Waking up at night to urinate is by far the most bothersome lower urinary tract symptom, wrote Gopal H. Badlani, MD, in an editorial for Urology Times.1 He further added that nocturias impact on quality of life and health is profound. In this interview, Badlani spoke with Jeffrey P. Weiss, MD, PhD, who discussed how he defines nocturia, how to separate the symptom from

overactive bladder, and how he conducts patient work-ups for nocturia. Weiss is professor and chair of urology at SUNY Downstate Health Sciences University, Brooklyn, New York. Badlani, an editorial consultant for Urology Times, is professor and vice chair of urology at Wake Forest Baptist Medical Center, Winston-Salem, North Carolina. Disclosure: Weiss is a consultant/study investigator for Ferring.

How do you define nocturia? Is it the number of times someone awakens to pass urine, or is it the bother related to it?

Nocturia is just a symptom. It means that somebody has arisen from intended sleep time because of the desire to pass urine. That could be once or any number of times. In terms of how many times it takes for it to be bothersome enough to merit treatment, it's up to the patient. We know from epidemiological studies that moderate to severe bother really begins at 3 times. Most of the literature considers 2 times to be significant. There are patients for whom nocturia times 1 is a chief complaint.

What if you get up at night for some other reason, without the desire to urinate, and then you urinate? That is basically a convenience void with no desire and antecedent whatsoever. Technically, that would not be nocturia, but from a practical standpoint, it's always going to be captured as a nocturic episode when analyzing a voiding diary.

If a person is bothered by getting up at night to urinate and they see their primary care physician, what should do that physician do for the patient?

They should take a history and physical examination. Nocturia is a symptom that has so many different causes. Questions should cover drinking habitstypes of fluids, amount of caffeine, amount of alcohol. Patients should also be asked about general sleep architecturesome people nap a lot during the day or have trouble sleeping at night. These things should be elicited by the primary care physician.

Do they have hypertension? Could they have nondipping hypertension, which can cause natriuresis at night and nocturnal polyuria. Do they have peripheral edema? A routine physical exam would disclose, for example, peripheral edema, that could be due to third spacing. Even dependent edema, which is not related to venous insufficiency, can cause nocturnal polyuria. People who stand a lot and people who eat a lot of sodium may get some fluid accumulation in the lower extremities during the day and excrete that at night.

Assessing a patient for peripheral edema, heart failure, and venous disease is general medicine. If they have renal insufficiency and they have problems with excretion of free water at certain times during the night, do they take diuretics? Are they taking long- or short-term thiazides? These are all basic internal medicine principles.

The real question is, who's responsible for synthesizing all of that? Is it general medicine, or is it urology? It's not a turf battle; it's whoever is going to take an interest in it. I would purport that none of these require the skill set of a urologist. As urologists, we certainly pay attention to lower urinary tract symptoms (LUTS), but nocturia typically is not a normal lower urinary tract symptom.

From the urologist's point of view, what is the key question that they should be asking in order to separate nocturia from overactive bladder?

It's very simple; you go right to the definition of overactive bladder. The hallmark is urgency. If a patient has urgency, day or night, then they have overactive bladder symptoms. Now, it is true that if they have nocturnal urgency, there is some evidence that they might benefit from an antimuscarinic. Otherwise, if they have no urgency, the chances are that antimuscarinics, which are so overused for nocturia, will not work.

It's important to distinguish between daytime and nighttime LUTS. Many patients are referred for LUTS/BPH and you talk to them and they say, "I'm getting up at night." When you ask, how about during the day, they say, "No, during the day there's no problem." That's not really going to be OAB unless there's a strong urgency component.

It's incumbent upon all of us, including primary care providers, to examine the lower abdomen and make sure that we're not dealing with urinary retention. Admittedly, it's hard to palpate a bladder even when it's fairly full, but you wouldn't want to miss the ones that are grossly overdistended.

What is your working algorithm when evaluating a patient for nocturia?

As I mentioned earlier, a history and physical exam should be performed. You should obtain an accounting of medications, behavior, underlying medical conditions, and physical exam findings that may relate to nocturnal polyuria. A urinalysis should be done, as you don't want to miss hematuria and bladder cancer. PSA screening may or may not be something that you wish to undertake as part of the nocturia workup. I don't think it's central.

However, what is central and is unequivocal is a voiding diary, which includes a frequency voiding chart, accounting for time and amount of voiding. You should also include subjective sensations, such as an urge perception grade, or a degree of incontinence. Now, you're talking about a diary, which adds some subjective findings to the objective time and amount on the frequency volume chart.

The gold standard for a frequency volume chart is a 24 hourtechnically 3 full 24 hours, because there is considerable variability. Will a nocturnal only diary suffice? Yes, if you have excluded 24-hour polyuria. No matter how good you are, no matter how much you talk to a patient, even if they're on medications that cause polyuria, such as lithium, you won't know that a patient has global polyuria until they do the 24-hour collection. That doesn't necessarily have to be a frequency volume chart. A simple 24-hour collection to assess their 24-hour output would exclude global polyuria, which would be defined as 24-hour volume in excess of 40 milliliters per kilogram. Let's say in an average person, that would be around 3 liters. If they are putting out 3 liters, they're drinking at least 3700 milliliters, which is a lot. Why is that? Are they thirsty? Are they doing it because they think it's good for their kidneys? Are they dieting? Do they have a behavioral problem, or do they actually have a thirst problem?

What instructions do you give patients when you send them home to do the voiding diary?

I think it's reasonable to tell patients that they can drink in accordance with thirst, and no more. Thirst is rarely abnormal in any patient. If you tell patients to restrict themselves to a certain volume and they are able to stick to it, but that volume is insufficient to cover obligatory losses, they will fall behind and they can become hypotensive. Therefore, it's dangerous to tell patients to take in a fixed low amount of fluids without knowing whether they can actually concentrate urine.

I will ask patients, when you take your medications, do you take a pill with an 8-ounce glass of water because you need that much to get it down? Could you get that pill down with a gulp or sip of water? If your mucous membranes are dry, do you drink a glass of water, or do you just wet your mucous membranes? I'm trying to get patients to minimize intake. I explain to them that the dumbest kidney is smarter than the smartest doctor, and try to get them to realize that they don't necessarily have to "flush" their body to keep their kidneys going properly, that their kidneys will be just fine even with less intake.

A frequent complaint I hear from patients is that they are always thirsty at night, whether they breathe through their mouth or wake up and drink more during the night. How do you address this?

Look at the medications they're taking and see if any of them cause xerostomia. If they are taking one of these medications, can they be exchanged for ones that do not cause xerostomia? If it's just a case of waking up and being thirsty, I tell patients to just wash their mouth out and maybe take a little sip, rather than drink an entire glass. That will make a big difference.

What about excess urine output at night? How do you treat that?

That's nocturnal polyuria, which has 2 definitions. One is when, on a 24-hour voiding diary, more than 33% of urine volume is made at night. The other definition is a urine volume greater than 90 milliliters per hour; that's an absolute measurement that is not determined by 24-hour output. Once you find that they have nocturnal polyuria, you look for a cause. It could be behavioraldrinking too much fluids at night.

It could be sleep apnea. Sleep apnea causes nocturnal polyuria due to the fact that hypoxemia causes pulmonary artery vasoconstriction, which causes increased pressure in the right heart. The heart thinks there is too much stuff in the vessels and it excretes atrial natriuretic peptide, which is a very potent natriuretic and it turns off antidiuretic hormone and causes tremendous diuresis. That can be treated with continuous positive airway pressure.

It could also be peripheral edema. One of the first things I do in the office when someone says they're getting up at night to pass urine is lift up their trouser legs and see if they have pitting edema. I ask them: Do you have swelling in the legs? Do your shoes start to get tight at night? Some of them know they've got swelling. Some don't know it at all, and then you push in on their pre tibial area and you'll see the pit and they go, "Wow, that's amazing."

Peripheral edema can be due to heart failure. It can also be due to venous insufficiency, which is probably more common. It could be due to dependent edema, which you'll see in people who stand all day; for example, people who work in a department store or surgeons. Some people just love salt, and eating too much sodium will cause fluid retention in the legs, which returns as gravity no longer is the factor to the central circulation and results in nocturnal diuresis.

Of course, medications can also play a role. Taking a diuretic at night might cause nocturnal polyuria because you're inducing diuresis during the hours of sleep. Short-acting diuretics, such as furosemide or hydrochlorothiazide, are given first thing in the morning. If you are accumulating fluid in your legs, and you're waking up dry and take your diuretic first thing in the morning, you can't get any drier than you're going to be. Therefore, it's best to take a diuretic in midday, if it's a short acting drug, or in the morning, if it's a long acting drug such as chlorthalidone, which probably is a better drug for nocturia. Taking the wrong diuretic and the wrong antihypertensive at the wrong time will clearly exacerbate nocturia, as was found in a recent study published in the New England Journal of Medicine.2

It seems as though there is no "quick fix" for addressing the problem.

That's what is so frustrating about nocturia. It's 1 symptom, and it has easily 20 different underpinnings, which means that it's so easy to find things that result in nocturia. But because of the multifactorial nature, we only make little increments when we fix each factor. In particular, the older the patient, the more multifactorial it gets and the more difficult it is to treat. In the younger patients, there tends to be 1 or 2 big problems that can be solved with 1 or 2 major maneuvers. For example, in a young person with sleep apnea and nocturia, there's a very high probability that treatment will resolve it. You don't find too many patients like that though.

What about a patient who has nocturia and insomnia?

That's a little tricky. Sleeping pills work great for nocturia, but I never use them. Why? They're addictive. It's just not the class of drug that I feel comfortable using to treat insomnia.

Does the patient have abnormal sleep architecture? Maybe they just like to stay up at night and read or watch television or do something stimulating. That's not going to work. I tell them, "You're upside down with regard to your life." Of course, it's hard to fix someone who's a shift worker; that's about 2% of the population.

The first step is to diagnose it properly. On my diary, for the lower urinary tract symptom score, we have an urge perception grade for each void. If the urge perception grade for most of the nocturic voids is zero, that means that they were not awakened by the desire to pass urine. That's a sleep disturbance, so I would send them to someone who practices sleep medicine.

In terms of practical advice, a little exercise at night is helpful, doing whatever it takes to make them really tired at night; for example, reading a book and then drifting off to sleep. Now, if they have a prolonged sleep latency, and if they have easy awakening, that may be a little bit above the pay grade of a urologist, and that requires intervention by a sleep specialist. Typically, they're going to give anxiolytics and sleeping pills. Anybody can do that, but I don't like it as a treatment for anybody, frankly.

When does desmopressin come in?

That's a very good question. If you're a pharma company, desmopressin is basically treatment for anyone with nocturia. But the reality is, desmopressin is for someone who has nocturia in the absence of an underlying medical condition that's contributing to it. All these conditions that we talked aboutheart failure, sleep apnea, anything causing peripheral edema, certain medicationsall of those should be addressed first. We did a study that found that the minimum number of patients who have what we call the nocturnal polyuria syndrome, which is the ideal patient to receive desmopressin, is somewhere between 17% and 40%, depending upon whether you include hypertension in the numbers and what definition of nocturnal polyuria use.3

Why is the penetration of this drug so low? Are urologists afraid to use it in adults?

I think it's less fear than the obligation that one has to spend a lot of time on that patient. You need to know their baseline sodium. If they're over the age of 65, which so many of our patients are, it's recommended that you obtain a serum sodium within the first week of starting the medication or a dose increment and then follow-up sodium thereafter. I think there's a concern, particularly on the part of urologists, that they don't necessarily have the bandwidth or the office capability to follow patients so closely regarding their sodium.

Are there any new innovations in that regard that could lessen that issue?

There is research that is ongoing with new chemicals that are antidiuretics. The approved versions of desmopressin, which would be the orally dispersible tablet (ODT, Nocdurna) and the spray (Noctiva), are probably about the same in terms of their net total bioavailability and so the incidence of hyponatremia is actually quite low. If you select your patients carefully, then you don't have to worry nearly as much about hyponatremia.

Who are those patients that you don't have to worry about? First, patients who have normal baseline serum sodium and normal renal function. If you have normal renal function, you'll be hard pressed to accumulate desmopressin to the extent that it will cause hyponatremia. Sex is another factor. Women are more sensitive to desmopressin than men, which is why there is a gender differential in terms of dosing, at least for Nocdurna. There is no gender distinction in dosing with Noctiva. That's just the way that the studies were done. Women were found to be more sensitive to desmopressin melt than men. We know that females, at least in laboratory studies using a murine model, are about 2.7 times more sensitive to desmopressin than males. That's felt to be due to the fact that the V2 receptors seem to be encoded on the X chromosome, so that there's this phenomenon of X escape that women are more resistant to. Women can actually get away with a much lower dosage of 25 micrograms, compared with the recommended dosage for males, which is 50 micrograms.

Is there anything else you'd like to add?

For me right now, the most exciting area in nocturia research is the nexus between nocturia as a symptom, and cardiovascular disease. It may turn out that nocturia is actually a symptom of hypertension. We tend to think of hypertension as being the "silent killer," but it may be that many individuals have nocturia due to pressure-natriuresis, in turn caused by failure of blood pressure to dip normally at night. This nondipping hypertension is an intriguing phenomenon that we've known about for a long time but haven't really studied so well.

Also of interest to me is what we found in terms of responders to nocturia among those who do not have nocturnal polyuria: In these patients, their nocturia did not improve because their small bladders got bigger. As you well know from many years of practice, it's virtually impossible to give a medication that increases volume per void. We have great medications for urgency, but not for low voided volumes. So it turns out that patients who improve their nocturia who do not have nocturnal polyuria got better because their nocturnal urine volume went down despite the fact that it was normal to begin with. Those patients who responded clearly had mostly behavioral modification causing their normal nocturnal urine output to go down further, but also leads me to conclude that those patients might very well be treated with an antidiuretic, which currently is indicated for nocturnal polyuria. Accordingly, it may be that desmopressin could be indicated for small bladders. This is something that definitely deserves further consideration from a research standpoint.

References

1. Badlani GH. Data shift thinking on nocturias causes, treatment. Urology Times. November 20, 2018. Accessed August 12, 2020. https://www.urologytimes.com/view/data-shift-thinking-nocturias-causes-treatment

2. Victor RG, Lynch K, Li N, et al. A cluster-randomized trial of blood-pressure reduction in black barbershops. N Engl J Med. 2018;378(14):1291-1301. doi:10.1056/NEJMoa1717250

3. Emeruwa CJ, Epstein MR, Michelson KP, Monaghan TF,Weiss JP. Prevalence of the nocturnal polyuria syndrome in men. Neurourol Urodyn. 2020; 39(6):1732-1736. doi:https://doi.org/10.1002/nau.24403

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