Eric Rovner: Well, thanks, Alan. And I want to thank UroToday also for the opportunity to present some of the work that, as you said, we presented in Bristol, England, last summer at the ICI Research Society meeting. I want to thank my co-authors here. Some of the work I'm going to show you was greatly assisted by my co-authors, Marcus Drake, Andrew Gammie, Sanjay Sinha, Eskinder Solomon, and John Speich. So I want to thank them for their contributions and thoughts on this important topic. So on this slide, you can see an example of a patient with impaired compliance. In the pressurize in the subtracted detrusor channel goes up proportionally with filling. In this particular example, the detrusor pressure is represented by the third channel from the bottom, and the filling rates are on the very bottom channel. But you can see that during filling, this young woman who had a radical hysterectomy as we fill her intravesical pressures rise proportionally with filling. This is an example of a woman with impaired compliance as a result of a radical hysterectomy. This is another example. This is a young male with spina bifida. The importance of compliance really equates to risk to the upper urinary tract. Often patients with impaired compliance also have a variety of lower urinary tract symptoms, urgency, frequency, and incontinence. But really what we care about the most is risk to the upper tract, that is elevated storage pressures in the lower urinary tract resulting in risk of upper tract deterioration, ultimately hydronephrosis and if not caught in time, renal failure. The definition of bladder compliance and the calculation is pretty well established. This is from the original definition from Neurourology and Urodynamics more than 20 years ago from the seminal article from Paul Abrams, and bladder compliance represents a relationship between the change in bladder volume and the change in detrusor pressure, the subtracted detrusor pressure, the intravesical subtracted detrusor pressure.
And the calculation is pretty simple. We divide the volume change by the change in detrusor pressure, and that gives us a number. That number is calculated from, again, the point where we stop filling or where the patient develops an involuntary detrusor contraction and the volume at which that happens and the pressure at which the bladder has attained, the detrusor pressure, again, the subtracted detrusor pressure just prior to the start of the involuntary bladder contraction. So this compliance is what was previously termed a passive property, not an active property. The actual pressures attained during a bladder contraction during a volitional or involuntary bladder contraction are pressures that the bladder attains only for a brief period of time during the micturition cycle. So those pressures, voiding pressures of 50 or 100 or 150, they're not quite as important as the end filling pressure, which in a normal person, that end filling pressure just prior to the start of a volitional or an involuntary bladder contraction is actually quite small. That change might be just a few centimeters of water pressure. But in patients with impaired compliance, that change in the passive filling properties of the bladder can be quite elevated. And although there's no magic number, the calculated compliance, or I should say the values by which it is determined that the intravesical pressures and therefore the compliance calculation are abnormal can vary from a low of about six or 12 up to almost 40. So the exact abnormal compliance value, which we'll talk about shortly, or I should say the value above which we get concerned about upper urinary tract changes, that number is somewhat variable depending on who wrote the article and how long ago it was written. And that number is not written in stone.
Again, we're pretty sure that above 40 is not very good, but in some papers, as little as six to 12 might be considered abnormal. So why do we care about bladder compliance? Well, first of all, it's generally asymptomatic except for some folks with lower urinary tract symptoms or maybe recurrent urinary tract infections. And because it's silent, it can result in fairly advanced upper urinary tract changes until it's finally detected by some type of imaging. Ultimately, long-term impaired compliance results in upper tract deterioration, and in some cases, irreversible changes in renal function. So who's at risk for abnormal compliance or abnormalities of bladder filling are resulting in abnormal compliance? We know that chronic bladder outlet obstruction, males with long-term bladder outlet obstruction can have changes to their detrusor. Certainly the neurogenic population, spina bifida patients, classically low spina bifida, spinal cord-injured patients, patients with radiation to pelvic organs for prostate cancer, gynecologic malignancy, denervated bladders, patients who've had abdominal perineal resections, low anterior resections, radical hysterectomy, as the young lady that I showed you earlier. Some types of inflammatory or infectious processes that result in bladder fibrosis can result in impaired compliance.
And also patients with prolonged indwelling catheters can develop impaired compliance as well. Although those patients are well protected because they have an indwelling Foley catheter, it's those in whom have long-term indwelling Foley catheters that we then remove the catheter and don't monitor their upper tracts or assess their compliance that run into trouble. Patients with prolonged indwelling catheters are draining their urine and keep very low pressures in their bladder by and large. We assess compliance with invasive urodynamics, generally with a catheter in the bladder and a catheter in the rectum. We like to think that this test is very objective. It's probably not particularly objective because again, as I mentioned earlier, the numbers that we use to determine abnormal compliance are not universally agreed upon. And the prognostic value of the test itself is not perfect. That is to say whatever value we check or we deem important for abnormal compliance, there are patients who do perfectly fine with these numbers, and there are other patients who do poorly with compliance value somewhat less than those which are considered abnormal. So again, the problems with the way we define abnormal in compliance is that normative values are not universally agreed upon. Not all abnormally compliant bladders have complications.
Not everybody with poor compliance develops upper tract deterioration. Urodynamics is an imperfect test in assessing upper tract risk for the reasons I just stated. And the technique that we even use to assess compliance is not standardized, although the ICS would have us believe that we do urodynamics in a very standard fashion. The way that we measure cystometry, the way that we measure compliance during filling cystometry is actually not standardized with respect to a number of factors, including filling solution, filling rate, and a number of other factors. We also are fairly poor at assessing compliance in an anatomically abnormal bladder, that is patients with bladder diverticula, patients with bilateral vesicoureteral reflux or unilateral reflux into a very dilated upper tract. We're not very good at assessing compliance in those patients because those diverticular or abnormal upper tracts actually act as a pressure sink, so we're not getting a very good measurement to compliance in those individuals. And the way that we currently measure it with pressure-flow urodynamics is expensive, it's invasive, it's uncomfortable, and we need better ways to assess compliance in a non-invasive way. So again, we need to standardize the way we assess compliance urodynamically.
We need to better assess compliance in the setting of abnormal lower urinary tract and upper urinary tract anatomy, and we need to come up with ways of assessing it non-invasively and improve its measurement and its prognostic value. And that's what we can say about poor compliance. I can't really define it, but I know it when I see it. So thank you very much for the time to discuss this important concept in lower urinary tract physiology.
Alan Wein: Terrific. So that's compliance in a nutshell. So just two questions. One, is there any drug or procedure that can normalize compliance or can lessen the problems that you see or else make the curve basically lower? I mean, do any of the oral drugs do it? Does Botox do it? Does sacral and any kind of neuromodulation do it? I mean, other than a cystoplasty or something, which obviously is the ultimate solution, are there any more simple things that you can do?
Eric Rovner: So it's a very good question, Alan. Can pharmacologic therapy or other interventions meaningfully alter abnormal compliance? And the answer is maybe sometimes. And the reason I give that answer is the underlying disorders that result in impaired compliance or run the spectrum. And I suppose there are patients, and there certainly are patients who do respond to pharmacologic therapy or Botox. I'm unaware of sacral neuromodulation altering compliance, although it may. There are studies, especially in Botox, looking at compliance in certain neurological disorders, and it can change compliance in some patients favorably. So the answer is yes, in some patients. I suspect in patients with impaired compliance from an end-stage bladder from fibrosis inflammation or even denervation, it is unlikely. But in other conditions, there is clearly some patients whose compliance can be improved with Botox and perhaps even pharmacologic measures.
Alan Wein: So the normal filling rate from the kidneys, it's like one to two mLs per minute. So we fill and we know what we're going to get if we fill between 50 and 100 mLs per minute. So sort of two questions in one, do you think that any of the non-invasive methods like where you put the catheter in the bladder, this new system that is being looked at now and there's just a catheter in the bladder, that's it, do you think that that can accurately measure it? If it can, is there going to be a difference in the norms for compliance with a physiologic filling rate as opposed to the way we do it, even though the way we do it works. But as you said, it's not physiologic.
Eric Rovner: Yeah, so great question. So the technology, basically it's ambulatory urodynamics to a large degree where the pressure transducer is in the bladder for an extended period of time and the patient has a much longer time that we are assessing filling pressures as compared to the five or 10 or 15-minute rapid fill that we do in the urodynamics laboratory. Those are two different physiologic situations. And I would offer that certainly one of the limitations of the way we currently measure compliance and its lack of sensitivity and specificity for predicting upper tract risk is probably related to the fact that we fill at unphysiologic rates with unphysiologic fluid at unphysiologic temperatures. Having said that, it may be that this new ambulatory urodynamic system might give us some insight and better prediction of upper tract deterioration due to the fact that it's a little bit more physiologic over time, and it'll give us a longer look at what's actually happening in these bladders over time when the patient is outside of the urodynamics lab filling physiologically. So maybe that will help us. It also may be, Alan, that maybe intravesical pressure isn't the only important factor in upper tract deterioration.
Maybe there are other factors in play here, wall tension and other physiologic factors that we haven't looked at in terms of upper tract deterioration. We all see patients in the clinic who carry residuals of 500 CCs and a thousand CCs and do perfectly fine and have normal compliance. And then there's the opposite of patients with small volumes who do terrible with respect to their upper tract. So there's got to be, in my opinion, something else that we have to investigate to really assess upper tract risk in these patients.
Alan Wein: Well, that was terrific. And I guess as the guy's name was Justice Potter Stewart.
Eric Rovner: Potter Stewart.
Alan Wein: Yep. So I can't define it, but I know how to recognize it, so that'll have to do for now. Let you get back to work. Thanks, Eric.
Eric Rovner: Thank you, Alan. Thank you very much. Thank you, UroToday. Appreciate it.