Post-TURP nocturia remains common. Desmopressin-oral-lyophilisate(“DOL”)  emerges to be the treatment of choice for nocturia with or without nocturnal polyuria (1). We reported the dynamics of the anti-diuretic action(ADA) of low dose DOL-60µg based on the variation of hourly nocturnal urinary production rate(HNUPR) across bedtime in comparison with the placebo

A  prospective, randomized, double blind, placebo-controlled trial(RCT) was conducted to study the clinical action of “DOL” in treating men bothered by nocturia (≥2/night) after transurethral prostate surgery(TURP) for LUTS or acute urinary retention(AUR). 

72 post-TURP men {mean-value[SD](range): Age: 69.52[4.21](57-75); IPSS: 14.28[7.83](2-33);  Nocturia(by bladder-diary): 3.56[0.88](2-7); Weight(kg): 66.99[9.10](47-93); BMI: 24.41[2.69](16.85-29.74); Qmax(ml/sec): 15.38[7.84](5-38); Voided-volume(ml): 267[152.58](40-831); PVR(ml): 50.5[60.58](0-292)} were recruited.  

They were then randomized to receive either DOL-60µg(N=37) or placebo(N=35) sublingually 60 min before bedtime nightly for 4 weeks.  They emptied their bladders before sleep and thoroughly fill out a bladder/sleep diary similar to “International Consultation on Incontinence Questionnaire(ICIQ)-bladder-diary” (2) for 4 consecutive days before and in the last 4 days of the study. 

The HNUPR was derived from “{volume of voided urine divided by time elapsed between 2 voidings(ml/hour). Its variation across the bedtime was compared between treatment-group and placebo-group for each hour spanning from one hour before sleep to 8 hours into sleep, based on the bladder&sleep diary data, to evaluate the ADA of DOL before and after the treatment.  

Adjusted changes of parameters of nocturia, duration of initial undisturbed sleep(DIUDS), time to first nocturia(TT1stNocturia) and hyponatraemia issues were also reported.

Continuous data were expressed as median(range) or mean(SD) and compared with Mann-Whitney-U test/Student’s test, where appropriate. Categorical variables were expressed as number of patients(percentage) and compared between the groups using Pearson’s χ2-test. Two-way repeated measures-ANOVA was performed to compare the HNUPR between the treatment-group and placebo-group across bedtime for all subjects and sub-groups stratified by mean age( ≤70/>70) /mean body weight(≤67kg/>67kg) / nocturnal polyuria index(Npi)(≤0.33/>0.33}.  Statistical significance was taken at p<0.05.

The demographics and baseline characteristics were tabulated in table 1. 

43(59.7%) men had nocturnal polyuria (NP). 

41(57%) subjects had hypertension(HT) and 31(76% of HT subjects) received amlodipine. HT subjects passed more nocturnal urine (800ml vs 580ml, p=0.006). Subjects receiving amlodipine had  increased their HNUPR in the initial 5 hours across bedtime, resulting in higher rate of diuresis before the first nocturia (2.24 ml/min vs 1.72 ml/min, p=0.06) when compared to subjects not taking amlodipine.
 
33(45.8%), 10(13.9%), 10(13.9%), 10(13.9%) and 9(12.5%) subjects had Npi>0.33 alone, Nocturnal Bladder Capacity Index (NBCi)>2 alone, both Npi>0.33+NBCi>2, mixed aetiology and global polyuria alone respectively to account for their nocturia based on bladder diary results. 

The baseline mean (SD) values for nocturia/night, maximal voided volume(MVV)(ml), DIUDS(min), TT1stNocturia(min) were 3.6(0.87), 400(170), 119.98(55.67), 148.52(58.13), respectively.
 
Pre-treatment HNUPR across bedtime did not differ between the two comparison groups (treatment / placebo) (Fig 2a) whereas its level was higher in men taking amlodipine than those not taking in the initial 5 hours across bedtime(p<0.05) [Fig not shown].

24-hour urine output was reduced similarly between the 2 comparison groups at end of study[∆=-16%(placebo) vs ∆=-14%(treatment), p=0.791].
 
As for placebo-group, its pre-treatment HNUPR sharply increased in the first two hours of sleep(∆28.5%, p<0.05) and sustained for another two hours before returning to pre-bedtime level(Fig 2a). Similar degree of nocturnal diuresis still persisted in the first 2 hours of sleep after 4-week study (Fig 2b) despite significant reduction of 24-hour and volume of nocturnal urine production across bedtime [∆Urine Output24hour= -278ml (p<0.05) and ∆VolNUPbedtime= -141ml (p<0.05) respectively]. Of note, the post-study HNUPR fell below its pre-study level from 3rd hour to 6th hour across bedtime, concluded by overall significant decrease of the volume of nocturnal urine production across bedtime (∆VolNUPbedtime = -141ml/night). 
 
In contrast, DOL-60µg additionally reduced the HNUPR by 40ml (p<0.01), 27ml (p<0.01), 17ml (p<0.05) in the 1st, 2nd and 3rd hour after sleep respectively [Fig 2(b)], together with significant decrease of HNUPR before the first nocturia (adjusted difference ∆HNUPR@1stNocturia: -0.661ml/min, p=0.001). This suppression of HNUPR sustained longer in men ≤67kg/>70yo than in men >67kg/≤70yo (3 hours vs 1 hour, p<0.05) [Fig 2(c)&(d)]; in men whose Npi ≤0.33 than in men whose Npi >0.33 (4 hours vs 1 hour,p<0.05) [Fig 2(e)&(f)]. However, the maximal magnitude of suppression of HNUPR by DOL did not differ between men ≤70yo and >70yo [Fig 2(g)&(h)]. 

The post-treatment nocturia episodes significantly decreased in both groups [DOL-60µg: -0.987 vs placebo: -0.533] yet more remarkable in the treatment-group [adjusted difference ∆Nocturia:  -0.454, 13.3% lower, p=0.025], which gained significant increment in DIUDS, [adjusted ∆DIUDS: +30.08min, 25.9% higher, p=0.05] and in TT1stNocturia [adjusted ∆TT1stNocturia: +68.78min (46.2% longer, p<0.001)]. However, the duration of the total sleeping time did not differ between the two groups (p=0.257). 

Serum [Na]≤135mmo/L was reported in 6 (16.2%) men(mean age 73, range:71-75) in the treatment-group; none in the placebo-group. Three (8.1%) men (mean age:73.3, range:71-75) had significant degree of hyponatraemia {s[Na]≤130mmol/L}. One (2.7%) man aged 74 had severe hyponatraemia {s[Na]=124mmol/L} reported on day 21 post-randomization. Two (5.4%) severe adverse events (SAEs) were reported; one (2.7%) subject with severe hyponatraemia, one (2.7%) placebo-group subject was admitted to the orthopaedic ward for accidental fall unrelated to the placebo.

Nocturia is highly associated with HT(57% of all subjects) to which the first-line treatment is Amlodipine(76% of HT-subjects)(3), which was noted to have lengthily elevated HNUPR to >60% bedtime from its beginning. 

We observed that post-treatment 24-hour urine output in all our subjects decreased by ~15%,  inferring that they had already reduced their daily fluid intake across the study period to alleviate their nocturia/NP. However, the nearly unchanged time lag between retiring to bed and the deceleration of HNUPR in the first half of bedtime suggested that fluid restriction(FR) alone reduced the VolNUPbedtime mainly in the latter half of sleep, being more pronounced in men <67kg [placebo-group, Fig2(b&c)]. FR probably did not lengthen TT1stNocturia sufficiently enough for the purpose of improvement of sleep, which in contrast may be realized by treatment with low-dose DOL-60µg.

We showed the pharmacodynamics ADA of DOL-60μg (3h, p<0.01) based on HNUPR derived from the ICIQ-bladder-diary without the need of measuring urine osmolality [Fig2(b)]. Our fixed, low-dose regime might bring more benefit to the light-weighted men (≤67kg) in the reversal of nocturnal over-diuresis. Light-weighted men could achieve longer (3 hours vs 1 hour) yet similar magnitude of ADA (ΔHNUPR~40ml/hour) as compared to men >67kg. 

In contrast, ADA of DOL-60µg waned off more rapidly from 4 hours to 1 hour in subjects <70y.o. and of Npi>0.33 respectively [Fig2(f)&2(g)], even though the maximal magnitude of their ADA remained the same (i.e. ∆HNUPR ~ - 40 ml/hour). We also observed that ADA lasted longer in men ≥70y.o (3 hours with max. ∆HNUPR:~ -40 ml/hour), implicating that even low-dose regime can still predispose elderly men to hyponatraemia. Indeed, all subjects who had hyponatraemia were >70y.o. in our study (men who need TURP are usually of advanced age), limiting the use of higher dosage of DOL in treating post-TURP nocturia.

HNUPR, derived from ICIQ-bladder-diary, is a plausible parameter to study the ADA of DOL. FR(∆= -16%) alone failed to reduce VolNUPbedtime in the first-half of sleep, which in contrast could be observed by additional treatment with  DOL-60µg, with its effect more pronounced in men >70yo., ≤67kg and Npi ≤0.33. However, this low-dose regime could still cause prevalent and significant hyponatraemia for post-TURP men >70y.o.

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