Managing nocturia

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TARGET AUDIENCE

Obstetrician/gynecologists and women's health practitioners.

EDUCATIONAL OBJECTIVES

After completing the following CME activity, the reader should be able to:

• Define "nocturia" and summarize its impact on quality of life.

• Identify the principal causes of nocturia and summarize the relationship between nocturia and obstructive sleep apnea.

• Distinguish between polyuria, nocturnal polyuria, and low nocturnal bladder capacity, and identify the comorbidities associated with each.

• Summarize both pharmacologic and nonpharmacologic options available to the health-care provider in the treatment of nocturia.

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Participants should study the article, log onto http://www.modernmedicine.com,click on the "CME/CE Center" tab at the top of the page and type inkeyword: COG082007. Participants will be taken to the activity, where they mustpass a post-test and complete an online evaluation. After passing the post-testand completing the online evaluation, a CME certificate will be automaticallygenerated. The release date for this activity is August 1, 2007. The expirationdate is August 1, 2008.

DISCLOSURES

Editors Elizabeth A. Nissen and Paul L. Cerrato and Instructional DesignConsultant Richard Currier, PhD, disclose that they do not have any financialrelationships with any manufacturer in this area of medicine.

The manuscript reviewer discloses that he is on the Speakers Bureaus of thefollowing manufacturers: Bard Urological (Covington, Ga.), American MedicalSystems (Minnetonka, Minn.), and CooperSurgical (Trumbell, Conn.).

Dr. Heit discloses that he has no financial relationships with anymanufacturer in this area of medicine.

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Quality of life for a woman with nocturia (waking during the night tovoid) goes increasingly downhill as the number of times her sleep is interruptedgoes up. Not surprisingly, the more often she goes back and forth to thebathroom in the middle of the night, the more exhausted she's likely to be thenext day. Nocturia is also a risk factor for falls, which can lead tosignificant complications, especially in the elderly.

Clinically defined by World Health Organization criteria as the need to voidtwo or more times per night, nocturia affects 10% of women outside nursinghomes. The age-adjusted prevalence increases from 32.9% of women aged 20 to 29to 88.9% of women 80 years and older.

Only 2% of men and women report a negative impact on quality of life fromwaking once during the night, compared with 17% who wake to void three timesnightly, and 70% who do so four or more times.¹

Nearly 50% of women who void twice or more nightly report falls, comparedwith only 27% of women who are not voiding at night or waking just once nightlyto do so.² The odds ratio of a fall associated with two to threenighttime awakenings is 1.84 (95% CI, 1.05?3.22), rising with three or morenighttime awakenings to 2.15 (95% CI, 1.04?4.44), compared to women reportingawakening only once to void, adjusting for age.²

What's causing the patient's nocturia?

A 24-hour voiding diary is the best tool for diagnosing women with symptomsof nocturia. We recommend asking a patient to complete three 24-hour void-ingdiaries to record the timing and amount of fluid intake, urinary frequency,urinary incontinence episodes, and her leaking condition (urge or stress).Three-day diaries are just as likely as 7-day diaries to provide the informationyou need, and patients are more likely to fill out the shorter forms.³The 24-hour voiding diary allows you to subclassify a patient's symptoms in anattempt to predict prognosis and initiate treatment.

Polyuria, defined as voiding more than 2.5 L of urine daily, can be diagnosedby totaling the volume voided on the three 24-hour voiding diaries and dividingby three. Polyuria is caused by overproduction of urine both day and night thatexceeds a person's bladder capacity. The most common causes of overproductionare diabetes mellitus, diabetes insipidus (from surgery, infection, tumor, ortrauma), nephrogenic diabetes insipidus from hypercalcemia, chronic renalfailure, lithium therapy, or primary thirst disorders like psychogenicpolydipsia, or dipsogenic polydipsia from brain trauma, tumor, surgery orradiation, and drugs such as anticholinergics or psychotropics. When polyuria isdiagnosed, refer patients to family practitioners or internists to determine itscause and begin treatment.

Nocturia can be caused by:

• nocturnal polyuria,

• low nocturnal bladder capacity, or

• a combination of the two (mixed).

Nocturnal polyuria is defined as producing 33% or more of a person's total24-hour urine production at night. This can be calculated by dividing the totalnocturnal urine volume produced between bedtime and the first morning void bythe total urine volume recorded on all three 24-hour voiding diaries (Figure 1).The first morning void should be included when calculating total nocturnal urinevolume because it was produced during the night rather than the morning.Consider referring patients diagnosed with nocturnal polyuria for evaluation andtreatment of the following medical disorders: congestive heart failure, diabetesmellitus, or nephrogenic diabetes insipidus.

Patients diagnosed with nocturnal polyuria produce a greater volume ofnocturnal urine than their bladders can hold because of either decreasedarginine vasopressin or increased secretion of atrial natriuretic peptide.Arginine vasopressin or antidiuretic hormone (ADH) is produced by the posteriorlobe of the pituitary to signal the distal renal tubules to regulate serumosmolarity.

Unaffected women secrete enough ADH at night to allow them to get a restfulnight's sleep undisturbed by the need to void. Patients with nocturnal polyuria,on the other hand, secrete less nocturnal ADH, causing their sleep to beinterrupted by the need to void. Insufficient production of arginine vasopressincauses central diabetes insipidus. Arginine vasopressin insensitivity, alsoknown as nephrogenic diabetes insipidus, can be seen with hypercalcemia, chronicrenal failure, lithium therapy, or excessive tetracycline or alcohol ingestion.

Could it be sleep apnea?

Atrial natriuretic peptide is secreted by the right atrium acting on thekidneys to increase urine production in response to the fluid overload ofcongestive heart failure. This peptide also mediates the relationship betweenobstructive sleep apnea and nocturnal polyuria. Morbidly obese or hypertensivepatients, as well as those who snore or have acromegaly, asthma, hypertension,noninsulin-dependent diabetes mellitus, and craniofacial abnormalities are allat risk for obstructive sleep apnea (OSA).

During OSA, hypoxia occurs in lung alveoli because of the increased airwayresistance (Figure 2). Hypoxia of the lung alveoli causes reflex pulmonaryvasoconstriction, which prevents ventilation-to-perfusion mismatches in the lungand hypoxemia. In turn, pulmonary vasoconstriction increases cardiac afterload,leading to right-sided congestive heart failure. This prompts the right atriumto increase nighttime secretion of atrial natriuretic peptide to maintainhomeostasis through diuresis, causing nocturnal polyuria.

Patients often blame their daily fatigue on waking up at night to void ratherthan on an occult sleep disorder. Be sure to maintain a high index of suspicionfor obstructive sleep apnea when nocturnal polyuria is diagnosed in high-riskwomen.

One researcher used polysomnography to establish the cause of nighttimeawakenings in patients with nocturia.⁴ Forty-eight (52.1%) of the 92diagnosed sleep-disordered awakenings were attributed to a need to void whenpatients were questioned at night, whereas 56 (60.9%) of these 92 awakeningswere chalked up to a need to void when patients weren't questioned until thenext morning. Only 1.1% (one of 80 patients) identified sleep disorders whenquestioned at night, while two patients (2.2%) did so during daytimequestioning.⁴ Patients diagnosed with nocturnal polyuria should bereferred to sleep disorder centers for consultation with sleep specialists(often pulmonologists) and polysomnography as a first step in the management ofthese symptoms.

Other causes of nocturnal polyuria include right-sided congestive heartfailure, lower extremity venous insufficiency, hypoalbuminemia, and excessivesalt intake leading to accumulation of third space fluid. Supine diuresis occurswhen third space fluid diffuses back into the intravascular space and is pumpedto the kidneys, where urine is produced during the night.

Not a big enough bladder?

The diagnosis of low nocturnal bladder capacity is established when thenocturnal bladder capacity index is greater than 0. This index is the differencebetween the actual numbers of nightly voids compared to the predictednumber of nightly voids. The predicted number of nightly voids can be calculatedby dividing the average urine volume voided on the three 24-hour voiding diariesby the functional bladder capacity, then subtracting 1 (which adjusts theresulting quotient for urine produced at night but eliminated during the firstmorning void). Functional bladder capacity is the maximum volume of urine voidedon any of the three 24-hour voiding diaries (Figure 1). Look to bladder-specificdiagnoses such as detrusor overactivity or decreased bladder compliance whenpatients are diagnosed with low nocturnal bladder capacity.

As the number of voids per night recorded on a 24-hour voiding diary climbs,the prevalence of low nocturnal bladder capacity rises compared with nocturnalpolyuria. More than a third (35%) of symptomatic patients who recorded twonighttime voids were diagnosed with low nocturnal bladder capacity compared with55% who were diagnosed with nocturnal polyuria and 10% who had normal bladderfunction.⁵ Some 21% of symptomatic patients who recorded three ormore nighttime voids had a mixed picture compared with 58% of those diagnosedwith low nocturnal bladder capacity and 21% who were diagnosed with nocturnalpolyuria.⁵

Treatment options for nocturia

Treatment of nocturnal polyuria includes fluid restriction, timeddiuretics, afternoon naps with compression stockings, desmopressin acetate (DDAVP,Aventis Pharmaceuticals), and nasal continuous positive airway pressure (CPAP)for patients diagnosed with obstructive sleep apnea (Table 1).

• RESTRICTING FLUIDS. Patients are commonly counseled to "drink plenty of fluids" to prevent urinary tract infection, "because it's healthy," or with medications.

Evening fluid restriction is beneficial when excessive fluid intake afterdinner is diagnosed by 24-hour voiding diary. These voiding diaries also givethe doctor and patient feedback about improvements in behavioral symptoms afterfluids are restricted.

• NAPS. Afternoon naps while wearing compression stockings benefit patients with the type of nocturnal polyuria caused by supine diuresis of third-space fluid accumulation. Elevating the legs during afternoon naps returns third space fluid to the intravascular space for elimination by the kidney as urine during the day.

A woman can wear compression stockings during the day to support thediffusion of third space fluid back to the intravascular space?an especiallygood approach for elderly patients with muscle atrophy and venous insufficiencywho are predisposed to swollen legs. The therapeutic goal is to eliminate asmuch of the accumulated third space fluid as possible during the day so patientscan get a restful sleep at night.

• AIRWAY PRESSURE for APNEA. Nasal CPAP is the treatment of choice for obstructive sleep apnea.

Sleep study specialists can measure the impact that nasal CPAP has onreducing the number of apneic episodes recorded. Patients sleep more restfullyby minimizing nighttime awakenings from apneic episodes, eliminating the"need to void."

• MEDICATION. Desmopressin is available as an oral tablet (0.1 to 0.4 mg) or a metered dose nasal spray (10?40 μg) for patients with nocturnal polyuria because of insufficient ADH secretion.

In one randomized clinical trial, a third of patients who receiveddesmopressin acetate cut their number of nighttime voids in half, compared withonly 3% in the placebo group.⁶ Study participants receivingdesmopressin acetate had a 78% increase in their first sleep duration comparedto a 20% increase for patients receiving placebo. Headache was the most frequentadverse event, occurring in approximately 3% of cases. There was no differencein adverse events between study participants receiving placebo or desmopressinacetate. Fourteen cases (6%) of hyponatremia were detected, 11 of which were inwomen older than age 65.

CLOSELY FOLLOW any patients you start on desmopressin acetate duringtheir dose titration period, and have them reduce their daily fluid intake.Start them on 10 μg per nostril nightly at bedtime (20 μg total) or0.2 mg orally every night at bedtime, and see them every 3 days to checkelectrolytes, obtain daily weights, and monitor them for lower extremity andpresacral edema to identify cases of hyponatremia and fluid overload. Increasethe dose until the desired effect is achieved, as long as side effects aretolerable, and the risk of hyponatremia is minimal. Once on a stable dose, apatient can be followed every 3 to 6 months to check electrolytes and assess forfluid overload (Table 2).

Diuretic drugs can be given 6 hours before bedtime to minimize the number ofawakenings related to excessive nighttime urine production. Some 37% ofparticipants receiving a diuretic in one randomized trial reported one lessnightly void, compared with only 5% in the placebo group.⁷Subjectively, 64% of study participants receiving diuretics reported help withtheir nocturia compared with only 23% receiving placebo.

Nocturia of any cause compromises quality of life because of interruptedsleep resulting in daytime fatigue. But the good news is that it's easilydiagnosed using a 24-hour voiding diary. Nocturia can be associated with manymedical conditions and can be successfully managed by referral to an internistor a family practitioner. Treatment of symptomatic patients should be directedat its causes, which include polyuria, nocturnal polyuria, low nocturnal bladdercapacity, or a combination of the last two.

DR. HEIT is a practicing Urogynecologist and Reconstructive PelvicSurgeon, Urogynecology Specialists of Kentuckiana, PLLC, Louisville, Ky.

REFERENCES

1. Schatzl G, Temmi C, Schmidbauer J, et al. Cross-sectionalstudy of nocturia in both sexes: analysis of a voluntary health screeningproject. Urology. 2000;56:71-75.

2. Stewart RB, Moore MT, May FE, et al. Nocturia: a riskfactor for falls in the elderly. J Am Geriatr Soc. 1992;40:1217-1220.

3. Nygaard I, Holcomb R. Reproducibility of the seven-dayvoiding diary in women with stress urinary incontinence. Int J Urogynecol JPelvic Floor Dysfunct. 2000;11:15-17.

4. Pressman MR, Figueroa WG, Kendrick-Mohamed J, et al.Nocturia. A rarely recognized symptom of sleep apnea and other occult sleepdisorders. Arch Intern Med. 1996;156:545-550.

5. Homma Y, Yamaguchi O, Kageyama S, et al. Nocturia in theadult, classification on the basis of largest voided volume and nocturnal urineproduction. J Urol. 2000;163:777-781.

6. Lose G, Lalos O, Freeman RM, et al. Nocturia study group.Efficacy of desmopressin (Minirin) in the treatment of nocturia: a double-blind,placebo-controlled study in women. Am J Obstet Gynecol.2003;189:1106-1113.

7. Reynard JM, Cannon A, Yang Q, et al. A novel therapy fornocturnal polyuria: a double-blind randomized trial of frusemide againstplacebo. Br J Urol. 1998;81:215-218.