Low-dose oral desmopressin for treatment of nocturia and nocturnal enuresis in patients after radical cystectomy and orthotopic urinary diversion Hanan Goldberg*†, Jack Baniel*†, Roy Mano*†, Gabriel Gillon*†, Daniel Kedar*† and Ofer Yossepowitch*† *Institute of Urology, Rabin Medical Center, Petach Tikva, †Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Objectives To assess the effect of oral desmopressin on nocturia and nocturnal enuresis in patients after orthotopic neobladder reconstruction.
Patients and Methods Of 55 patients who underwent radical cystectomy and orthotopic neobladder reconstruction at our medical centre in the period 2004–2011, 34 patients were deemed eligible for the present study. Inclusion criteria were estimated glomerular filtration rate >50 mL/min/1.73 m2, normal baseline sodium serum level, intact daytime urinary continence, and any degree of nocturia or nocturnal enuresis. Patients were treated daily with oral desmopressin 0.1 mg at bedtime for 30 days and completed the Nocturia, Nocturnal Enuresis and Sleep Interruption Questionnaire at trial enrolment and closure. Sodium serum levels were monitored throughout.
Results Three patients withdrew from the trial because of headaches or anxiety. The mean (SD) number of nocturnal voids
Introduction Over the past two decades, orthotopic neobladder reconstruction has gained wide popularity as a standard form of urinary diversion after radical cystectomy [1]. Advances in surgical technique and growing experience have resulted in reduced morbidity and improved oncological and functional outcomes [1]. The purported advantage of bladder substitution over non-continent urinary diversion is an improved quality of life [2]. The recovery of urinary continence, considered one of the major determinants of patient satisfaction [3], is therefore critical. Diurnal urinary continence is achieved in nearly all patients with neobladders [4]; however, despite the attainment of low-pressure, large-capacity and highly compliant reservoirs, nocturia and © 2013 The Authors BJU International © 2013 BJU International | doi:10.1111/bju.12598 Published by John Wiley & Sons Ltd. www.bjui.org
decreased from 2.5 (1.4)/night at baseline to 1.5 (1.3)/night at trial closure (P = 0.015). The number of patients with one or no episodes of nocturnal enuresis per week increased from six to 12 (19 to 39%; P = 0.065). Thirteen patients (42%) reported an increase of a minimum 1–2 h of sleep until the first nocturnal void; all of them asked to continue the drug. No significant adverse events or changes in sodium level were observed.
Conclusions Bedtime treatment with low-dose oral desmopressin appears to decrease episodes of nocturia and nocturnal enuresis effectively and safely in ∼50% of the patients with neobladder, allowing longer undisrupted sleep time and improved quality of life. Further investigation is warranted to determine if higher doses would result in a more meaningful clinical response.
Keywords desmopressin, nocturia, nocturnal enuresis, NNES-Q
nocturnal enuresis remain highly prevalent, affecting up to 66% of patients with all forms of neobladders [5–7]. Several solutions have been proposed to reduce the number of nocturnal voids and night-time urinary leakage in patients with a neobladder. In addition to behavioural measures such as nocturnal ‘dehydration’ and preemptive voiding immediately before going to bed, some patients set an alarm clock and void at predetermined intervals, thereby preventing overfilling of the reservoir which often culminates in enuresis [8]. Others use diapers or urinary condoms at night so they can maintain undisrupted sleep. Regardless of the preferred method of management of nocturia and nocturnal enuresis, both have a detrimental impact on quality of life [9].
BJU Int 2014; 114: 727–732 wileyonlinelibrary.com
Goldberg et al.
The antidiuretic hormone arginine vasopressin plays a major role in controlling the volume of urine. Desmopressin is a synthetic analogue of vasopressin with established efficacy in the treatment of diabetes insipidus and idiopathic nocturnal enuresis in children [10,11]. Recently, studies have also found it effective for the management of nocturia and nocturnal incontinence in adult men and women [12–15]. We hypothesized that bedtime treatment with oral desmopressin in patients with neobladder could reduce the night-time urine volume, thereby decreasing the number of nocturnal voids and enuresis and potentially improving quality of life. The aim of the present study was to assess the effect of oral desmopressin on nocturia and nocturnal enuresis in this specific patient population.
Patients and Methods The study was conducted at a tertiary medical centre and registered on the US National Institute of Health website (ClinicalTrials.gov identifier NCT01582542). The bladder cancer registry of the Department of Urology was searched for all living patients who underwent radical cystectomy with orthotopic neobladder reconstruction in the period 2004–2011. Inclusion criteria for the study were estimated GFR >50 mL/min/1.73 m2 (calculated by the Modification of Diet in Renal Disease study equation [16]); normal baseline sodium serum level, diurnal urinary continence, any degree of nocturia or nocturnal enuresis, no known allergy to desmopressin, and ability to provide informed consent. We received institutional review board approval to administer low-dose desmopressin to participants aged ≥65 years, provided strict monitoring of serum sodium levels was confirmed. At initiation of the trial, a complete medical history was obtained for all study participants, including comorbidities, follow-up data, neoadjuvant and adjuvant chemotherapy, and current disease status. Treatment consisted of once daily oral desmopressin 0.1 mg at bedtime for a consecutive period of 30 days. In addition, patients completed the validated Nocturia, Nocturnal Enuresis and Sleep-Interruption Questionnaire (NNES-Q) at trial entrance and closure. The NNES-Q comprises 12 questions pertaining to nocturia, enuresis, sleep interruption, treatment and physical functioning within the preceding 4 weeks [17–19]. It is used to measure the number of voiding episodes per night and frequency of enuresis and to assess the impact of nocturia, enuresis and sleep interruption on quality of life on the basis of a ‘bother’ scale, rated from 0 (no bother at all) to 10 (maximum bother). Sodium serum levels were monitored throughout the study at three specific time points: trial entrance, 15 days after initiation of the medication and trial closure. All patients were given oral and written instructions regarding the proper administration of desmopressin and the importance of timely sodium monitoring and immediate reporting of any adverse event.
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© 2013 The Authors BJU International © 2013 BJU International
Specifically, patients were asked to pay particular attention to new-onset headaches as an early indicator of hyponatraemia. Descriptive statistics (range, median, mean and SD values) were calculated for continuous variables, and ANOVA was used for comparative tests. All analyses were performed using SPSS software version 19.0 (SPSS Inc., Chicago, IL, USA). The level of statistical significance was set at 5%.
Results Of the 55 living patients who underwent radical cystectomy and orthotopic neobladder reconstruction at our hospital in the period 2004–2011, 18 were ineligible for the study. The main reason for exclusion was impaired renal function (estimated GFR >50 mL/min/1.73 m2). Thirty-four of the remaining 37 eligible patients (92%) agreed to participate. They included 32 men (94%) and two women (6%) whose median (range) age was 64 (45–76) years. Three patients (9%) withdrew before completing the trial because of headaches which they attributed to desmopressin (n = 2) or anxiety (n = 1). Out of the 34 patients participating in the trial, 31 (91%) had no evidence of disease at last follow-up, while three (9%) were alive with disease, but none with disease involving the urethra. The mean (SD) time from surgery to the present study was 35.4 (34.2) months. The mean (SD) age-adjusted Charlson comorbidity index score was 4 (1.2). All demographic and basic surgical data are shown in Table 1. Analysis of the NNES-Q results before initiation of antidiuretic therapy showed that 13% of patients never/rarely had nocturia, 16% regularly had 1 void/night, 19% had 2 voids/night, 26% had 3 voids/night and 26% had ≥4 voids/night. After 30 consecutive days of desmopressin Table 1 Basic patient demographics and surgical data. Characteristic Median (range) age, years Sex, n (%) Male Female Mean (SD) age-adjusted Charlson comorbidity index score, Neoadjuvant therapy, n (%) Type of neobladder, n (%) Ileal Ileocolonic Adjuvant therapy, n (%) Median (range) time from surgery to enrolment, months No. patients
Objectives To assess the effect of oral desmopressin on nocturia and nocturnal enuresis in patients after orthotopic neobladder reconstruction.
Patients and Methods Of 55 patients who underwent radical cystectomy and orthotopic neobladder reconstruction at our medical centre in the period 2004–2011, 34 patients were deemed eligible for the present study. Inclusion criteria were estimated glomerular filtration rate >50 mL/min/1.73 m2, normal baseline sodium serum level, intact daytime urinary continence, and any degree of nocturia or nocturnal enuresis. Patients were treated daily with oral desmopressin 0.1 mg at bedtime for 30 days and completed the Nocturia, Nocturnal Enuresis and Sleep Interruption Questionnaire at trial enrolment and closure. Sodium serum levels were monitored throughout.
Results Three patients withdrew from the trial because of headaches or anxiety. The mean (SD) number of nocturnal voids
Introduction Over the past two decades, orthotopic neobladder reconstruction has gained wide popularity as a standard form of urinary diversion after radical cystectomy [1]. Advances in surgical technique and growing experience have resulted in reduced morbidity and improved oncological and functional outcomes [1]. The purported advantage of bladder substitution over non-continent urinary diversion is an improved quality of life [2]. The recovery of urinary continence, considered one of the major determinants of patient satisfaction [3], is therefore critical. Diurnal urinary continence is achieved in nearly all patients with neobladders [4]; however, despite the attainment of low-pressure, large-capacity and highly compliant reservoirs, nocturia and © 2013 The Authors BJU International © 2013 BJU International | doi:10.1111/bju.12598 Published by John Wiley & Sons Ltd. www.bjui.org
decreased from 2.5 (1.4)/night at baseline to 1.5 (1.3)/night at trial closure (P = 0.015). The number of patients with one or no episodes of nocturnal enuresis per week increased from six to 12 (19 to 39%; P = 0.065). Thirteen patients (42%) reported an increase of a minimum 1–2 h of sleep until the first nocturnal void; all of them asked to continue the drug. No significant adverse events or changes in sodium level were observed.
Conclusions Bedtime treatment with low-dose oral desmopressin appears to decrease episodes of nocturia and nocturnal enuresis effectively and safely in ∼50% of the patients with neobladder, allowing longer undisrupted sleep time and improved quality of life. Further investigation is warranted to determine if higher doses would result in a more meaningful clinical response.
Keywords desmopressin, nocturia, nocturnal enuresis, NNES-Q
nocturnal enuresis remain highly prevalent, affecting up to 66% of patients with all forms of neobladders [5–7]. Several solutions have been proposed to reduce the number of nocturnal voids and night-time urinary leakage in patients with a neobladder. In addition to behavioural measures such as nocturnal ‘dehydration’ and preemptive voiding immediately before going to bed, some patients set an alarm clock and void at predetermined intervals, thereby preventing overfilling of the reservoir which often culminates in enuresis [8]. Others use diapers or urinary condoms at night so they can maintain undisrupted sleep. Regardless of the preferred method of management of nocturia and nocturnal enuresis, both have a detrimental impact on quality of life [9].
BJU Int 2014; 114: 727–732 wileyonlinelibrary.com
Goldberg et al.
The antidiuretic hormone arginine vasopressin plays a major role in controlling the volume of urine. Desmopressin is a synthetic analogue of vasopressin with established efficacy in the treatment of diabetes insipidus and idiopathic nocturnal enuresis in children [10,11]. Recently, studies have also found it effective for the management of nocturia and nocturnal incontinence in adult men and women [12–15]. We hypothesized that bedtime treatment with oral desmopressin in patients with neobladder could reduce the night-time urine volume, thereby decreasing the number of nocturnal voids and enuresis and potentially improving quality of life. The aim of the present study was to assess the effect of oral desmopressin on nocturia and nocturnal enuresis in this specific patient population.
Patients and Methods The study was conducted at a tertiary medical centre and registered on the US National Institute of Health website (ClinicalTrials.gov identifier NCT01582542). The bladder cancer registry of the Department of Urology was searched for all living patients who underwent radical cystectomy with orthotopic neobladder reconstruction in the period 2004–2011. Inclusion criteria for the study were estimated GFR >50 mL/min/1.73 m2 (calculated by the Modification of Diet in Renal Disease study equation [16]); normal baseline sodium serum level, diurnal urinary continence, any degree of nocturia or nocturnal enuresis, no known allergy to desmopressin, and ability to provide informed consent. We received institutional review board approval to administer low-dose desmopressin to participants aged ≥65 years, provided strict monitoring of serum sodium levels was confirmed. At initiation of the trial, a complete medical history was obtained for all study participants, including comorbidities, follow-up data, neoadjuvant and adjuvant chemotherapy, and current disease status. Treatment consisted of once daily oral desmopressin 0.1 mg at bedtime for a consecutive period of 30 days. In addition, patients completed the validated Nocturia, Nocturnal Enuresis and Sleep-Interruption Questionnaire (NNES-Q) at trial entrance and closure. The NNES-Q comprises 12 questions pertaining to nocturia, enuresis, sleep interruption, treatment and physical functioning within the preceding 4 weeks [17–19]. It is used to measure the number of voiding episodes per night and frequency of enuresis and to assess the impact of nocturia, enuresis and sleep interruption on quality of life on the basis of a ‘bother’ scale, rated from 0 (no bother at all) to 10 (maximum bother). Sodium serum levels were monitored throughout the study at three specific time points: trial entrance, 15 days after initiation of the medication and trial closure. All patients were given oral and written instructions regarding the proper administration of desmopressin and the importance of timely sodium monitoring and immediate reporting of any adverse event.
728
© 2013 The Authors BJU International © 2013 BJU International
Specifically, patients were asked to pay particular attention to new-onset headaches as an early indicator of hyponatraemia. Descriptive statistics (range, median, mean and SD values) were calculated for continuous variables, and ANOVA was used for comparative tests. All analyses were performed using SPSS software version 19.0 (SPSS Inc., Chicago, IL, USA). The level of statistical significance was set at 5%.
Results Of the 55 living patients who underwent radical cystectomy and orthotopic neobladder reconstruction at our hospital in the period 2004–2011, 18 were ineligible for the study. The main reason for exclusion was impaired renal function (estimated GFR >50 mL/min/1.73 m2). Thirty-four of the remaining 37 eligible patients (92%) agreed to participate. They included 32 men (94%) and two women (6%) whose median (range) age was 64 (45–76) years. Three patients (9%) withdrew before completing the trial because of headaches which they attributed to desmopressin (n = 2) or anxiety (n = 1). Out of the 34 patients participating in the trial, 31 (91%) had no evidence of disease at last follow-up, while three (9%) were alive with disease, but none with disease involving the urethra. The mean (SD) time from surgery to the present study was 35.4 (34.2) months. The mean (SD) age-adjusted Charlson comorbidity index score was 4 (1.2). All demographic and basic surgical data are shown in Table 1. Analysis of the NNES-Q results before initiation of antidiuretic therapy showed that 13% of patients never/rarely had nocturia, 16% regularly had 1 void/night, 19% had 2 voids/night, 26% had 3 voids/night and 26% had ≥4 voids/night. After 30 consecutive days of desmopressin Table 1 Basic patient demographics and surgical data. Characteristic Median (range) age, years Sex, n (%) Male Female Mean (SD) age-adjusted Charlson comorbidity index score, Neoadjuvant therapy, n (%) Type of neobladder, n (%) Ileal Ileocolonic Adjuvant therapy, n (%) Median (range) time from surgery to enrolment, months No. patients
