* Internal Medicine; Operative Dentistry, National Cheng Kung University Hospital; Institute of Clinical Pharmacy; Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University; and || Department of Internal Medicine, Kuo’s General Hospital, Tainan, Taiwan
Address correspondence to: Dr. Jeng-Jong Huang, Division of Nephrology, Department 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: jjhuang{at}mail.ncku.edu.tw
Received for publication April 3, 2005.
Accepted for publication July 26, 2005.
Decreased salivary flow rate causes xerostomia (symptoms oforal dryness) in patients who undergo hemodialysis (HD); however,whether it thus contributes to thirst and excess interdialyticweight gain (IDWG) remains undetermined. In the observationalstudy, 3 mo of data of 90 stable HD patients were collected,and sensations of thirst and xerostomia were assessed by 100-mmvisual analog scales (VAS). Multivariate analyses revealed thatthe VAS oral dryness score was an independent determinant forthirst, daily IDWG, and IDWG%. Unstimulated whole salivary flowrate (UWS) was measured in 45 participants and was negativelycorrelated with VAS oral dryness score (r = –0.690, P 0.001), daily IDWG (r = –0.361, P = 0.016), and dailyIDWG% (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 randomlyassigned 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 35participants completing the trial. During the 2-wk crossoverperiod (the first to seventh weeks), pilocarpine increased UWSand decreased xerostomia and thirst. The IDWG2d decreased (byapproximately 0.2 kg; P = 0.013) but not IDWG3d. During the3-mo interventional period, pilocarpine increased UWS but decreasedboth IDWG2d (by 0.76 kg; P = 0.021) and IDWG3d (by 1.07 kg;P = 0.007). It also modestly increased serum albumin and decreasedmean BP. Pilocarpine-related adverse effects were generallymild. In conclusion, decreased salivary flow is a dipsogenicfactor in HD patients, and pilocarpine can alleviate it.
Failure to restrict fluid is the rule rather than the exceptionin patients who undergo long-term hemodialysis (HD), despitefrequent exhortations from staff, including warning about thecomplications of fluid overload (1–5). Three types ofinterventions for reducing thirst (the urge to drink) and interdialyticweight gain (IDWG) are identified in the literature: dialysisprotocol 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 beexplained by the fact that many of the underlying mechanismsfor thirst and drinking behavior remain unknown.
Known dipsogenic factors (factors that cause thirst and highfluid intake) in HD patients include high sodium intake, potassiumdepletion, increased blood urea, sugar and angiotensin II (AngII) levels, and psychologic factors (2,3,5,10–16). Anotherpotential dipsogenic factor is the reduction of salivary flowrate. Recently, Brunstrom et al. (17) demonstrated that healthyvolunteers consume more water and drink more frequently in thexerostomic state, which is induced by decreasing saliva in theoral cavity. Because xerostomia (symptoms of oral dryness),which is caused by the reduction of salivary flow, is prevalentamong HD patients (18–23), it is conceivable that thedecreased salivary flow leads to thirst and excess IDWG. Someobservational studies (24,25) have described an associationbetween xerostomia and IDWG in HD patients; however, other knowndipsogenic factors (e.g., blood urea, Ang II, sugar level) werenot controlled in those studies. In addition, no interventionaltrial in the literature indexed by Medline has demonstratedthe impact of the decreased salivary flow on IDWG. Therefore,whether the decreased salivary flow influences fluid intakein HD patients remains undetermined.
We conducted a 3-mo prospective observational study followedby a trial of pilocarpine—a parasympathomimetic agentthat has been shown effectively to increase salivary flow inradiation-induced xerostomia or Sjögren syndrome (26–29)—todetermine whether the reduction of salivary flow contributesto exaggerated thirst and excess IDWG in HD patients and whetherpilocarpine can alleviate it.
The study protocol was approved by ethics committees of NationalCheng 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 fromDecember 2002 to February 2003 on 90 participants who were recruitedfrom a pool of 217 patients who were undergoing HD at the outpatientdialysis unit of the Kuo’s General Hospital. Inclusioncriteria were age older than 18 yr, HD three times weekly forat least 6 mo, daily urine output <200 ml, and stable clinicalconditions including stable dry weight and hematocrit. Exclusioncriteria were hemodynamic instability preventing sufficientultrafiltration, hospitalization within the preceding 3 mo,dementia or terminal diseases, logistic impossibility of investigation,anxiety or depression (which cause xerostomia possibly as aresult of the dysfunction of both brain and salivary glands),use of xerogenic medications (including anticholinergics, antidepressants,antipsychotics, antihistamines, antiparkinsonian agents, anddiuretics), and unwillingness to participate in this study.
The inclusion and exclusion criteria for the interventionaltrial (March to October 2003) were the same as those in theobservational study except that only hyperdipsic patients (IDWG%>2%/d [10]) were included, and patients who were using thexerogenic medications were included when these drugs could bestopped 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 weighedbefore and after each dialysis session. All patients were routinelyasked to disrobe (except for their underwear), remove theirshoes, and put on a clean gown before entering the dialysisunit. The patient was offered two options: to finish his orher meal before starting dialysis or to eat his or her mealwithin 1 h after starting dialysis. After choosing an option,the patient was asked to continue with it throughout the studyperiods. If the patient chose to eat after starting dialysis,then the meal would be weighed to guide the setting of the ultrafiltrationrate. IDWG is defined as the difference between the predialysisweight and the weight at the end of the previous dialysis session,and IDWG% is obtained by dividing IDWG by the patient’starget dry weight. The IDWG was expressed as daily IDWG, dailyIDWG%, IDWG2d, and IDWG3d as indicated. The target dry weightwas determined according to standard clinical criteria (30)and was reviewed continuously by nephrologists. To allow betterassessment of the changes of IDWG, we set the ultrafiltrationrate according to the IDWG in each dialysis session and correctedthe postdialysis body weight to the target dry weight. Becausewe recruited patients with stable dry weight and excluded patientswith hemodynamic instability preventing sufficient ultrafiltration,the target dry weights did not change, and the postdialysisbody weights of the participants were comparable with targetdry weights throughout the study.
Assessment of Xerostomia, Thirst, and Stress of Fluid Restriction
Participants first were asked to respond to two-point categoricalquestions (yes or no) on sensations of xerostomia and thirstduring each study period and then to questions about their sensationsof five xerostomic items (oral dryness, oral comfort, requirementto sip liquid to speak, sleep, and chew and swallow), thirst,and stress of fluid restriction by 100-mm self-rating visualanalog scales (VAS) with the negative and the positive on theleft and right, respectively (e.g., 100 mm = extremely dry).VAS scores of speak, sleep, chew, and swallow were estimatesof the requirement to sip liquid to speak, sleep, chew, andswallow. These VAS questions for xerostomia were identical tothose in two previous Phase III trials that led to the Foodand Drug Administration approval of pilocarpine for treatmentof radiation-induced xerostomia (26,31) and in a multicenterclinical trial of pilocarpine in patients with Sjögrensyndrome (32). A trained investigator, blind to the clinicaldata, administered all questionnaires.
Saliva Collection
The unstimulated salivary flow rate (UWS) and test drug–stimulated(by pilocarpine or placebo) whole salivary flow rates were determinedbefore commencement of HD unless otherwise specified. Participantswere instructed not to eat, drink, smoke, chew gum, or performoral hygiene for at least 60 min before the collection. Wholesaliva was collected for 10 min using an established spittingtechnique (33,34). Test drug–stimulated whole saliva wascollected at 30, 60, and 90 min after stimulation as indicated.The collection volumes were determined gravimetrically (assumingspecific gravity of 1.0), with saliva flow rates expressed inmilliliters per minute. The salivary collection was performedby a trained investigator who was blind to all clinical data.
Study Medications
As pilocarpine tablets were not licensed in Taiwan during thestudy period, 5 mg of pilocarpine OPD solution (1% pilocarpineophthalmic solution; Shionogi Co. Taipei, Taiwan) was used,a dose that is recommended as safe and effective for Sjögrensyndrome (27). The placebo was a 3:7 mixture of normal salineand Milli-Q water. The sodium concentration of the two solutionswas identical, with both administered in fixed doses (10 dropsfour times/d, 30 min before each meal and at bedtime). Ten dropsof pilocarpine OPD solution is equivalent to 5 mg of pilocarpine.
Study Protocol Observational Study.
Age, gender, underlying diseases, HD duration, and the use ofACEI or Ang II receptor antagonists (AIIA) were recorded. Meanvalues of Kt/V, normalized protein catabolic rate (nPCR), dailyIDWG, daily IDWG%, hematocrit, and biochemistry values werecalculated from monthly predialytic data. VAS scores of xerostomiaand thirst and UWS were assessed twice in the study period (middleand end), and the mean values were used for analyses. PlasmaAng II and atrial natriuretic peptide (ANP) levels were determinedat the end of the observational period.
Pilot Study before Clinical Trial.
No previous study has documented the effect of pilocarpine onsalivary flow in HD patients with hyposalivation (UWS < 0.150ml/min [34]); therefore, we performed a pilot study to evaluatewhether pilocarpine could increase salivary flow and the timecourse of its effect in this population. Fifteen patients wererandomly selected from 60 eligible candidates (who were hyperdipsicand were expected to have hyposalivation) of the interventionaltrial, and 15 healthy control subjects were enrolled. The UWSand test drug–stimulated (by pilocarpine or placebo) wholesalivary 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 eitherprotocol 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 randomizationlist technique by numbered containers. A third party that wasnot involved in the conduct of the study generated the allocationsequence, assigned participants to their groups, and maintainedthe test drugs. The sequence was concealed until interventionswere assigned. Pilocarpine and placebo solutions had identicalappearance and packaging, and the participants were blindedas to the test drug. Before entering and at the end of eachtreatment and washout period, laboratory and UWS measurementswere conducted under fasting state, and VAS scores of xerostomia,thirst, and stress of fluid restriction were obtained. The meanIDWG2d and IDWG3d during each study period were calculated,and each participant was queried about possible adverse events.
Figure 1. 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 receivedthe placebo treatment, and 20 who had completed the placebo(2 wk)–washout (3 wk)–pilocarpine (2 wk) protocolreceived pilocarpine treatment (Figure 1). Each treatment lastedfor 3 mo, and clinical data and laboratory measurements weremade before and after each treatment. The UWS and VAS scoresof xerostomia, thirst, and stress of fluid restriction of eachpatient were assessed. The mean IDWG2d and IDWG3d were calculatedin the last study month.
Withdrawal, Outcome Measures, and Sample Size in the Interventional Trial.
Patients were withdrawn when they missed >30% of the dosesof either regimen, experienced severe adverse effects or acuteillness requiring hospitalization, or were unwilling to continue.An adverse event was defined as any clinically significant changein physical signs or symptoms or a significant change in laboratorytest results.
The primary outcomes were changes in the VAS scores of xerostomia,thirst, and stress of fluid restriction; UWS; and mean IDWG2dand IDWG3d in each intervention period. The secondary outcomeswere changes in mean BP, adverse events, and blood test results.
Under the scenario of a two-sided significance level of 0.05and a power of 0.8 (a error of 0.2), a sample size of 52 (26in each group) was found to be sufficient for a t test to detecta standardized effect size of 0.80. We added four more participantsin 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 assessthe correlations between continuous variables. Predictors thatshowed the significance level of 0.15 in the correlation analysesand the known dipsogenic factors (2,3,10) were included in themultiple linear regressions with stepwise selections and therebyto identify factors that were independently associated withVAS thirst score, daily IDWG, and daily IDWG%. The multivariateanalyses were repeated forcing all variables left in the stepwiseselection model, together with gender, the presence of diabetes,use of ACEI or AIIA, nPCR, sodium, potassium, and Ang II levelsinto the final regression model. In the interventional trial,data were expressed as mean ± SEM, and Mann-Whitney Uand Wilcoxon signed-rank tests were applied to evaluate differencesin unpaired and paired continuous variables respectively. 2,Fisher exact, and McNemar tests were applied to evaluate differencesin categorical variables. The ANOVA with baseline and washoutmeasurement model were applied to evaluate the efficacy andcarryover effect of drugs. All statistical analyses were conductedusing the statistical software SAS at the two-tailed significancelevel of 0.05.
Observational Study
Ninety patients (42 men and 48 women) were enrolled in the observationalstudy. The mean age was 57.1 ± 14.3 yr, and patientswere on HD for 51.3 ± 43.6 mo. Causes of the ESRD includedchronic 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 biochemicaldata 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 scorewas 47.1 ± 24.5 mm, which was significantly correlatedwith daily IDWG (r = 0.842, P 0.001) and IDWG% (r = 0.542,P 0.001).
Table 1. Clinical data of 90 HD participants in the observational studya
The correlation coefficients between various predictors andVAS 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), andplasma osmolality and ANP levels in the table because none ofthe correlation coefficients had a P < 0.15, and none wasleft or forced into the final model of multiple linear regressionswith stepwise selections. The VAS xerostomia scores seemed tobe correlated with VAS of thirst, daily IDWG, and IDWG%. Inmultiple regression analyses (Table 3), daily IDWG was independentlyassociated with the nPCR, VAS oral dryness score, and bloodurea nitrogen and hematocrit levels. Daily IDWG% was independentlyassociated with age, VAS oral dryness score, and blood ureanitrogen level. This indicates that xerostomia is an independentdeterminant for IDWG in HD patients.
Table 3. 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 demographicdata of these 45 participants did not differ from those of theother participants (data not shown). The UWS was normal (0.250to 0.500 ml/min [35]) in 13 (29%) participants, and the overallmean was 0.162 ± 0.107 ml/min. Twenty (44%) participantshad hyposalivation (UWS <0.150 ml/min [34]), and 4 (8%) hadno measurable saliva. The UWS was significantly correlated withVAS 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 participantswas correlated with the decreased UWS, which might be a targetof intervention for reducing IDWG.
Figure 2. 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; durationof 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 salivaryflow rate, the rate did not increase to the baseline level ofhealthy control subjects. The time course of the pilocarpine’seffect on the whole salivary flow rate in HD patients was comparableto that in healthy control subjects, and no effect on salivaryflow rate was noted with the placebo treatment. In addition,the predialysis UWS and pilocarpine-stimulated whole salivaryflow rates were significantly greater than those of postdialysisat each time point. This demonstrated that the hydration statuscould affect the salivary flow rate in HD patients.
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 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 assignedto one of the two treatments (Figure 1), and 35 participantswho completed this study period were included in the analyses.After the pilocarpine treatment, we demonstrated a significantimprovement in UWS and the VAS scores of oral dryness, oralcomfort, and speaking, with overall improvements in thirst andstress of fluid restriction. A modest but statistically significantdecrease in IDWG2d (approximately 0.2 kg; P = 0.013) was alsoobserved, but no significant change was found in IDWG3d or bloodtest results (Table 4). A total of 25 patients withdrew duringthis study period, and the reasons for withdrawals and adverseeffects in the remaining 35 participants are presented in Table 5.
Table 5. 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, amongwhom 20 received placebo treatment and 15 received pilocarpinetreatment. There was no significant between-group differencein age, gender, time on HD, and underlying diseases that causedESRD. After 3 mo of pilocarpine treatment, significant improvementswere observed in three of the five xerostomia-related items(oral dryness, oral comfort, and speaking), VAS scores for thirstand 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 inserum sodium. No such effects were observed in the placebo treatmentgroup. Adverse effects were generally of mild or occasionallymoderate severity and mostly appeared within the first severaldays of drug administration and improved within 2 wk. The mostfrequent side effect was sweating (in nine participants [45%]in the pilocarpine treatment group), and other adverse effectsincluded anorexia, dizziness, headache, dyspepsia, and diarrhea.There was no withdrawal in this study period.
To our knowledge, this study is the first report to documentthe impact of decreased salivary flow rate on the thirst andIDWG in HD patients on the basis of both observational and interventionaldata. These findings have an important implication for the careof HD patients because thirst and fluid overload are unsolvedstressors in the daily life of many patients (1–5). Wedemonstrated that pilocarpine treatment increased UWS and reducedboth the subjective feeling of thirst and the objective IDWG.It also led to a modest decrease in the mean arterial BP andan increase in the serum albumin level.
Taiwan has the highest incidence and the second highest prevalenceof dialysis in the world (36). A nationwide survey at the endof 2001 showed that the mean patient age was 56.1 ± 9.8yr 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 comparableto that survey. Xerostomia was reported by 68.9% of the 90 participantsin our observational study, which also agreed with other studies(19,25). Measurement of UWS is the most reliable method forquantifying the salivary function (38), and the mean UWS (0.162± 0.107 ml/min) of our patients was significantly lowerthan the normal reference value of 0.25 to 0.5 ml/min (35).We also found that hyperdipsic patients had extremely low baselineUWS (0.09 ml/min in the pilot study [Figure 3]; 0.11 and 0.09ml/min in each group, respectively, in the interventional trial[Tables 4 and 6]), which was comparable with that of patientswho 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). Theresults suggest a high prevalence of severe salivary gland dysfunctionin HD patients, especially in hyperdipsic ones.
The multivariate analyses in our study revealed that VAS oraldryness score (a xerostomic score) was an independent determinantof thirst, IDWG, and IDWG% in HD patients (Table 3). We alsodemonstrated that the UWS was correlated with several VAS scoresfor xerostomia, daily IDWG, and IDWG%, especially oral drynessscore (Figure 2), suggesting that xerostomia in our participantswas caused by the decreased UWS, which is in agreement withother studies showing that uremic xerostomic symptoms are associatedwith salivary gland dysfunction (18–20). These observationaldata strongly suggested that decreased salivary flow might contributeto IDWG, and the subsequent pilocarpine interventional trialfurther confirmed the dipsogenic effect of decreased salivaflow. Whereas pilocarpine has a weak central dipsogenic effect(17,41), it is unlikely that pilocarpine reduces IDWG by directlyinhibiting the thirst center. The results of this study agreewith previous physiologic researches (17,42,43), suggestingan oropharyngeal factor that influences drinking. Ramsay etal. (42) found that dehydrated dogs drank water rapidly butstopped well before normal blood osmolality was restored. Thisearly inhibition of thirst (and vasopressin secretion) occurredeven when the water was drained from the stomach through a gastricfistula to prevent rehydration. These observations suggest neuralinputs from the oropharynx to the brain that allowed dogs toregulate their drinking volume (42). This phenomenon has beenconfirmed in humans by Figaro et al. (43). Brunstrom et al.(17) induced a xerostomic state by placing two absorbent rollsin each cheek to reduce salivary flow and confirm that decreasedsalivary flow may cause more fluid intake in healthy volunteers.Our study further demonstrated that the magnitude of decreasedsalivary flow rate was sufficient to cause exaggerated thirstand large IDWG in hyperdipsic HD patients.
The mechanism of salivary gland dysfunction in HD patients isunknown; however, some researchers (18,19) have proposed thatit is caused by dehydration and direct uremic injury. In normalindividuals, there is a relationship between the salivary flowrate and body hydration, and the UWS is larger in well-hydratedstatus than that in dehydrated status (33–35). This relationshipis maintained in dialysis patients and can be demonstrated byFigure 3, which shows that the predialysis UWS and pilocarpine-stimulatedwhole salivary flow rates were significantly greater—butmodest—than those of the postdialysis period in each correspondingtime point. In HD patients with persistent large IDWG, it ispossible that large IDWG increases UWS initially; however, largeIDWG also leads to large ultrafiltration in dialysis session;it thus compromises the tissue perfusion and causes damage ofsalivary glands. In such a condition, the UWS will decreasewith time, and the effect of hydration to increase UWS may beattenuated subsequently. Because low UWS further increases fluidintake, the hyperdipsic HD patients will have lower UWS eventually.In addition, Bots et al. (25) argued that salivary glands maintaintheir secretory capacity because they observed a remarkabledifference between UWS and chewing-stimulated whole salivaryflow. In our trial, however, pilocarpine treatment only modestlyincreased the salivary flow rate. Noteworthy, any mechanicalstimulation would increase the fluid from a nonsalivary glandsource, such as gingival crevicular fluid, and might interferewith the interpretation of salivary function tests (18,44).Recent studies (20,45) demonstrated that the uremic salivarydysfunction is associated with glandular atrophy, fibrosis,and accumulation of fibrillar components, which suggest thaturemic salivary dysfunction is not only a functional disturbancebut also an organic change.
Pilocarpine exerts its effect through cholinergic stimulationof saliva from residual salivary gland tissues, and an increaseof a relatively modest amount of saliva seems to be sufficientto overcome the xerostomia (40). Although pilocarpine alleviatedthe subjective feeling of xerostomia, thirst, and the stressof fluid restriction in our 2-wk interventional trial period,the objective reduction in IDWG was minimal; it took 8 to 12wk to demonstrate a significant reduction in IDWG. As xerostomiadevelops insidiously (27–29,40) and fluid intake is amild form of addiction (14–16), the delay in the reductionof IDWG is reasonable. This suggests that prolonged pilocarpinetreatment is required to see benefits in IDWG. A 2-wk crossoverstudy of Bots et al. (46) evaluated the effect of chewing gumor saliva substitute on thirst, xerostomia, and IDWG and foundno change in IDWG. The 2-wk period might be too short, and theinclusion of both hyperdipsic and nonhyperdipsic patients mightmake the effect of deceasing IDWG difficult to demonstrate.Furthermore, other researchers have demonstrated that salivasubstitutes and chewing gum were generally ineffective in treatingxerostomia caused by a variety of diseases, including Sjögrensyndrome, radiation treatment, and idiopathic salivary glanddysfunction (26–28,40,47). In addition, gustatory andmasticatory stimulation have only short effect, and their long-termuse may irritate the oral tissue (13,40). Our long-term pilocarpinetrial also showed a modest increase in albumin level and a reductionin mean BP. The increase of serum albumin might be due to achange of appetite after alleviation of xerostomia, and theBP change might be secondary to the decrease in IDWG. Althoughpilocarpine has a parasympathetic effect, previous studies didnot observe an antihypertensive property (26–29). Furthermore,pilocarpine tended to increased serum sodium, suggesting thatfluid intake, rather than salt, was influenced.
The dryness symptoms that are experienced by HD patients possiblyare not restricted to the oral cavity but also involve the wholebody. General exocrine gland dysfunction has been describedin HD patients, including the reduced acid secretion, impairedpeptic secretion, dry eyes, and cutaneous xerosis (20,48–50).The pharmacologic properties of pilocarpine suggest that itcan stimulate exocrine gland secretion in other organ systemsbesides the oral cavity. Although we did not assess effectsof pilocarpine on extra-oral sicca symptoms in this study, previousresearch has shown its beneficial effects on extra-oral symptomsin patients with Sjögren syndrome, including dry eyes,nasal dryness, dry skin, vaginitis sicca, and the inabilityto expectorate (27,28). It will be intriguing to assess extra-oraleffects in further studies.
The most prevalent pilocarpine-related adverse effects in ourstudy included sweating, vomiting, and diarrhea (Table 5). Despitethe high incidence of sweating, this and other adverse effectswere perceived as minor by most patients and improved within2 wk. The withdrawal rate as a result of pilocarpine-relatedadverse effects was 15.3% (8 of 52) in this trial. Approximately34.6% (18 of 52) of participants experienced a mild bitter tasteduring pilocarpine treatment, whereas 9.8% (5 of 51) of participantshad the same perception during placebo treatment. However, thishad no impact on the single-blind design of our study. Eachparticipant was told that we would provide two solutions forxerostomia, and although to some participants the pilocarpinesolution tasted a little bitter, they did not know which ofthe solutions contained the pilocarpine during the study period.
There were several limitations to our interventional trial.Although long-term effectiveness and safety of pilocarpine treatmentfor radiation-induced xerostomia (26,31) and Sjögren syndrome(32) have been documented, those of this treatment in HD patientshave not been established in our study because of the smallsample size and short duration. In addition, only clinicallystable patients were enrolled in our study; therefore, it remainsuncertain whether our findings can be generalized to individualswith multiple concurrent diseases. In addition, a portion ofthe patients complained of inconvenience and the bitter tasteof the pilocarpine solution, and it is reasonable to speculatethat tablets will improve compliance and eliminate unfavorabletaste.
In conclusion, our study clearly demonstrated the dipsogeniceffect of decreased salivary flow in HD patients. In the 3-moclinical trial, pilocarpine significantly alleviated the exaggeratedthirst and large IDWG of hyperdipsic HD patients. On the basisof these findings, we suggest that pilocarpine could serve asa 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 HospitalResearch Committee research grants NCKUH-2003-05 and NCKUH-2004-63.
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Received for publication April 3, 2005.
Accepted for publication July 26, 2005.
This article has been cited by other articles:
J.-M. Sung, S.-C. Kuo, H.-R. Guo, S.-F. Chuang, S.-Y. Lee, and J.-J. Huang The role of oral dryness in interdialytic weight gain by diabetic and non-diabetic haemodialysis patients
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[Abstract][Full Text][PDF]
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Abstract
Introduction
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. 
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. 
2, 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. 
