Dr. Alan Wein, Professor and Chief of the Division of Urology at the Perelman School of Medicine, University of Pennsylvania, and the Hospital of the University of Pennsylvania, both in Philadelphia, discusses nocturia with Dr. Tony Nimeh, Urology Research Physician at Brigham and Women’s Hospital, Harvard Medical School, in Boston.
Nocturia is defined as getting up once or more at night to urinate. Sleep apnea is a common and correctable cause of nocturia. Before deciding on a course of management, it is important to understand the amount of bother the nocturia represents to the patient and his or her expectations from treatment.
Dr. Nimeh: Dr. Wein, what makes nocturia such a challenging clinical entity?
Dr. Wein: Nocturia is defined as getting up twice or more at night to urinate. It is an extremely common entity, especially if assessed in terms of the “bother” to the patient. The main challenge with nocturia is that it is generally regarded as a natural consequence of aging. It is commonly assumed to occur in older men secondary to prostatic obstruction, or in women because of an overactive bladder. It is seen as more annoying than serious. Therefore, it is not given the attention it deserves. However, nocturia is associated with significant adverse effects and should be regarded as a significant health problem.
Dr. Nimeh: What adverse effects are associated with nocturia?
Dr. Wein: The associated adverse effects include reduced health-related quality of life, mood disturbances, reduced work productivity, increased falls, increased fractures, and increased mortality. More research is needed to show a reverse parallel association between these outcomes and nocturia to demonstrate that these associations disappear if we successfully treat nocturia over a long period of time.
Four categories of nocturia
Dr. Nimeh: Why are the frequency volume charts such an important part of the workup?
Dr. Wein: Frequency volume charts are the key to diagnosis and categorization of patients with nocturia. The causes of nocturia can be divided into four categories: sleep disturbances (eg, sleep apnea), psychological factors, polyuria, and bladder storage problems.
Bladder storage problems are indicated by frequent voiding of low volumes, either because of urgency (overactive bladder) or simply a frequent urge to void (eg, increased postvoiding residual volume and decreased functional bladder capacity).
Polyuria refers to either making too much urine over a 24-hour period (24-hour polyuria) or making too much urine only at night (nocturnal polyuria). An especially critical issue for physicians dealing with the lower urinary tract, such as urologists and urogynecologists, is recognizing and ruling out a diagnosis of nocturnal polyuria. Lack of recognition of nocturnal polyuria is the reason that many therapies unexpectedly fail.
The degree of “bother”
Dr. Nimeh: What is the key to successfully managing patients with nocturia?
Dr. Wein: The key is focusing on the patient’s degree of bother. The International Continence Society (ICS) defines nocturia as waking up at night one or more times to urinate, with each void preceded by and followed by sleep.1 The problem with this definition is that each void should not have to be “followed by sleep” but rather by the intent to go back to sleep. Furthermore, the definition does not include the concept of bother. A lot of people get up once per night, but the degree of bother experienced is different for every patient. Many studies have been conducted to try to quantify how many awakenings are necessary before the patient expresses a feeling of bother. The magic number appears to be two or three. Although bother is not part of the definition of nocturia, it is something that we should take into account when deciding to initiate a workup and treatment regimen.
Sleep apnea and nocturia
Dr. Nimeh: What is the relationship between obstructive sleep apnea and nocturia?
Dr. Wein: Sleep apnea is an under-recognized cause of nocturia, even by urologists. Interestingly, this important association has been studied and written about very little.
Obstructive sleep apnea as a contributor to nocturia is one of the few clinical scenarios in which successful treatment of the cause can lead to complete resolution of the nocturia. The mechanism involved is as follows: Obstructive sleep apnea leads to increased airway resistance, which leads to hypoxia, which leads to pulmonary vasoconstriction. This induces increased right atrial transmural pressure, which triggers an increase in atrial natriuretic peptide, leading to increased renal sodium and water excretion.
Treatment of sleep apnea (eg, by referral to a sleep laboratory and treatment with CPAP) results in a most startling response with regard to the nocturia: It can reduce awakenings from three times per night to zero. Therefore, it is highly recommended that patients suspected of having sleep apnea—typically, a middle-aged person who is obese or who snores at night—be referred to a sleep physiologist for a sleep apnea workup and treatment.
Management of nocturia, and when to refer
Dr. Nimeh: Nocturia is a multifactorial condition. How do you approach patient management in a comprehensive manner?
Dr. Wein: The first step is classifying the patient’s condition into the correct nocturia category or categories, and then treating it accordingly. As a rule, behavioral modifications should be tried first before implementing other treatments, depending on the severity and nature of the condition.
Certain types of patients are best referred for evaluation. These include patients with the following presentations:
- 24-Hour polyuria. Most urologists would refer a patient to an endocrinologist for a diabetes insipidus workup if the patient has 24-hour polyuria
- Nocturnal polyuria in a patient with congestive heart failure or peripheral edema due to other causes. The commonly accepted definition of nocturnal polyuria is nighttime urine output that is greater than 33% of 24-hour urine output. The causes include congestive heart failure and peripheral edema as a result of either congestive heart failure or venous disease. At night, when the patient is in the supine position, the extracellular fluid reenters the general circulation, and the increased blood volume leads to increased urinary output. Patients with these comorbid conditions should also be referred to an internist.
- Urologic causes. If a patient has a low nocturnal bladder capacity, we look for a remediable urologic cause such as decreased bladder capacity, bladder cancer, a neurogenic bladder, or an obstruction with secondary detrusor overactivity. Even a stone at the ureterovesical junction can cause this. Unless the patient has a large residual urine volume related to obstruction, he will not benefit from transurethral resection (TUR) of the prostate. In clinical studies of nocturia, the difference in outcomes between patients treated with TUR and those receiving placebo is surprisingly small. This is contradictory to popular opinion in the urology community, which maintains that older patients with nocturia and some outlet obstruction automatically improve with TUR. Patients may get a little better, but whether that’s enough to be considered satisfactory is debatable. The number of patients who improve is much smaller than expected, and certainly smaller than the promises made by urologists to their patients.
Unless patients have severe, frequent nocturnal urgency, they will not benefit significantly from the standard treatment regimens for overactive bladder that include an antimuscarinic agent or a beta-3 agonist. Antimuscarinic agents only work for patients with overactive bladder and severe nocturnal urgency, which is actually quite unusual. Those patients regularly get up several times every night with severe urgency: “If I don’t get to the bathroom right this second, I am going to pee in my pants.” Furthermore, even when antimuscarinics do work, they are not completely effective.
After all nonurologic causes such as congestive heart failure have been addressed, and behavior modification has been attempted and urologic causes have been treated, the only remaining measure that could help would be to decrease nocturnal urine volume using an antidiuretic. The problem is that, although antidiuretics work, they also can cause hyponatremia.
Role of desmopressin
Dr. Nimeh: When do you use desmopressin?
Dr. Wein: A desmopressin preparation is approved in Europe for nocturia, but, in the United States, it is only approved for refractory nocturnal enuresis, not nocturia. The important issue with desmopressin is deciding on the acceptable level of hyponatremia. The number mentioned in the literature is 7.6%, but that is unacceptably high.2
An interesting finding was discussed at the meeting of the International Consultation on Incontinence Research Society (ICI-RS); specifically, the effect of desmopressin is different in women and men. It is hypothesized to be attributable to a difference in density of the V2 receptors in the renal tubules between men and women. It seems that the optimal dose of desmopressin for women should be much lower than the optimal dose for men. That would significantly decrease the risk of hyponatremia in women. The optimal dose for men is not clear, however; according to one of the papers presented at the meeting, it is somewhere between 2 and 2.6 times the dose in women.3 This is a very significant and surprising finding, because this male–female difference is not seen in other pharmacologic categories. The science behind this phenomenon was worked out by Kristian Juul.4
Dr. Nimeh: During the nocturia sessions at the ICI-RS meeting, the definition for successful treatment in patients with nocturia was discussed. Was a consensus reached?
Dr. Wein: Success is relative to each patient and depends on the baseline condition. For a patient who gets up four times per night, success will be different from that for a patient who originally gets up two times per night. A patient’s baseline status can also be defined in terms of the length of the first interval of uninterrupted sleep, which is the most important and restful part of sleep, according to sleep physiologists.
It is very important to understand and document the baseline for each patient by asking, “What is it you expect? What is it that you want?” Patients cannot expect to get up zero times a night if they currently get up four times a night, unless they have sleep apnea. They may be able to get to the point where they get up only two times per night, or only once per night; but, it is not realistic for them to expect to sleep through the night. We may get lucky, and we do try, but we know what is unlikely.
van Kerrebroeck P, Abrams P, Chaikin D, et al. The Standardisation of Terminology in Nocturia: Report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn. 2002;21(2):179-183.
Weatherall M. The risk of hyponatremia in older adults using desmopressin for nocturia: a systematic review and meta-analysis. Neurourol Urodyn. 2004;23(4):302-305.
Yamaguchi O, Nishizawa O, Juul KV, Nørgaard JP. Gender difference in efficacy and dose response in Japanese patients with nocturia treated with four different doses of desmopressin orally disintegrating tablet in a randomized, placebo-controlled trial. BJU Int. 2013;111(3):474-484.
Juul KV, Klein BK, Sandstrom R, et al. Gender difference in antidiuretic response to desmopressin. Am J Physiol Renal Physiol. 2011;300(5):F1116-F1122.