostomia, thirst, and the stress of fluid restriction in our 2-wk interventional trial period, the objective reduction in IDWG was minimal; it took 8 to 12 wk to demonstrate a significant reduction in IDWG. As xerostomia develops insidiously (27–29,40) and fluid intake is a mild form of addiction (14–16), the delay in the reduction of IDWG is reasonable. This suggests that prolonged pilocarpine treatment is required to see benefits in IDWG. A 2-wk crossover study of Bots et al. (46) evaluated the effect of chewing gum or saliva substitute on thirst, xerostomia, and IDWG and found no change in IDWG. The 2-wk period might be too short, and the inclusion of both hyperdipsic and nonhyperdipsic patients might make the effect of deceasing IDWG difficult to demonstrate. Furthermore, other researchers have demonstrated that saliva substitutes and chewing gum were generally ineffective in treating xerostomia caused by a variety of diseases, including Sjögren syndrome, radiation treatment, and idiopathic salivary gland dysfunction (26–28,40,47). In addition, gustatory and masticatory stimulation have only short effect, and their long-term use may irritate the oral tissue (13,40). Our long-term pilocarpine trial also showed a modest increase in albumin level and a reduction in mean BP. The increase of serum albumin might be due to a change of appetite after alleviation of xerostomia, and the BP change might be secondary to the decrease in IDWG. Although pilocarpine has a parasympathetic effect, previous studies did not observe an antihypertensive property (26–29). Furthermore, pilocarpine tended to increased serum sodium, suggesting that fluid intake, rather than salt, was influenced.
The dryness symptoms that are experienced by HD patients possibly are not restricted to the oral cavity but also involve the whole body. General exocrine gland dysfunction has been described in HD patients, including the reduced acid secretion, impaired peptic secretion, dry eyes, and cutaneous xerosis (20,48–50). The pharmacologic properties of pilocarpine suggest that it can stimulate exocrine gland secretion in other organ systems besides the oral cavity. Although we did not assess effects of pilocarpine on extra-oral sicca symptoms in this study, previous research has shown its beneficial effects on extra-oral symptoms in patients with Sjögren syndrome, including dry eyes, nasal dryness, dry skin, vaginitis sicca, and the inability to expectorate (27,28). It will be intriguing to assess extra-oral effects in further studies.
The most prevalent pilocarpine-related adverse effects in our study included sweating, vomiting, and diarrhea (Table 5). Despite the high incidence of sweating, this and other adverse effects were perceived as minor by most patients and improved within 2 wk. The withdrawal rate as a result of pilocarpine-related adverse effects was 15.3% (8 of 52) in this trial. Approximately 34.6% (18 of 52) of participants experienced a mild bitter taste during pilocarpine treatment, whereas 9.8% (5 of 51) of participants had the same perception during placebo treatment. However, this had no impact on the single-blind design of our study. Each participant was told that we would provide two solutions for xerostomia, and although to some participants the pilocarpine solution tasted a little bitter, they did not know which of the solutions contained the pilocarpine during the study period.
There were several limitations to our interventional trial. Although long-term effectiveness and safety of pilocarpine treatment for radiation-induced xerostomia (26,31) and Sjögren syndrome (32) have been documented, those of this treatment in HD patients have not been established in our study because of the small sample size and short duration. In addition, only clinically stable patients were enrolled in our study; therefore, it remains uncertain whether our findings can be generalized to individuals with multiple concurrent diseases. In addition, a portion of the patients complained of inconvenience and the bitter taste of the pilocarpine solution, and it is reasonable to speculate that tablets will improve compliance and eliminate unfavorable taste.
In conclusion, our study clearly demonstrated the dipsogenic effect of decreased salivary flow in HD patients. In the 3-mo clinical trial, pilocarpine significantly alleviated the exaggerated thirst and large IDWG of hyperdipsic HD patients. On the basis of these findings, we suggest that pilocarpine could serve as a therapeutic agent to reduce IDWG in hyperdipsic HD patients. Further large-scale trials, preferably with pilocarpine tablets, should be conducted to confirm its long-term effects.
Acknowledgments
This study was supported by the Cheng Kung University Hospital Research Committee research grants NCKUH-2003-05 and NCKUH-2004-63.
This study is registered as ISRCTN41671411 (http://www.controlled-trials.com/isrctn/trial/|/0/41671411.html).
We thank the hemodialysis unit staffs of the Kuo’s General Hospital, Tainan, Taiwan, for help.
Footnotes
Published online ahead of print. Publication date available at www.jasn.org.
Access to UpToDate on-line is available for additional clinical information at http://www.jasn.org/
- © 2005 American Society of Nephrology
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