Decreased Salivary Flow Rate as a Dipsogenic Factor In

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Decreased Salivary Flow Rate as a Dipsogenic Factor inHemodialysis Patients: Evidence from an ObservationalStudy and a Pilocarpine Clinical Trial

Junne-Ming Sung,* Shih-Chen Kuo, How-Ran Guo, Shu-Fen Chuang, Szu-Yuan Lee,

and Jeng-Jong Huang*Departments of *Internal Medicine and Operative Dentistry, National Cheng Kung University Hospital; Institute of

Clinical Pharmacy and Department of Environmental and Occupational Health, College of Medicine, National Cheng

Kung University; and Department of Internal Medicine, Kuos General Hospital, Tainan, Taiwan

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 (r0.690,P< 0.001), daily IDWG (r0.361,

P 0.016), and daily IDWG% (r 0.302, P 0.045). In the interventional trial, the test drug was 5 mg of oral pilocarpinesolution 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.

J Am Soc Nephrol16: 34183429, 2005. doi: 10.1681/ASN.2005040346

Failure to restrict fluid is the rule rather than the excep-tion in patients who undergo long-term hemodialysis

(HD), despite frequent exhortations from staff, includ-

ing warning about the complications of fluid overload (15).

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) (69), pharmaceutical (an-

giotensin-converting enzyme inhibitors [ACEI]) (1013), and

dietetic interventions (10,14). However, no definite effective-

ness could be shown (5), which might be explained by the fact

that many of the underlying mechanisms for thirst and drink-

ing behavior remain unknown.

Known dipsogenic factors (factors that cause thirst and high

fluid intake) in HD patients include high sodium intake, potas-

sium depletion, increased blood urea, sugar and angiotensin II

(Ang II) levels, and psychologic factors (2,3,5,1016). Anotherpotential 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 (1823), it is conceivable that the decreased

salivary flow leads to thirst and excess IDWG. Some observa-

tional 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 fol-

lowed by a trial of pilocarpinea parasympathomimetic agent

that has been shown effectively to increase salivary flow in

radiation-induced xerostomia or Sjogren 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.

Received April 3, 2005. Accepted July 26, 2005.

Published online ahead of print. Publication date available at www.jasn.org.

Address correspondence to: Dr. Jeng-Jong Huang, Division of Nephrology, De-

partment of Internal Medicine, National Cheng Kung University Hospital, 138

Sheng-Li Road, Tainan, Taiwan 70428, R.O.C. Phone: 886-6-2766138; Fax: 886-

6-3028036; E-mail: [email protected]

Copyright 2005 by the American Society of Nephrology ISSN: 1046-6673/1611-3418


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Materials and MethodsThe study protocol was approved by ethics committees of National

Cheng Kung University Hospital and Kuos 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 De-

cember 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 Kuos 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 instabil-

ity preventing sufficient ultrafiltration, hospitalization within the pre-

ceding 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, an-

tipsychotics, 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]) wereincluded, 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 IDWGThe 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 patients target dry weight. The

IDWG was expressed as daily IDWG, daily IDWG%, IDWG2d, and

IDWG3das 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 sufficientultrafiltration, the target dry weights did not change, and the postdi-

alysis body weights of the participants were comparable with target

dry weights throughout the study.

Assessment of Xerostomia, Thirst, and Stress ofFluid 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-in-

duced xerostomia (26,31) and in a multicenter clinical trial of pilo-

carpine in patients with Sjogren syndrome (32). A trained investigator,

blind to the clinical data, administered all questionnaires.

Saliva CollectionThe unstimulated salivary flow rate (UWS) and test drugstimulated

(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

drugstimulated 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 per-

formed by a trained investigator who was blind to all clinical data.

Study MedicationsAs 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 recom-

mended as safe and effective for Sjogren 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 adminis-

tered 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 ProtocolObservational Study. Age, gender, underlying diseases, HD du-

ration, 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 val-

ues 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 docu-

mented 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 flowand 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

drugstimulated (by pilocarpine or placebo) whole salivary flow rates

were compared.

Interventional Clinical Trial.

Short-Term, Single-Blind, Placebo-Controlled, Crossover Clinical Trial Pe-

riod. 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

J Am Soc Nephrol 16: 3418 3429, 2005 Decreased Salivary Flow Rate and Pilocarpine Trial in HD Patients 3419


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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 IDWG 2dand IDWG3d during each study period were calculated, and each

participant was queried about possible adverse events.

Long-Term, Single-Blind, Placebo-Controlled Clinical Trial Period. Fif-

teen 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 Interven-

tional Trial. Patients were withdrawn when they missed 30% ofthe

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 phys-

ical signs or symptoms or a significant change in laboratory test results.

The primary outcomes were changes in the VAS scores of xerosto-

Figure 1. Flow diagram of the progression through the phases of the pilocarpine interventional trial.

3420 Journal of the American Society of Nephrology J Am Soc Nephrol 16: 3418 3429, 2005


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mia, thirst, and stress of fluid restriction; UWS; and mean IDWG2dand

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 (aerror 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 AnalysesIn 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 indepen-

dently 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 Uand Wilcoxonsigned-rank tests were applied to evaluate differences in unpaired and

paired continuous variables respectively. 2, Fisher exact, and McNe-

mar 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.

ResultsObservational Study

Ninety patients (42 men and 48 women) were enrolled in theobservational 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 bio-

chemical data of the 90 participants are presented in Table 1.

Sixty-two (68.9%) patients reported abnormal sensation of xe-

rostomia. 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 withdaily IDWG (r 0.842,P 0.001) and IDWG% (r 0.542,P

0.001).

The correlation coefficients between various predictors and

Table 1. Clinical data of 90 HD participants in the observational study a

Variables N(%) or Mean SD

Kt/V 1.4 0.2nPCR (g/kg per d) 1.2 0.2Pre-HD SBP/DBP (mmHg) 133.8 11.6/78.4 5.4

Post-HD SBP/DBP (mmHg) 125.5

8.8/74.2

5.2Daily IDWG (kg/d)/daily IDWG% 1.4 0.4/2.3 0.6VAS score of thirst (mm) 47.1 24.5Sensation of abnormal xerostomia 62 (68.9)VAS score of oral dryness (mm) 49.2 25.2VAS score of oral comfort (mm) 44.0 21.2VAS score of speak (mm) 37.0 24.1VAS score of sleep (mm) 37.2 22.3VAS score of chew and swallow (mm) 38.1 24.3BUN (mg/dl) 72.7 18.2Sodium (mmol/L) 137.3 2.1Potassium (mmol/L) 5.0 0.6Hematocrit (%) 28.5 4.0Serum albumin (g/dl) 3.9 0.3AST/ALT (U/L) 18.0 10.0/19.6 14.6ALK-P (U/L) 129.0 44.3Uric acid (mg/dl) 6.2 1.1Fasting cholesterol/triglycerides (mg/dl) 178.4 37.5/166.5 106.0Plasma Ang II (pg/ml) 185.8 75.9Plasma ANP (pg/ml) 1326.3 708.1Fasting blood sugar (mg/dl) 104.7 41.5Hemoglobin A1c (n 28) 7.0 1.5

aHD, hemodialysis; nPCR, normalized protein catabolic rate; SBP, systolic BP; DBP, diastolic BP; IDWG, interdialytic weightgain; IDWG%, IDWG/target dry weight; VAS, visual analog scales; AST, aspartate aminotransferase; ALT, alanineaminotransferase; ALK-P, alkaline phosphatase; BUN, blood urea nitrogen; Ang II, angiotensin II; ANP, atrial natriureticpeptide.



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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 aP 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 inde-

Table 2. Correlates of VAS thirst score, mean daily IDWG, and daily IDWG% in the observational study

VariablesVAS of Thirst Daily IDWG Daily IDWG %

r P r P r P

Age 0.436 0.001 0.502 0.001 0.432 0.001Kt/V 0.259 0.014 0.239 0.023 0.074 0.489

nPCR 0.011 0.920 0.181 0.089 0.135 0.205Pre-HD SBP 0.233 0.027 0.244 0.021 0.138 0.196Pre-HD DBP 0.190 0.073 0.159 0.134 0.066 0.534VAS oral dryness 0.932 0.001 0.828 0.001 0.555 0.001VAS oral comfort 0.884 0.001 0.725 0.001 0.477 0.001VAS speak 0.495 0.001 0.426 0.001 0.254 0.016VAS sleep 0.612 0.001 0.465 0.001 0.148 0.165VAS chew and swallow 0.607 0.001 0.458 0.001 0.302 0.004BUN 0.380 0.001 0.449 0.001 0.429 0.001Sodium 0.180 0.090 0.181 0.088 0.171 0.108Potassium 0.029 0.783 0.038 0.724 0.132 0.216Hematocrit 0.098 0.360 0.160 0.131 0.058 0.588Serum albumin 0.001 0.991 0.169 0.111 0.189 0.075AST 0.161 0.130 0.142 0.181 0.024 0.821ALK-P 0.075 0.481 0.215 0.042 0.067 0.531Uric acid 0.150 0.159 0.230 0.029 0.013 0.900Plasma Ang II 0.022 0.838 0.047 0.658 0.151 0.156

Table 3. Multiple linear regression analyses for thirst, daily IDWG, and daily IDWG% in the observation period(final models)a

VariablesVAS of Thirst (R2 0.876) IDWG (R2 0.720) IDWG % (R2 0.437)

(95% CI) P (95% CI) P (95% CI) P

Age 0.019 (0.037 to 0.002) 0.032 0.003 (0.007 to 0.001) 0.123 0.009 (0.019 to 0.001) 0.046Gender 0.249 (0.135 to 0.634) 0.200 0.016 (0.078 to 0.111) 0.732 0.141 (0.353 to 0.072) 0.191Diabetes 0.264 (0.714 to 0.186) 0.246 0.003 (0.110 to 0.103) 0.949 0.106 (0.359 to 0.147) 0.407Use ACEI

or AIIA0.009 (0.386 to 0.403) 0.95 0.008 (0.101 to 0.085) 0.870 0.129 (0.091 to 0.350) 0.247

Kt/V 0.993 (1.993 to 0.007) 0.052 nPCR 0.235 (0.012 to 0.459) 0.040 Pre-HD SBP 0.004 (0.001 to 0.008) 0.085 VAS oral

dryness0.580 (0.411 to 0.749) 0.001 0.099 (0.076 to 0.122) 0.001 0.098 (0.045 to 0.152) 0.001

VAS oralcomfort

0.322 (0.145 to 0.500) 0.001

BUN 0.005 (0.006 to 0.016) 0.380 0.003 (0.000 to 0.006) 0.027 0.009 (0.002 to 0.015) 0.007Sodium 0.031 (0.128 to 0.065) 0.520 0.013 (0.035 to 0.010) 0.265 0.014 (0.068 to 0.039) 0.590Potassium 0.047 (0.253 to 0.346) 0.757 0.002 (0.047 to 0.069) 0.949 0.133 (0.035 to 0.301) 0.120Hematocrit 0.012 (0.000 to 0.024) 0.043 Plasma Ang II 0.002 (0.001 to 0.005) 0.121 0.000 (0.000 to 0.001) 0.647 0.001 (0.000 to 0.003) 0.145

aCI, confidence interval; ACEI, angiotensin-converting enzyme inhibitor; AIIA, Ang II receptor antagonist.



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pendently 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 xero-

stomia is an independent determinant for IDWG in HD pa-

tients.

The UWS was measured in 45 of the 90 participants, and the

demographic data of these 45 participants did not differ fromthose 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 signifi-

cantly 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.

Pilot Study before Clinical TrialFifteen 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). Al-

though 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 pilocarpines effect on thewhole 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 predi-

alysis 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.

Interventional Clinical TrialShort-Term, Single-Blind, Placebo-Controlled, Crossover

Study Period. Sixty hyperdipsic patients were enrolled and

randomly assigned to one of the two treatments (Figure 1), and35 participants who completed this study period were included

in the analyses. After the pilocarpine treatment, we demon-

strated a significant improvement in UWS and the VAS scores

of oral dryness, oral comfort, and speaking, with overall im-

provements 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 IDWG3dor 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 partic-

ipants are presented in Table 5.

Long-Term, Single-Blind, Placebo-Controlled Study Pe-

riod. 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, signif-

icant improvements were observed in three of the five xeros-

tomia-related items (oral dryness, oral comfort, and speaking),

VAS scores for thirst and stress of fluid restriction, UWS,

IDWG2d(2.95 0.31versus3.71 0.32;P 0.021), and IDWG3d(3.31 0.45versus4.38 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 so-

dium. 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.

DiscussionTo 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

Figure 2. The unstimulated salivary flow rate (UWS) in 45 he-modialysis (HD) patients. (A) The UWS was significantly cor-related with visual analog scales (VAS) score of oral dryness(r 0.69,P 0.001). (B) The UWS was modestly correlatedwith mean daily interdialytic weight gain (IDWG; r 0.361,

P 0.016).



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Figure 3.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 HDpatients;dP 0.05 as compared with baseline levels in each group;eP 0.01 as compared with baseline levels in each group. Errorbars SE.

Table 4. Results of short-term (2 wk), single-blind, placebo-controlled, crossover intervention perioda

Sequence of Treatment Baseline Course 1(2 wk)Washout

(3 wk)Course 2

(2 wk)OEP

COP

UWSP-C 0.11 (0.02)b 0.14 (0.02) 0.08 (0.04) 0.09 (0.03) 0.017 0.194C-P 0.09 (0.02) 0.10 (0.03) 0.09 (0.02) 0.15 (0.02) 0.325

VAS of thirstP-C 74.8 (3.5) 55.4 (4.8) 75.4 (3.5) 71.6 (4.2) 0.001 0.706C-P 65.4 (3.7) 64.0 (4.0) 67.9 (2.9) 34.3 (2.0) 0.254

VAS of fluid restrictionP-C 68.5 (10.2) 39.7 (8.7) 56.7 (10.9) 62.3 (10.2) 0.023 0.824C-P 72.3 (8.9) 68.9 (9.2) 59.7 (10.4) 41.7 (9.4) 0.728

VAS of oral drynessP-C 71.8 (3.7) 46.2 (3.0) 70.3 (3.6) 65.8 (4.5) 0.001 0.517C-P 64.2 (3.0) 52.9 (3.3) 65.2 (2.8) 31.5 (2.1) 0.075

VAS of comfortP-C 66.4 (5.8) 48.7 (5.1) 65.8 (5.3) 60.4 (5.4) 0.008 0.829C-P 56.6 (3.7) 50.8 (3.8) 57.0 (3.0) 28.7 (3.0) 0.187

VAS of speakP-C 44.7 (8.0) 34.2 (7.2) 48.4 (8.3) 51.7 (6.6) 0.034 0.949C-P 31.7 (6.0) 31.8 (6.0) 35.0 (6.5) 21.1 (4.4) 0.408

IDWG2 dP-C 3.69 (0.23) 3.51 (0.23) 3.68 (0.19) 3.68 (0.23) 0.013 0.789C-P 3.45 (0.18) 3.57 (0.21) 3.49 (0.18) 3.29 (0.19) 0.565

IDWG3 dP-C 4.41 (0.22) 4.32 (0.23) 4.48 (0.25) 4.37 (0.2) 0.514 0.246C-P 4.34 (0.25) 4.15 (0.22) 4.24 (0.19) 4.13 (0.18) 0.310

aOE, overall treatment effects; CO, carryover effects; UWS, unstimulated whole salivary flow rate; P-C, pilocarpine, placebo(n 15); C-P, placebo, pilocarpine (n 20); IDWG3 d, mean interdialytic weight gain during a 3-d period; IDWG2 d, meaninterdialytic weight gain during a 2-d period.

b

Mean (SE).



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interventional data. These findings have an important implica-

tion for the care of HD patients because thirst and fluid over-

load are unsolved stressors in the daily life of many patients

(15). 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 glomerulo-

nephritis (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 andneck tumors (0.113 ml/min) (39). Such low flow rates indicate

massive salivary gland damage (approximate 75% of total sal-

ivary glandular tissue) (40). The results suggest a high preva-

lence 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 patient-

s (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 de-creased UWS, which is in agreement with other studies show-

ing that uremic xerostomic symptoms are associated with sal-

ivary gland dysfunction (1820). These observational data

strongly suggested that decreased salivary flow might contrib-

ute to IDWG, and the subsequent pilocarpine interventional

trial further confirmed the dipsogenic effect of decreased saliva

flow. Whereas pilocarpine has a weak central dipsogenic ef-

fect (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), suggest-

ing an oropharyngeal factor that influences drinking. Ramsayet

al. (42) found that dehydrated dogs drank water rapidly butstopped 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 sug-

gest neural inputs from the oropharynx to the brain that al-

lowed dogs to regulate their drinking volume (42). This phe-

nomenon has been confirmed in humans by Figaro et al.(43).

Brunstromet al.(17) induced a xerostomic state by placing two

absorbent rolls in each cheek to reduce salivary flow and con-

firm 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 (3335). This

relationship is maintained in dialysis patients and can be dem-

onstrated by Figure 3, which shows that the predialysis UWS

and pilocarpine-stimulated whole salivary flow rates were sig-

nificantly greaterbut modestthan those of the postdialysis

period in each corresponding time point. In HD patients with

Table 5. Withdrawal and adverse effects in short-term (2wk) intervention period (60 hyperdipsic patients)

PilocarpinePhase

(n %)

PlaceboPhase

(n %)

Withdrawal in the precrossover

period (n 17)

9 (30.0) 8 (26.7)

sweating 4 (13.3) 0 (0)vomitinga 1 (3.3) 0 (0)headache 1 (3.3) 1 (3.3)diarrhea 1 (3.3) 1 (3.3)noncompliance 3 (10.0) 6 (20.0)

Withdrawal in the postcrossoverperiod (n 8)

2 (9.1) 6 (28.6)

sweating 1 (4.5) 0 (0)nauseab 1 (4.5) 0 (0)palpitation 1 (4.5) 0 (0)dizziness 0 (0) 1 (4.8)noncompliancec 0 (0) 5 (23.8)

Adverse effects (n 35)sweatingc 24 (68.6) 3 (8.6)vomitingc 6 (17.1) 0 (0)nausea 4 (11.4) 0 (0)diarrhea 3 (8.6) 0 (0)asthenia 3 (8.6) 1 (2.9)hypertension 2 (5.7) 0 (0)headache 1 (2.9) 1 (2.9)abdominal distension 1 (2.9) 1 (2.9)dizziness 1 (2.9) 2 (5.7)myalgias 1 (2.9) 0 (0)insomnia 1 (2.9) 0 (0)

taste change 1 (2.9) 0 (0)palpitation 1 (2.9) 1 (2.9)visual blurring 1 (2.9) 0 (0)abdominal pain 1 (2.9) 1 (2.9)

aOne case withdrew because of sweating and vomiting.bOne case withdrew because of sweating and nausea.cP 0.05.



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persistent large IDWG, it is possible that large IDWG increases

UWS initially; however, large IDWG also leads to large ultra-

filtration 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 hyperdip-

sic HD patients will have lower UWS eventually. In addition,

Bots et al.(25) argued that salivary glands maintain their secre-

tory capacity because they observed a remarkable difference

between UWS and chewing-stimulated whole salivary flow. In

our trial, however, pilocarpine treatment only modestly in-

creased 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 dysfunc-

tion is associated with glandular atrophy, fibrosis, and accu-

mulation 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 (2729,40) and fluid intake is a mild form

of addiction (1416), 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

Table 6. Results of long-term (3 mo), single-blind, placebo-controlled intervention perioda

VariablePilocarpine (n 20) Placebo (n 15)

Pd Pe

Before After Pb Before After Pc

UWS (ml/min) 0.11 (0.03) 0.15 (0.02) 0.008 0.09 (0.03) 0.10 (0.02) 0.506 0.312 0.038

Whole saliva 60 min

after drug

0.21 (0.04) 0.25 (0.04) 0.123 0.11 (0.04) 0.09 (0.02) 0.765 0.023 0.006

VAS thirst (mm) 78.1 (2.8) 49.1 (3.4) 0.007 75.4 (3.2) 62.5 (4.5) 0.31 0.605 0.031

VAS stress of fluidrestriction (mm)

62.7 (3.4) 25.4 (2.3) 0.003 58.9 (12.7) 62.5 (9.4) 0.213 0.453 0.004

VAS oral dryness(mm)

67.8 (3.9) 48.8 (3.1)


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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 demon-

strate. Furthermore, other researchers have demonstrated that

saliva substitutes and chewing gum were generally ineffective

in treating xerostomia caused by a variety of diseases, including

Sjogren syndrome, radiation treatment, and idiopathic salivarygland dysfunction (2628,40,47). 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 albu-

min 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 parasympa-

thetic effect, previous studies did not observe an antihyperten-

sive property (2629). Furthermore, pilocarpine tended to in-

creased 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 de-

scribed in HD patients, including the reduced acid secretion,

impaired peptic secretion, dry eyes, and cutaneous xerosis

(20,4850). The pharmacologic properties of pilocarpine sug-

gest 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 Sjogren syndrome, in-

cluding dry eyes, nasal dryness, dry skin, vaginitis sicca, andthe 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). De-

spite 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. Approx-

imately 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 treat-

ment. 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 partici-

pants 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 Sjogren

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 exagger-ated 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.

AcknowledgmentsThis 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 Kuos General Hospital,

Tainan, Taiwan, for help.

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