Functional: Nocturia

Background

• Definition of nocturia: voiding that is preceded and followed by sleep
  • ≥2 voids per night appears to be clinically significant
  • Definition does not take into account the patient’s degree of bother
• Prevalence increases with age in both men and women
• Associated with:
  1. Decreased survival
  2. Decreased quality of life
  3. Decreased sleep efficiency and sleep latency
     • Sleep efficiency: actual time asleep (minutes) divided by total time of intended sleep (minutes); normal > 85%
     • Sleep latency: time it takes to go from being completely awake to being completely asleep
     • Sleep loss can negatively affect health by decreasing immune function, increasing the risk for cardiovascular disease, obesity and type 2 diabetes
  4. Increased prevalence of depressive symptoms
  5. Increased risk for metabolic syndrome
  6. Increased risk of falls
  7. Increased impairment in work and non-work activities
• Factors that inhibit ADH and cause diuresis (inhibit water reabsorption) include prostaglandin E2, ANP, hypercalcemia, hypokalemia, lithium, and tetracyclines.

Diagnosis and Evaluation

UrologySchool.com Summary (2):

1. History and Physical Exam
2. Voiding diary/frequency-volume chart

History and Physical Exam

History

• Nocturia be a symptom of serious systemic illnesses including hypertension, diabetes, heart disease, and kidney disease
• Drug effects causing nocturia
  • Increased urine output (5):
    1. SSRIs (block antidiuretic hormone secretion)
    2. Tetracycline (attenuates antidiuretic hormone via decreases in cAMP accumulation and action)
    3. Calcium channel blockers (increases atrial natriuretic peptide, blocks sodium reabsorption in proximal convoluted tubule)
    4. Lithium (drug-induced nephrogenic diabetes insipidus)
    5. Diuretics: timing of diuretic administration should be mid-afternoon, to allow for elimination of lower extremity excess body fluid during normal waking hours. Men with nocturnal polyuria may benefit from diuretic therapy 6 hours before sleep
  • Insomnia and CNS effects
    • CNS stimulants: dextroamphetamine, methylphenidate
    • Antihypertensives: α-Blockers, β-Blockers, methyldopa
    • Respiratory: albuterol, theophylline
    • Decongestants: phenylephrine, pseudoephedrine
    • Hormones: corticosteroids, thyroid
    • Psychotropics: MAOIs, SSRIs, atypical antidepressants
    • Dopaminergic agonists: carbidopa
    • Antiepileptics: phenytoin
  • Direct lower urinary tract effects
    • Ketamine: direct bladder toxin
    • Tiaprofenic acid (Surgam): toxic cystitis
    • Cyclophosphamide

Physical exam

• Peripheral edema resulting from cardiac disease, nephrotic syndrome, venous insufficiency
• Obesity and short neck may be suggestive of obstructive sleep apnea and be associated with nocturnal polyuria

Voiding Diary/Frequency-volume chart

• Most useful tool in evaluating and classifying the cause of nocturia

Classification (3):

1. Nocturnal polyuria: increased production of urine at night
2. Decreased bladder capacity
3. Global polyuria

Nocturnal polyuria

Definitions

• If nocturnal urine volume (3):
  • >20%-33% of total 24-hr volume (age dependent)
    • Normal circadian urine production is age dependent and the proportion of total urine output at night increases with age.
      • Age < 25: nocturnal urine volume/total = 14%
      • Age > 65: nocturnal urine volume/total = 34%
  • >6.4 mL/kg
  • >54 mL/hr

Causes

Diuretics Can Over Do Evening Pee (6):

1. Diuretics (depending on time of administration)
2. Congestive heart failure
3. Obstructive sleep apnea
   • Defined as the sudden cessation of respiration during sleep because of airway obstruction
     • Increased airway pressures lead to hypoxia, which in turn causes pulmonary vasoconstriction, the latter leading to increased right atrial transmural pressure with resulting increase in ANP production and ultimately increased renal sodium and water excretion
   • Common cause of nocturnal polyuria
4. Diabetes mellitus
5. Excessive nighttime fluid intake
6. Peripheral edema

Management

• Treat underlying contributing medical comorbidities
  • Treating sleep disturbances, hypertension, and obesity may decrease the number of nightly voids and improve quality of life
  • Treating sleep apnea with continuous positive airway pressure (CPAP) can improve nocturia
• Conservative management (3)
  1. Cessation of fluid intake 4 hours before bedtime
  2. Compressive lower extremity stockings
  3. Administration of diuretics in the mid-afternoon for edema states
• Medical management (2):
  1. Demopressin (antidiuretic therapy at bedtime)
     • Mechanism of action: binds to V2 receptors in the renal collecting tubules, resulting in increased water permeability, enhanced water reabsorption, diluted extracellular fluid, and concentrated urine.
     • Adverse events:
       • Hyponatremia
         • Risk is <1% in those age < 65 and 8% in those age > 65
     • Contraindications:
       • Campbell’s: Elderly patients (>65 years) with baseline hyponatremia
       • Product monograph:
         • Patients with type IIB or platelet-type (pseudo) Willerbrand disease, because of the risk of platelet aggregation and thrombocytopenia
         • Any condition associated with impaired water excretion, such as:
           • Hyponatremia
           • Severe liver disease
           • Nephrosis
           • Cardiac insufficiency
           • Chronic renal insufficiency
           • Congestive heart failure
           • Habitual or psychogenic polydypsia
         • Any medical conditions which lead to sodium losing states such as:
           • Vomiting
           • Diarrhoea
           • Bulimia
           • Anorexia nervosa
           • Adrenocortical insufficiency
           • Salt losing nephropathies
     • There appears to be a lower risk of hyponatremia in patients with the nasal spray as opposed to oral preparations.
     • Dosing of desmopressin melt
       • Females are more sensitive to demopressin in terms of effects on nocturnal urine production and duration of action;
         • 50 μg of desmopressin melt may be the lowest therapeutically beneficial dose for males while females do well with a lower dose of 25 μg
     • Monitoring
       • Obtain a baseline serum sodium before initiating therapy
       • Monitor the serum sodium within 7 days and then 28 days after initial or incremental dosing, then continue to check sodium levels every 6 months (or more often as indicated).
  2. Imipramine
     • MOA: a tricyclic antidepressant with a complex pharmacologic profile including:
       • Nonsubtype-selective antimuscarinic effect
       • Effects in modulating vasopressin release
       • Potentiating renal proximal tubular sodium and water reabsorption
     • Adverse events:
       • Arrythmia, should be used with caution
         • Has been shown to prolong the PR, QRS, and QTc intervals, increase heart rate, and lower T-wave amplitude during a 4-week treatment course. There have been rare reports of torsades de pointes and sudden death resulting from imipramine administration

Decreased Bladder Capacity

Definitions

• Nocturnal urine volume exceeds nocturnal bladder capacity and the patient awakens because of the need to void
  • Can result from either a (2)
    1. Global decrease in bladder capacity, as expressed by a low maximum voided volume (MVV)
       • Maximum voided volume (MVV): the largest single voided volume in a 24-hr period
    2. Simply a decrease in nocturnal bladder capacity i.e. small nocturnal bladder capacity, as expressed by a nocturnal bladder capacity index (NBCi) > 0
• Nocturnal bladder capacity index (NBCi)
  • Useful means to examine the relationship between the patient’s own bladder capacity and nocturnal voided volumes during a 24-hour period.
  • NBCi = Actual number of nightly voids (ANV) − Predicted number of nightly voids (PNV)
    • Actual number of nightly voids (ANV) or nighttime frequency: number of voids recorded from the time the individual goes to bed with the intention of sleeping, to the time the individual wakes with the intention of rising
    • Predicted number of nightly voids (PNV) = (Nocturia Index (NI) − 1)
      • Nocturia index (Ni) = Nocturnal urine volume (NUV)/Maximum voided volume (MVV)
        • Nocturnal urine volume (NUV): Total volume of urine passed during the night, including the first morning void
        • If Ni > 1, nocturia or enuresis occurs because functional bladder capacity (MVV) is exceeded
  • If NBCi > 0, nocturia occurs at volumes less than MVV i.e. small nocturnal bladder capacity
  • Example: a patient who voids 8 times per night (ANV = 8), who voids a total of 800 mL during the intended hours of sleep (NUV = 800 mL), and who has an MVV of 200 mL would have an Ni of 4 (Ni = NUV/MVV = 800 mL/200 mL = 4). This patient’s PNV = Ni − 1 = 4 − 1 = 3. Therefore this patient’s NBCi = ANV − PNV = 8 − 3 = 5. An NBCi of 5 indicates a substantially diminished nocturnal bladder capacity

Causes (11):

1. Ureteral calculi
2. Bladder calculi
3. Cystitis (bacterial, interstitial, tuberculous, radiation)
4. Cancer of the bladder, prostate, or urethra
5. Bladder outlet obstruction
6. Neurogenic bladder
7. Low bladder compliance
8. Medications such as xanthines (caffeine, theophylline) and β-blockers
9. Idiopathic nocturnal detrusor overactivity
10. Anxiety disorders
11. Learned voiding dysfunction

Management

• Directed at underlying cause
  • Phytotherapies
    • Pygeum africanum and cernilton are associated with improvement in nocturia
  • Medical therapy
    • α-blockers, 5-ARIs, antimuscarinics, and antimuscarinics plus α-blockers have occasionally been found to have a statistically significant reduction in nocturia episodes, but clinical significance appears to be minimal.
    • When 5-ARIs and α-blockers are used in combination, they have the same degree of success as α-blockers alone
    • The optimal patients to treat with medications that target the bladder and the prostate appear to be those who have a large number of nocturia episodes (mostly resulting from severe urgency)
  • Surgery
    • Patients with high-pressure urinary retention causing nocturnal enuresis are treated by initial catheterization to relieve the pressure, followed by appropriate assessment with a view to using endoscopic surgery to resect, vaporize, or enucleate the prostate, or open removal of the prostate
      • Treating bladder outlet obstruction is thought to improve nocturia by:
        • Lowering postvoid residual volume
        • Increasing functional bladder capacity
        • Reducing urinary frequency
      • TURP appears to be superior to tamsulosin for treatment of BPH-related nocturia

Global polyuria

Definition

• 24-hour urine output > 40 ml/kg causing both daytime urinary frequency and nocturia

Causes (3):

1. Primary polydipsia (dipsogenic (damage to thirst mechanism in hypothalamus) and psychogenic)
2. Diabetes mellitus
3. Diabetes insipidus

Diabetes Insipidus

• Disorder of water balance
• Inappropriate excretion of water leads to polydipsia in an effort to prevent circulatory collapse
• Classified (2): central vs. nephrogenic
  • Central diabetes insipidus occurs when there is deficiency in ADH (synthesis or secretion)
    • Can be due to loss of neurosecretory neurons in the hypothalamus or the posterior pituitary gland as a result of trauma, primary pituitary tumors (e.g., craniopharyngioma), metastatic disease (e.g., breast, lung), infiltrative diseases (e.g., sarcoid), infarction (e.g., Sheehan syndrome postpartum), or infection (e.g., tuberculosis, meningitis) or can be idiopathic.
  • Nephrogenic diabetes insipidus occurs when there is normal ADH levels but the kidneys do not respond appropriately to the hormone
    • Can be due to chronic kidney disease

Questions

1. What is the definition of nocturia?
2. How many episodes of nocturia are considered clinically significant?
3. List medications associated with nocturia
4. Which characteristics on physical exam are associated with nocturia?
5. How are the causes of nocturia categorized?
6. What are 2 definitions of nocturnal polyuria?
7. What are the causes of nocturnal polyuria?
8. What is the potential medications used to treat nocturnal polyuria? What is their mechanism of action? What is the most serious potential adverse events related to their use?
9. Describe your approach to prescribing desmopressin
10. List causes of reduced bladder capacity
11. What is the definition of global polyuria
12. List causes of global polyuria

Answers

1. What is the definition of nocturia?
   • Voiding preceded and followed by sleep
2. How many episodes of nocturia are considered clinically significant?
   • ≥2

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 78