on 28-Jul-2024 (Sun)

Nocturia is a common symptom rather than a disease and is defined as waking at night to void, where each micturition is preceded and followed by sleep [1]. Nocturia is likely clinically meaningful if a patient voids two or more times nightly [2].

New-onset adult nocturnal urinary incontinence or nighttime bed-wetting (enuresis) is distinct from nocturia and likely requires a different approach focusing on sleep problems or urinary obstruction [3,4].

In adults with no daytime symptoms or past history of pediatric bed-wetting enuresis, consideration should be given to causes of nocturnal syncope, including seizures or arrhythmia [ 5,6].

Approximately 50 percent of adults between the ages of 50 to 79 have nocturia. Symptoms are occasional among those aged 50 to 59 years, and estimated as at least twice nightly among men between 70 and 79 [8].

Many, but not all women with nocturia also have other urinary tract symptoms (eg, overactive bladder syndrome or polyuria) [7,12,14].

While pregnant women commonly have nocturia, it nearly always resolves by three months postpartum [ 15].

modifiable conditions that likely cause nocturia include obesity, uncontrolled hypertension, poorly controlled diabetes, restless leg syndrome and periodic limb movements, obstructive sleep apnea (OSA), gastroesophageal reflux [16], benign prostatic hyperplasia (BPH), and congestive heart failure [17-21].

Nocturia is associated with increased rates of depression [17], work absenteeism [30], and lower self-rated physical and mental health [18]. In older patients, it is associated with higher rates of accidental falls [31-33] and subsequent fractures [34,35].

Nocturia can be attributed to any disorder or condition (table 1) that causes one of the following [36,37]:

● Low-volume bladder voiding

● Increased volume of nighttime urinary output

● Sleep disturbance

Low-volume bladder voids — Low-volume voids may be due to either reduced bladder capacity or impaired bladder function. The two most common causes of low-volume bladder voids are an overactive bladder and bladder outlet obstruction, often related to benign prostatic hypertrophy (BPH). Reduced bladder volume is common in older patients, likely due to age-related changes in the bladder or detrusor hyperactivity [38,39].

Increased nighttime urinary volume — An increase in urinary volume at night may be due to a higher percentage of the total daily urine output being excreted at night (nocturnal polyuria) or an increase in the total 24-hour urine output (polyuria).

Nocturnal polyuria — The normal physiologic pattern of urination is a decrease in nighttime, relative to daytime, urine output. Overproduction of urine at night, with a normal 24-hour urine output, is called nocturnal polyuria [40]. It is defined as a urine volume during sleep greater than 33 percent of the 24-hour urine volume [41]. Causes include:

● Decrease in arginine vasopressin – There is a normal diurnal periodicity in arginine vasopressin (AVP), with higher AVP plasma levels in the evening leading to decreased nighttime urine output [42]. However, this diurnal variation is absent in many older subjects and likely contributes to age-related increases in nocturia. [43,44]

There are also age-related changes in the action of AVP [45,46]. AVP, a peptide hormone secreted by the neurohypophyseal system, is released when plasma osmolality is increased or blood pressure has decreased (as seen with orthostasis, vasodilation, or significant blood loss). AVP targets receptors in the renal distal tubules to increase urine concentration.

● Heart failure or other edematous states (nephrotic syndrome and venous insufficiency) cause interstitial edema. Assumption of the supine position permits mobilization of some of the edema fluid into the vascular space and leads to a solute diuresis.

Polyuria — Global polyuria is defined as a 24-hour urine volume that exceeds 3 liters per day (or 40 mL per kg) and is mainly caused by a water diuresis. Solute-induced polyuria is rare and mainly seen in the inpatient setting following a high-solute load (eg, enteral or parental feedings) or following relief of urinary obstruction [47]. Causes of polyuria seen in the outpatient setting include uncontrolled diabetes mellitus, arginine vasopressin disorders, and primary polydipsia.

Sleep disorders — Nocturia is the most frequently cited cause of poor sleep quality and insomnia in older adults, and it is a common feature in patients with obstructive sleep apnea (OSA) [48-51].

OSA may cause nocturnal polyuria by release of atrial natriuretic peptide (ANP) due to negative intrathoracic pressure and stretching of the myocardium [52]. ANP release causes vasodilation and inhibits aldosterone, resulting in increased sodium and water excretion. Continuous positive airway pressure can result in significant reductions in ANP levels, nighttime urine volume, and in nocturia episodes in patients with OSA [53-56].

In addition, patients with other primary sleep problems (restless leg syndrome, and periodic limb movements at night) may awaken due to sleep disturbance but recall this as an awakening to void [57]. Some nocturia treatment strategies target sleep disturbance directly. (See 'Sleep disorder medications' below.)

Symptoms are usually gradual in onset and have variable night-to-night occurrence.

Occasionally, nocturia can be an indicator of worsening of an underlying disease, such as chronic kidney disease [58], lithium toxicity [59], diabetes mellitus, or congestive heart failure.

Summary of important diagnostic considerations in the evaluation of the patient with nocturia

Element	Specific aspect	Rationale
History	Review of medical history	Heart failure, diabetes mellitus, hypertension, obstructive sleep apnea, and peripheral edema particularly relevant; narrow angle glaucoma is a contraindication for bladder relaxant therapy
Fluid intake	Evaluation for excessive fluid intake (psychogenic polydypsia, health belief)
Medications, especially for diuretics	Late afternoon or evening diuretic use may cause nocturia
Sleep and related conditions	Information about nighttime pain, depression, or insomnia or difficulty with sleep maintenance is important
Dizziness, low blood pressure or orthostasis, or history of accidental falls	May be a contraindication for nonselective alpha-blocker therapy
Dementia or mild cognitive impairment	May be contraindication, use antcholinergic drugs with caution
Physical examination	Supine and orthostatic blood pressure	Particularly if alpha-blocker therapy (for men) is considered
Cardiovascular and pulmonary examination	Examination for fluid overload or heart failure
Abdominal examination	Evaluation for suprapubic distention and tenderness (insensitive, but highly specific if found)
Rectal examination	Evaluation for prostate size, rectal masses, or fecal impaction; analysis of resting and volitional contraction (useful for employing behavioral therapy, including urge suppression strategies)
Neurologic examination	Neurologic conditions (spinal cord injury or multiple sclerosis)
Laboratory studies	Urinalysis	Urinary tract pathology, hematuria
Electrolyte panel	Evaluation for abnormal renal function; check for glycemic control in patients with diabetes mellitus; examination for low serum sodium (especially for consideration of desmospressin therapy or monitoring)
Frequency volume chart	Nocturnal polyuria, functional bladder capacity, total 24-hour urine output	More accurate description of patient nocturnal urinary patterns
Additional studies	Noninvasive uroflowometry (in men)	Low urine flow rate (4 to 15 mL/sec) more suggestive of BPH; very low flow rate (<4 mL/sec) may indicate need for surgical treatment
PVR by ultrasound	PVR over 200 mL may be causative of nocturia or may prevent use of a bladder relaxant

History — Elements of the history include nocturia symptoms, fluid intake patterns, medications, comorbid conditions, dry mouth, and urinary tract symptoms:

Patients with nocturia should have a targeted evaluation (table 2) [60]. It is more valuable to quantify and understand how much distress nocturia causes the patient than to focus on obtaining a precise count of nightly episodes [61].

Medications – Certain prescription and over-the-counter medications (eg, diuretics, xanthines, beta blockers, cholinesterase inhibitors) may be related to nocturia onset or worsening.

Comorbid conditions – Relevant, addressable conditions include congestive heart failure, diabetes mellitus, peripheral edema, depression, and nighttime pain [19,64]. Nocturia may improve with treatment of one of these conditions if it is a direct and principal cause [65].

Sleep dysfunction – Obstructive sleep apnea (OSA) should be considered as a possible diagnosis in patients with nocturia, and the close association between the conditions has led to a suggestion that nocturia should be a screening question for OSA [66]. Insomnia (difficulty returning to sleep) and daytime sleepiness contribute to increased bother from nocturia [29].

Urinary tract symptoms – These include obstructive symptoms (hesitancy, weak stream, incomplete emptying, or intermittency), irritative symptoms (urinary frequency, urgency), and urinary incontinence.

Physical examination — We perform the following elements of the physical examination:

● Measure orthostatic vital signs in all patients due to the risk of nocturnal falls, and in men with benign prostatic hyperplasia (BPH) due to the consideration of prescribing alpha-1-adrenergic antagonists.

● Evaluate for volume overload suggestive of congestive heart failure or nephrotic syndrome.

● Palpate the lower abdomen to evaluate for bladder distention.

● Perform a rectal examination to detect fecal impaction, evaluate resting and volitional rectal tone (which may be important for teaching pelvic floor muscle exercise-based strategies), and estimate gross prostate size in men.

● Inspect for peripheral edema [67].

For example, documentation of a low functional bladder capacity (the largest bladder volume void in 24 hours) may suggest that low-volume voiding is the problem. By contrast, a normal functional bladder capacity during the day but low volume voids at night may suggest a primary sleep disorder. Results can highlight the presence of high-volume urine output, either just at night (nocturnal polyuria) or over the entire day. A sample log is provided (form 1).

Although patients may find it difficult to perform properly, a 24-hour recording of void time and void amount (using a collection device), along with times of going to bed and awakenings, can be helpful in identifying the causes of nocturia. We find this a useful tool in initial diagnosis, but it can also be used in patients who do not respond to initial management [68]. Results can help determine whether nocturia is due to low-volume voiding, increased nocturnal polyuria, or both [69].

A determination of nocturnal polyuria can be made if the nighttime urine volume (including the first morning void) is greater than 35 percent of the 24-hour urine volume [40].

Clinical testing — Measurement of urinary peak flow rate is not necessary. Post-void residual (PVR) measurement is used selectively.

Certain physical examination findings increase the suspicion for urinary retention, including abdominal fullness, suprapubic tenderness, or a patient’s strong urge to void during suprapubic palpation or percussion.

Urinary retention may also be suspected in patients with neurologic conditions affecting the bladder such as diabetic neuropathy, older men with prominent symptoms of intermittent or low flow with voiding, and those with a history of genitourinary surgery.

An elevated PVR (greater than 200 mL) should limit the use of a bladder relaxant medication as these patients are at increased risk of urinary retention (beyond the baseline risk of 1 in 200 treated patients) [71].

In general, a PVR of less than 50 mL is considered adequate emptying, and a PVR greater than 200 mL requires further evaluation, which might include a medication review for discontinuation of any anticholinergic medications, or initial treatment with an alpha-blocker [ 72].

Laboratory tests — We measure renal function, electrolytes, and serum glucose and obtain a urinalysis in all patients, with urine culture if an infection is suspected.

Treatment of underlying medical conditions — Medical conditions which may cause or contribute to nocturia should be treated as part of initial management. These include:

● Polydipsia – Psychogenic (>10L per day) or other

● Congestive heart failure or peripheral edema

● Poorly controlled diabetes mellitus

● Gastroesophageal reflux disease (GERD) or nighttime cough

● Sleep disorders such as obstructive sleep apnea (OSA), periodic limb movements/restless leg syndrome, and insomnia [77]

● Obesity – Discuss weight optimization as part of healthy lifestyle advice [78]; in morbid obesity treated with surgery, nocturia may diminish [79]

Decreasing nocturnal urine output

• Reduction of overall fluid intake, especially if it is excessive, and specific reduction of evening intake by taking in this fluid earlier in the afternoon [80]. Care should be taken not to restrict fluid intake in older patients who have borderline or inadequate fluid intake to meet daily needs.

• Reduction of salt intake [81,82], particularly for those with congestive heart failure [63].

• Reduction of evening consumption of diuretic fluids, including caffeine and alcohol.

• Avoiding use of nighttime diuretics. Clinicians may direct patients on twice-daily diuretics to move the nighttime dose to the mid-afternoon.

• Treatment of peripheral edema by use of compression stockings or afternoon elevation of the legs.

• Avoidance of nocturnal hyperglycemia in patients with diabetes.

• Double-voiding prior to bedtime, which can be described as urinating while sitting comfortably on the toilet (men included), leaning slightly forward, and then waiting for 20 to 30 seconds to urinate again, may be helpful in individuals who feel that they have not completely emptied their bladder.

Decreasing the impact of nocturia – The use of a handheld urinal or a bedside commode may be helpful for patients bothered by trips to and from the bathroom at night. Nighttime ambulation may be particularly worrisome or hazardous in older adult patients or others at high risk of falling, so attention to environmental safety (eg, clear pathway, motion-activated floor way lighting) is also important.

In addition, adopting good sleep hygiene can reduce episodes of nighttime voiding. Elements include sleeping in a quiet room with low lighting and appropriate temperature, avoiding nighttime use of electronic devices, and avoiding daytime naps.

Behavioral treatment, including pelvic floor muscle exercises — Pelvic floor muscle exercises (PFME, or Kegel exercises) and urge-suppression strategies (a combination of remaining still and not running to the bathroom, use of relaxation strategies with three to five rapid contractions of the pelvic floor muscles) are useful in females and males with nocturia [60,83-87]. PFME strengthen the muscular components of the urethral closure mechanism using principles of strength training: small numbers of isometric repetitions at maximal exertion.

The patient’s ability to perform these exercise can be tested on rectal examination and will not usually require the use of computer-assisted biofeedback [87,88]. Primary care providers should refer patients to physical therapists who specialize in this training. The basic recommended regimen is three sets of 8 to 12 slow-velocity contractions sustained for six to eight seconds each, performed three or four times a week and continued for at least 15 to 20 weeks [89].

In clinical trials, benefits from this therapy can be seen as early as two to four weeks, with full benefit at 10 to 12 weeks [88]. Reduction in nocturia from these interventions has ranged from 0.5 to 1.4 episodes per night [85,88] and in pilot studies has shown improvements in sleep quality, reduced bother from nocturia, and improvement in nocturia symptom-specific quality-of-life metrics [88]. (See "Patient education: Pelvic floor muscle exercises (Beyond the Basics)".)

Simultaneous behavioral treatment of nocturia and insomnia will likely be effective in reducing nocturia and bother from nocturia [90,91].

We offer pharmacologic therapy to patients who continue to have symptoms after initial measures.

We start therapy with alpha-1-adrenergic antagonists. These agents target the dynamic component of bladder outlet obstruction and can reduce several BPH symptoms, including nocturia. The presence of dizziness, low blood pressure, or orthostasis may be contraindications. Symptom reduction, if it occurs, can be expected within a month.

Reductions in nocturia with alpha-1-adrenergic antagonists are modest (on average net 0.2 to 0.4 fewer episodes versus placebo) and less than the response to other BPH-related symptoms [92]. In one secondary data analysis of a randomized trial, nocturia reduction of 50 percent or greater occurred in 39 percent of men treated with terazosin, compared with 22 percent of men treated with placebo [92]. This relatively small effect in research trials with populations selected to have the best chance for benefit and carefully monitored for compliance [93,94] suggests that nocturia response in the general population will likely be even more minimal.

Terazosin and doxazosin are often associated with dizziness and orthostatic hypotension, which may be of particular concern in patients with nocturia. These side effects can be minimized with gradual dose titration. Tamsulosin and alfuzosin do not require dose titration, and initial starting doses are usually well-tolerated with an incidence of dizziness and orthostasis of 1 to 2 percent [95,96]. Higher doses may result in higher frequency of side effects.

Combination therapy — We suggest combination therapy for patients who continue to have symptoms on an alpha-1-adrenergic antagonist. Most patients can be offered combination therapy with either PFME or with a bladder relaxant [97]. Contraindications to and side effects of bladder relaxant medications limit their usefulness

For men over age 70 who have continued symptoms on an alpha-1-adrenergic antagonist and who have a prostate larger than 35 g or a prostate-specific antigen (PSA) greater than 1.5, we consider adding a 5-alpha reductase inhibitor. These agents decrease nocturia by reducing the size of the prostate gland. Treatment for four to six months is generally needed before prostate size is sufficiently reduced to improve symptoms.

However, the efficacy of long-term therapy with 5-alpha reductase inhibitors is limited [93]. The Medical Therapy of Prostatic Symptoms (MTOPS) trial demonstrated benefit with finasteride on a combined endpoint of reduction of BPH symptoms, need for intervention for urinary retention, and reduction of urinary symptoms. Combination therapy (finasteride plus doxazosin) was superior to therapy with either single agent. However, the net benefit of combination therapy compared with placebo, with respect to nocturia, was small, with a difference of less than 0.2 fewer nightly episodes at one- and four-year follow-up [98].

Role of surgery — Prostatectomy for BPH relieves many symptoms, but nocturia is the symptom that persists most frequently following surgery [99].

Women, and men without benign prostatic hypertrophy

Initial monotherapy: bladder relaxant therapies — We offer bladder relaxant therapies as first-line pharmacologic treatment. Bladder relaxant medications may reduce nocturia by increasing bladder capacity and decreasing urge-associated voids. Agents differ in drug class, efficacy, side effects, costs, and impact on comorbid conditions. However, the demonstrated benefit of bladder relaxants over placebo in nocturia reduction has been small [85,102,103], perhaps owing to the inability of these medications to increase nighttime voided volumes [104].

There are two major drug classes: antimuscarinics and beta-3 agonists. In general, the initial choice of agents is guided by side effects to avoid.

Antimuscarinic agents and B-3 agonists can be combined, but there has been no demonstrated improvement in nocturia with combination therapy [ 105]. Antimuscarinic agents should be avoided in patients with cognitive dysfunction (eg, dementia, delirium, confusion), dry mouth, or severe constipation. Beta-3 agonists should be given with caution in patients with baseline tachycardia or poorly controlled hypertension. These agents are discussed in detail elsewhere. (See "Urgency urinary incontinence/overactive bladder (OAB) in females: Treatment", section on 'Medication prescribing details'.)

There is concern that bladder relaxant therapies may predispose men to urinary retention. Although urodynamic studies have shown a small increase in the post-void residual (PVR) with use of tolterodine this small change has not proven to be clinically meaningful [71,106] and both tolterodine and oxybutynin have been used successfully, with clinical monitoring, in older male patients [86,107].

Antimuscarinic agents — These agents have direct antispasmodic effects and inhibit the action of acetylcholine on smooth muscle. Oxybutynin is the most commonly used; other agents include tolterodine and solifenacin.

All antimuscarinic agents have anticholinergic effects which include dry mouth, constipation, blurred vision for near objects, tachycardia, drowsiness, and decreased cognitive function. These agents are contraindicated in patients with uncontrolled tachyarrhythmias, myasthenia gravis, gastric retention, and narrow angle-closure glaucoma and are discouraged in patients with cognitive impairment.

Additional concerns with antimuscarinic agents include increased risk of gastric ulceration in patients taking slow-release potassium chloride due to delayed gastric emptying [108] and increased risk of urinary retention in patients with severe BPH symptoms [55].

Oxybutynin is available in immediate release (IR), extended release (ER), and transdermal formulations. We recommend the ER formulation as it has fewer side effects (particularly less dry mouth), and a better safety profile.

While most individuals benefit from oxybutynin 10 mg ER, some patients will still have benefit at a lower dose (5 mg ER), and rarely will patients require 20 or 30 mg ER [86,87]. The effect of antimuscarinic agents on nocturia are small with reduction of nocturia by approximately 0.30 episodes per night compared with placebo (no reduction) [85,87,102,109,110].

Beta-3 agonists — Mirabegron and vibegron [111,112], beta 3-adrenoceptor agonists, are an option for patients who have a contraindication to antimuscarinic medications. These agents work by promoting selective beta receptor stimulation of the detrusor muscle to enhance smooth muscle relaxation. Mirabegron has similar efficacy to antimuscarinics [113]. Hypertension is the most common side effect with mirabegron; additional side effects are mostly secondary to elevated blood pressures. Mirabegron and vibegron has been shown to reduce nocturia by a modest degree [114,115]. Patients with severe or uncontrolled hypertension should not be prescribed a drug in this class [113].

Vaginal estrogen therapy (women only) — For postmenopausal women, it is reasonable to use topical vaginal estrogen therapy either alone or in combination with other therapies (table 3).

A systematic review of randomized and observational studies evaluating topical estrogen for the treatment of nocturia in postmenopausal women reported that three of the five studies (60 percent) that reported this outcome reported a reduction in frequency of nocturia compared with placebo [116]. There did not appear to be a difference in efficacy or safety among the different preparations (vaginal tablets, ovules, creams, gels, or rings).

Sleep disorder medications — Sleep medications can provide a decrease in nocturia episodes. One randomized study investigated melatonin as a potential treatment for nocturia associated with bladder outlet obstruction in older men [142]. Baseline frequency of nocturia was 3.1 episodes per night. Melatonin showed a nonsignificant reduction in nocturia compared with placebo (-.3 and -0.05 episodes respectively) and significantly reduced reported bother.

Afternoon diuretic therapy — Several small studies have evaluated the effectiveness of an afternoon diuretic dose specific prescribed for nocturia. In two randomized trials, nocturia was reduced by approximately 0.5 episodes per night [143,144]. Combining antidiuretic therapy (at bedtime) with diuretic therapy (six hours prior to bedtime) increased the effect size of reduction of nocturia but was accompanied by hyponatremia in several cases [145].

Desmopressin — In 2018, the US Food and Drug Administration (FDA) approved two lower-potency [117] desmopressin analogs, of which one is still available (a sublingual pastille [Nocdurna]), for treatment of nocturia due to nocturnal polyuria [118,119]. However, United States insurance companies have asked for patients to be tried on a higher-potency (generic) formulation(s) of desmopressin acetate prior to receiving approval for the sublingual pastille [120].

While there are data showing the efficacy of desmopressin, there is a substantial risk of hyponatremia, which can be life-threatening if severe, that limits its use. Specifically, it has been demonstrated to cause hyponatremia at a 13-fold higher rate than other medications for lower urinary tract symptoms [121].

Desmopressin is a neuropeptide similar to endogenous vasopressin; like vasopressin, it has a potent antidiuretic effect, but unlike vasopressin it has no vasopressor activity [123]. desmopressin, taken two hours prior to bedtime, reduces nighttime free-water excretion to provide an opportunity for adequate sleep free from voiding; however, the safety of its use depends on compensatory daytime free-water diuresis, which helps to prevent hyponatremia.

The author avoids the use of desmopressin in patients aged ≥65 years due to the high likelihood that older adults with nocturia are highly likely to have contraindications to use and because the manufacturers as well as an expert consensus panel have failed to provide clear instructions for the frequency of needed monitoring [117]

● Desmopressin should be avoided in patients who have:

• An underlying disease that would be made worse by fluid retention (eg, uncontrolled hypertension, increased intracranial pressure)

• A history of urinary retention

● The nasal preparation should not be given to patients who have nasal conditions that may increase absorption (eg, atrophy of nasal mucosa, acute or chronic rhinitis).

Efficacy — These agents have demonstrated efficacy over placebo in trials. However, their effect has not reached the threshold of minimally important clinical difference, which is likely around a 1.5 to 2.2 reduction in voids per night.

Posterior tibial nerve stimulation — Posterior tibial nerve stimulation (PTNS) treatment involves 12 weekly 30-minute sessions of transcutaneous needle nerve stimulation near the ankle, approximating pudendal nerve stimulation. PTNS has been studied in a sham-controlled randomized trial of 214 patients with overactive bladder [139]. The number of nocturia episodes in the group assigned to weekly PTNS for 12 weeks decreased compared with sham control (a decrease of 0.7 versus 0.3 episodes from a baseline of 2.9 nightly episodes).