Diane Newman: Welcome everybody to UroToday. I'm Diane Newman. I'm a nurse practitioner at the University of Pennsylvania and an editor on the UroToday website. Today I have a colleague of mine that I'm very proud to present, Dr. Jeannette Potts, who's the co-founder of Vista Urology in San Jose, California. This is a second part of a three-part series on nocturia, and Dr. Potts is going to share her knowledge and where we are at the current stage with nocturia risk factors or marker. Thanks for coming, Dr. Potts.

Jeannette Potts: Thank you. Thank you. It's a vicious cycle. Nocturia can be the cause of serious medical illness or it actually can be a marker, a sign to us that something else is going on that is more serious to our patient, not just the nuisance of getting up at night.

How do we really approach this? In the previous talk I talked about is this really a sleep disturbance only or is this really the bladder waking the patient up because they're full. Is it because it's a bladder issue or is it polyuria? So to get to the bottom of that, we need to understand the onset of the symptoms and the past medical history, things that may be risk factors for renal insufficiency or cardiovascular insufficiency, the medications that are taken and the time of day, this cannot be overstated, and finally, the physical examination. There are clues there for us, checking the heart, making sure there's no pulmonary edema, pedal edema and such.

In the urinalysis we're looking at specific gravity and of course an abnormal sediment. Lab studies, depending on where we're guided by the physical exam, would probably include things to assess renal function. But the most important tool is the voiding diary. The voiding diary, the voiding diary, the voiding diary. If anything, we just need the time of day and the precise volume of urine voided at that time, and this gives us a clue to many diagnoses. In fact, I would say that any symptom that involves the lower urinary tract should always include a voiding diary. I can tell you, Dr. Payne and I in the past eight years have yet to have a patient come in with a voiding diary or know what that is, and we're usually the fifth or sixth opinion.

Here's an example of a voiding diary I had from a man who was repeatedly treated for his BPH. As you can see, the patient has the nighttime urination is in yellow. What I've done is I marked all the urine volumes that occur after he has retired, after he's gone to bed, and he did confirm to me that at 11:00 at night he went to bed after this void. To calculate or add up the nocturnal urinations, you have to start from the first void after retiring and include the first void upon awakening. When we do this in this patient, we get the nocturnal volume, which is 1600 ccs and divide it by the total 24-hour amount, and that gives us an NPI or Nocturnal Polyuria Index of 0.565. Clearly abnormal. The NPI should be less than 0.33 for patients over the age of 65, and some would argue that it should be less than 0.20 for those who are younger. There may be a little bit of latitude there, but clearly someone who is voiding more than one-third of their total 24-hour volume has, by definition, nocturnal polyuria.

Is this a risk factor or a marker? First, we're going to look at nocturia as a causal risk factor. The first issue is just sleep. It's good to know that there is now more and more research, much of which is included in this book, regarding the importance of sleep and its value. Both the quantity and quality of sleep are important. For most people a total of seven to nine hours of sleep are necessary. There are some exceptions, and there is also evidence that some people do well with breaking up sleep into two different segments.

The first four hours of sleep are our deepest sleep, and as you can see here, there's very little REM sleep. We don't dream as much in this period of time, but this is when we get our deepest sleep. This is very important for our cognitive function, for our memory, and for just a battery reset, if you will.

The second half is for dreaming, and we'll go back here and see that the REM sleep dominates here, and there is a little bit lighter sleep during that period. You'll see some of the research is a little bit dismissive of this second half of sleep, but I would submit to you that this is equally important. In fact, for things like post-traumatic stress disorders and other psychological diagnoses, having dreams and even promoting the opportunity to dream even if it includes nightmares, is found to be very therapeutic for our mental health.

Nocturia disrupts the sleep and more including, like I said, dreams. Obviously this predisposes to chronic fatigue, predisposes to depression, it disrupts our circadian rhythms which govern much of our endocrinological function, so it's not surprising that there's hormonal disturbances. Trauma can occur, immediate through falls or even things subsequently from being sleep deprived: driving, automobile accidents, accidents at work. It also leads to hypertension and a higher mortality rate.

Nocturia has been shown to increase the risk of falls, and it increases the risk twofold of hip fractures in a kind of a little bit of confusing study, but it still points to the importance of nocturia. 178 patients who had previously fallen were compared with their cohort of elderly patients who had never fallen. If they did not take into account nocturia, their mortality rates were similar. But once nocturia was factored into the analysis, the group that had already fallen had an increased risk of mortality that was 75% higher, and there was a 53.6% increase in the people who had never fallen. In nine observational studies that included over 5,000 subjects, nocturia was associated with a 20% increase in falling and a 32% increase in fractures. The risk, of course, is magnified with older age and voiding episodes of greater than two per night.

Nocturia alone has been shown to increase mortality in this study by 72%. Interestingly, when nocturia was combined with disturbed sleep, the risk was lower but still overall higher at 43%. I believe that's because the disturbed sleep may be driving the nocturia in those patients so they're dealing with disruptive sleep alone, whereas the patients who have nocturia as their only factor waking them up may have an underlying medical condition which is actually magnifying their mortality risk. Lightner showed that nocturia in older men also increased the mortality rate by up to 50%.

In this meta-analysis, which was international, included over 28,000 subjects and people were followed five to 17 years, again, there's increased mortality seen and with three or more episodes avoiding per night, that mortality was up by 46%. Again, below a little bit of a paradox. The persons who were younger than 60 with nocturia had a higher mortality rate than those who were over 60. Again, it causes me to wonder that someone may have a more serious medical condition if at a younger age they are experiencing nocturia.

This graph is very interesting, and it illustrates the risk for developing hypertension. Each factor taken by itself is a risk factor for developing hypertension. For example, a subject is more than twice as likely to develop hypertension if they have diabetes. They are 0.5 times more likely to develop hypertension if they are consuming alcohol. Or BMI may play a role, maybe 20%. But what this shows is that just the number of voids can also impact hypertension. For example, here the risk goes up with one void per night, goes up even higher with two, three, and four. So we're getting a risk of hypertension that's linear to the relationship of how many times one gets up to pee at night.

So why may that happen? It's because our blood pressures are supposed to dip by about 10% every night, and things that may impair that are oxygen desaturation, fragmented sleep, diuresis or nocturia. This Japanese study group set out to find, well what is the greatest factor ... I love the methodology ... Using a home blood pressure monitor, pulse oximeter and a wrist actigraphy. Actigraphers are used a lot for studying sleep because they just measure physical activity. Anyway, nearly 6,000 patients went through this, and the results showed that the circadian blood pressure abnormalities and the smaller dips in blood pressure were strongly and independently associated with nocturia. So this may actually be one of the reasons why without that dip that people are then experiencing daytime nocturia as well.

But what if it's a marker, that the nocturia actually is an ominous sign? Again, it's not just LUTS on a urological questionnaire, it's an ominous sign of something else and that it is again this vicious cycle where there can be an underlying cause and then the perpetuation of the nocturia just makes things worse.

Causes of nocturia include obesity, diabetes mellitus, we see that a lot clinically in people who maybe are not diagnosed either and then their hyperglycemic hypertension can cause it, renal disease, nephrogenic diabetes insipidus, hypercalciuria or renal insufficiency where the kidney is no longer capable of concentrating the urine. Then there are neurological disorders like multiple sclerosis, Parkinson's, stroke, and Alzheimer's. That is not because it's causing people to get up because their sleep is disrupted ... That is a factor ... But indeed, people with neurological disorders such as these also have nocturnal polyuria because they have an autonomic nervous system dysfunction associated with their neurological disorder. This in turn can cause nocturnal hypertension and also lead to polyuria, or some of these conditions also create a lack of diurnal variation of the antidiuretic hormone, and so that also creates a scenario where you get nocturnal polyuria. Again, neurological disorders are like hitting the patient from every angle. Their sleep is disrupted to begin with, but then they end up with, many times, polyuria. This also can be associated with increased volume of the central vascular system. This is like another form of cardiovascular insufficiency. Finally, sleep apnea.

So first we'll talk about this possible compensatory action for diurnal latent cardiac failure, and that sometimes this nocturnal urination or as I've tried to put forth, nocturnal polyuria, is really a sign of this compensatory action. What's happening there is that when people have this insufficiency, they get decreased renal plasma flow, which in turn causes increased filtration while the patient is up and about ambulating. This leads to increased sodium retention. Well, that in turn creates that central volume. When one is recumbent, which would be typically overnight, this recumbency reverses the cascade and hence the development of polyuria.

Then sleep apnea, which again, it's not just the snoring, it's the fact that people are having episodes of hypoxia and all the other things, the cascade that is set up in this setting. The American Academy of Sleep Medicine estimates that 26% of the US population has sleep apnea, is growing in prevalence and that more than 80% are undiagnosed. So again, I feel very rewarded when a patient comes in to see me because he thinks he has nocturia because of his prostate, but he needs a sleep study and then he gets better.

Nocturia is independently associated with sleep-disordered breathing and its severity, and this intermittent hypoxia causes sympathetic hyperactivity. This variation in intrathoracic pressure leads to increased secretion of natriuretic hormones. I am not really that good with words, so I like images so I created this cartoon to help me better understand the phenomenon. So someone is snoring, which means they're inhaling against a closed valve. That creates a negative intrathoracic pressure. When the intrathoracic pressure is increasing, I'm saying, the negative pressure is increasing, then the heart actually increases in volume. This distension of the heart causes the atrial natriuretic peptide to be secreted. This creates in turn the activation of the renin-angiotensin-aldosterone system and increases sodium and water excretion. That's how we get nocturnal polyuria in that setting.

Obstructive sleep apnea also, because of the hypoxia, can cause irreversible damage to the detrusor muscle. Wow! Who knew that? I didn't know that. So the lower bladder capacity is now being further harmed, and then the patient now has also nocturnal polyuria to boot. So it's an important diagnosis to make. In this study, the men who are entering were greater than 60 years of age with nocturia. They had full night polysomnography done, they had their lab tests done. The BNP is a beta natriuretic protein, that's the one that's involved. Their urine osmolality was measured at 6:00 am and of course they did urinary diaries. So of the evaluable patients, it was corroborated that in fact they all had sleep apnea because of their apnea hypopnea score. They all had a greater BMI, they all had elevated systolic blood pressure measurements, they had a higher BMP, higher urine sodium and higher osmolarity. Interestingly, in the sleep apnea cohort or at least this sleep apnea cohort, there was no change in ADH, which means that this is probably not the mechanism by which the polyuria is occurring. I just kind of demonstrated that with the cartoon.

So what happens when we treat the condition? Here's five publications containing 307 patients. Everything was improved with CPAP. I've highlighted this in yellow. The number of voids per night decreased by an average of -2.28. Please keep this number in mind because it's going to come into play in the subsequent talk I'm going to give. There is no pharmacological intervention whatsoever that comes even close to the way CPAP reverses nocturia. So again, we're missing the ball if we don't treat or look for the underlying cause.

Diane Newman: Thank you very much, Dr. Potts. A really great overview of other causes of nocturia and then of course the whole mechanism for nocturnal polyuria. The thing about the CPAP I think is interesting because you do find many patients that when you ask them have they been tested for sleep apnea, many of my patients say, "Yes, I have it, but I don't use the CPAP machine." You do see in clinical practice that once they start using it, their nocturia improves.

The dilemma that I find in practice though is that it's so different for so many patients. Patients will tell me they get up once at night and they can't function during the day. Then you'll have, say, three patients who get up three times at night that that's been their norm and they've just adjusted to that type, not realizing the impact it has on other areas of their whole physique. That's I think what some of the problem is in the clinical setting.

Jeannette Potts: When people are younger and they get up once at night, especially in the wee hours of the morning when they know they have two more hours that they can stay in bed before the alarm goes off, that's the worst. For that, I try all the things, which they've already tried too, all the behavioral things. But what they're missing though is the behavioral part of sleep, just the sleep hygiene. I empathize greatly because that is just such a ... If you can't fall back to sleep, getting up once is a problem.

Diane Newman: Then you have the whole issue too, as far as patients will tell you that you're right, once they're up, they can't get back to sleep, so then that impacts their daytime function, which is really a concern. I find that it's such a bothersome symptom that, you're right, we need to really look at other reasons why they have that nocturia. I think a diary is so very helpful. Now, when you were talking about the diary, we're talking about a frequency volume chart where they actually measure their output. How many days do you have them do that?

Jeannette Potts: I used to have them do 48 hours ... Well, for this situation I do prefer 48 hours because I want to be able to make my calculation based on the lines I draw, and with 48 hours I have a good chunk of time. But if a patient can do 24, that should suffice. I used to always do intake and output strictly 48 hours, and my partner told me I was very mean.

Diane Newman: That's hard to do.

Jeannette Potts: But it really does give you a great picture. But then the more you ask patients to do, the more you're taking the risk that they will be noncompliant so it's better to just make it simple. I know there's other criteria too, by just simply measuring how much people put out and doing the kilogram calculation and knowing that no, they are producing more even though they're not drinking anything before bed.

Diane Newman: I had a case that stuck with me and happened several years ago that a patient who came to me saying that he was getting up three or four times at night. He'd had BPH and he'd come from another provider and he moved into my area and he just kept telling me how much. It was large amounts, large amounts. When I had him do a diary where I had him measure at night, he was going over three liters at night, and I just happened at that time, do some blood work and his sugar was 800.

What you brought up the fact of, you're right, it's sometimes undiagnosed diabetes. There are so many other medical reasons that someone may have to get up at night to urinate. Clinicians I think really have to take those extra steps and sometimes it was just [inaudible 00:22:31] and that diary then really pushed it and said, "Well, wait." Once he was treated, guess what? His nocturia improved.

Jeannette Potts: Yeah. No, that's a great story. I was just thinking too, again, simplifying things for the patient. I mean, you really do want to get a functional capacity by getting every volume measured all the time. But the fact is if you got that for all day, all the waking hours, I've sometimes had patients just leave the hat in the toilet and just measure the total once they put that first pee in the morning in because then they've kind of done the calculation for you. Now you don't have to do the addition for the nighttime. You just know that okay, they peed, dispose of that. Now I want you to just for the rest of the night and the first void in the morning, just do it in that hat or the urinal or whatever. Then you've got your numerator over the denominator done.

Diane Newman: That's a really good point that just put that hat in the toilet and just have them go in that then just the whole day and see that because that volume will tell you something right there. But it's important that you also track that intake though because some people are really into lots of fluids, lots of fluids and you've got to look at that and strategize what is it.

Jeannette Potts: I realize that this is not related to this topic of nocturia, but just to tell you in the past month ... Even though I'm retired, I'm still doing virtual consults ... But in the same month I had men with exactly the same symptoms, and I asked them to do a voiding diary. One of them is a voiding 50 to 125 ml day and night. He clearly, I mean he's had this issue for five years and it's progressing. He was told he had prostatitis. He's got interstitial cystitis, and we're about to get the final treatment done. He's abroad so we're trying to get that done for him. Otherwise, he's going to fly here.

Then the other man with exactly the same symptoms, he sent the diary ... This is a record, 7.6 liters a day because he's this young compulsive athlete with post void dribble and all these things and he has prostatitis and was about to get a million dollar workup for this. But again, there was really no other evidence but a voiding diary had never been done. But again, one guy he can hold 1100 ccs. He has 1100 cc capacity. So I told him, "Well, if you're lucky, you're young enough, we can rehabilitate your bladder."

Diane Newman: Wow. But it just goes to show you what the diary tell you. Sometimes what the patient's saying and then you see the diary, they just don't connect. So that's why it's so important to have another piece of information. Well, thanks so much. This was so informative, and we are going to have another presentation by Dr. Potts that's going to be on treatment.