CME Slides Forum - S.C.W. Tang

FLUID BALANCE, NOCTURNAL PD AND SLEEP APNEA

Sidney Tang, Hong Kong, Hong Kong SAR, China

Chair: Giovanni Cancarini, Brescia, Italy

Rafael Selgas, Madrid, Spain

tang

Dr S.C.W. Tang
The University of Hong Kong
Queen Mary Hospital
Hong Kong, China

Thank you Chairman, Ladies and Gentlemen. I just want to take this opportunity to thank the organisers, particularly Doctor Zoccali in inviting me here to this beautiful city to speak before you on this topic about sleep apnoea and peritoneal dialysis. I have just realised that this may be a perfect setting for a nap in the afternoon, particularly in patients or subjects with sleep apnoea.

Before I talk about sleep apnoea and peritoneal dialysis, I just want to digress a little bit to talk about sleep disturbances in dialysis patients which were first described about 25 years ago by Strub in Germany who reported a substantial proportion of his patients who complained about diminished and fragmented sleep and increased time lying awake in bed. Nowadays of course, we know that sleep disturbances in uremic patients comprise a combination of presentations ranging from sleep apnoea to restless legs syndrome and excessive daytime sleepiness etc.

Now, the factors responsible for these sleep disturbances in uremic patients are multifactorial ranging from treatment-related to psychological to disease-related factors and for the purpose of the next 20 minutes or so I would just focus on fluid balance as well as sleep apnoea.

So I just want to tell you why sleep apnoea is so important and of course, you know that sleep apnoea is emerging as a very important medical condition because of its medical and also socioeconomic implications ranging from reduced performance at work, to increased risk for motorcycle accidents and the risk of stroke and sudden death and so on.

This is a study performed by Doctor Zoccali reported several years ago which showed that indeed in about 50 haemodialysis patients that the existence of nocturnal hypoxemia defined in this study as a saturation below 95% was indeed associated with an increased risk of fatal and non-fatal cardiovascular events upon a longitudinal follow-up of up to 5 years.

So just a brief word on the definition of sleep apnoea which is characterised by intermittent episodes of breathing disruption during sleep either from airway collapse in which it would be termed obstructive type of sleep apnoea or cessation of respiratory effort in which it would be called central type of sleep apnoea or a combination of both types. In both obstructive and central sleep apnoea associated with disturbances of sleep architecture as well as daytime sleepiness. The Gold standard for making a diagnosis of sleep apnoea would rely on the use of overnight polysomnography which would report the presence of the number of apnoea events per hour of sleep or the respiratory disturbance index (RDI) or the so-called apnea-hypopnea index (AHI) and this letter index will be used throughout my talk.

I just want to show this typical tracing, polysomnographic tracing. This is a 2 minute tracing, 120 seconds as shown here of a patient while being monitored on PSG and what is found here was that after several breaths of normal airflow there was reduction in airflow and that was coincided with the presence of paradoxical breathing. You would note that the coordination between airflow and abdominal movement was sort of normal during the normal phase of breathing but here you would see a paradoxical type of breathing meaning a breathing which is out of phase between the airflow and the abdominal movement. After several seconds this was followed by a drop in saturation from a baseline of 95-96% to 93% and this was followed by snoring which was recorded on the microphone and some arousal in the brain waves leading to restoration of normal breathing. So this is a typical tracing of obstructive apnoea.

In contrast, this is a tracing typical of central sleep apnoea. I won’t need to go into the details because all the lines here are flat there is no flow there is no abdominal movement and there is desaturation and then there’s no snoring.

The prevalence of sleep apnoea ranges from 2-4% in the general population but in uremic patients, the prevalence is as high as over 50% based on survey questionnaires as well as overnight polysomnographic findings. This is data from our group which uses questionnaires which show that among Chinese patients on CAPD over 60% of patients or more than 1 in 2 patients on CAPD indeed complained of sleep disturbance.

So why would uremic patients be at risk in developing sleep apnoea? Well, obviously the comorbid conditions affecting uremic patients such as cardiovascular disease, diabetes and obesity are also very prevalent in uremic patients and that may give rise to some potential patient selection bias. But there is accumulating evidence to show that indeed the accumulation of uremic toxins during uraemia may play a pathogenetic role although the exact mechanism of uraemia-induced sleep apnoeas is still not known.

This is a study published just last year by a group in Pittsburgh which showed a remarkable 4-fold increase in sleep apnoea and severe nocturnal hypoxemia after adjusting for cardiovascular disease and diabetes in 46 haemodialysis patients compared with matched controls from the Sleep Heart Health Study indicating, of course, the pathogenetic role or the possible causative role of uraemia in inducing sleep apnoea in patients on dialysis.

The basis for uraemia-induced sleep apnoea is best exemplified by this landmark paper published by Doctor Patrick Hanly a couple of years in the New England Journal who showed that there was a corrective potential of converting patients on conventional haemodialysis to nocturnal haemodialysis carried out 5-6 times per week 8 hours per session. What he showed was a remarkable reduction in his 14 patients in this study that the age I reduced from very high levels to near normal levels after the pair being converted from daytime conventional haemodialysis to nocturnal haemodialysis.

The same group from Toronto, this is a paper published by Doctor Christopher Chan who showed that apart from a reduction in the AHI after conversion to nocturnal haemodialysis that there was correction or restoration of autonomic modulation of heart rate related to the correction of sleep apnoea. Never mind about the small print but note here that there was an increase in vagal heart rate modulation from very low values to near normal control values and also a reduction in sympathetic over activity after conversion from conventional to nocturnal haemodialysis.

However, there was a scarcity of data on peritoneal dialysis whether or not switching patients from daytime or conventional CAPD to nocturnal PD would also achieve a similar or comparable degree of improvement in sleep apnoea is not known.

So we set out to perform a study some time ago to compare our patients who are on NPD to patients who are on CAPD and what we found was that the CAPD group, by the way were matched to the nocturnal peritoneal dialysis group in terms of these parameters here and what we found was that there was a remarkably low incidence of sleep apnoea in patients who were on NPD.

Look at these bars here whereas, for patients without sleep apnoea meaning an AHI below 15 more patients with NPD did not have sleep apnoea. Note also that when we look at the PSG raw data that there was a marked difference between the AHI values between the NPD group and the CAPD group, as well as the minimum oxygen saturation during sleep between these two groups.

A subtype analysis also showed that in fact, there was a difference in all the three types of apnoea in both groups of patients.

But the most marked difference was in the obstructive form of apnoea, leading us to perhaps speculate that it was volume overload or airway oedema in the CAPD subjects that gave rise to an increased prevalence of sleep apnoea.

We have heard from Doctor Krediet and also Doctor Van Biesen previously that our CAPD patients are by default fluid overloaded. So was it really fluid overload in our CAPD patients that gave rise to an increased risk of sleep apnoea? To answer this question, of course, we need to perform some proper conversion studies as Doctor Hanly in his haemodialysis patients did but we reckoned that one of the difficulties in performing conversion studies in patients on PD is that there’s technical, as well as logical, as well as ethical difficulties in converting patients and you can imagine that it takes a while for the patients to be trained on a certain connectology of PD and it would not be easy to convert them from one type of CAPD to an automated nocturnal form of PD. Nevertheless, we took advantage of the fact that incident patients would require a period of in hospital nocturnal PD anyway while were they were waiting for their turn to be trained so we took advantage of this and performed a PSG in these patients while they were waiting for training and receiving in-hospital nocturnal PD and after they had been trained on CAPD we then repeated another PSG when they have established and they were established on stable CAPD.

What we found was that when these patients, they are now serving as their own control, when these patients were on NPD the AHI values were low and when they were subsequently established on CAPD their AHI values went up.

We then wanted to examine whether it was fluid that contributed to the increased severity of sleep apnoea in patients on CAPD after conversion from nocturnal PD and therefore, we measured these patients’ body water composition using multifrequency bioelectrical impedance analysis and what we found shown here on the white bars are the patients who are on NPD and on the solid bars were the same patients when they were converted to CAPD and note that there was a difference in their body water content in terms of total body water, extracellular water and also intracellular water.
All these parameters, all these water contents were lower when these patients were on nocturnal PD than when they were on CAPD.

This is a plot to show the changes in fluid balance after conversion from CAPD to NPD and we performed BIA measurements before nocturnal PD and right after nocturnal PD to examine the amount of fluid of water that was removed during the process of NPD and we performed the same measurements in the CAPD subjects before the overnight dwell, as well as after the overnight dwell of CAPD and what we found was that there was a dramatic reduction in total body water, extracellular fluid and as well as intracellular water, when these patients were on NPD after the overnight NPD process than when these patients were on CAPD.

We also calculated the total body water reduction in terms of hydration fraction which was expressed as the body weight which was contributed by total body water times 100%, so that’s the hydration fraction. Once again what we found was that when these patients were on NPD, there was marked reduction or removal of hydration or reduction of hydration fraction after NPD than when these patients were on CAPD.

So indeed, these data would suggest that indeed it was fluid or water that mattered that gives rise to a difference in the severity as well as the prevalence of sleep apnoea in these subjects.

Now in support of these findings, this is a study published last year by Doug Bradley’s group also from Toronto which show that among 11 patients they applied a lower body positive pressure to these patients by using anti-shock trousers and applied 40 mmHg for 1 minute or 5 minutes and what they found in these 11 healthy subjects in the supine position that there was an increase in neck circumference, as well as an increase in transpharyngeal pressure indicating an increase in pharyngeal resistance. So, this is a tracing from a typical patient.

When they looked at the 11 patients together, there was once again an increase in pharyngeal resistance when these patients received a lower body positive pressure stockings than when they were not exposed to these manoeuvres. Likewise there was also reduction in lower limb fluid and also an increase in neck circumference. Obviously, this design is to simulate the clinical condition of fluid overload. Therefore, when fluid overloaded patients, when they lie supine during sleep, it is possible that some of the fluid in the lower limbs would move to the upper part of the body, notably in the neck and notably also causing an increase in pharyngeal resistance. This may give rise to obstructive sleep apnoea.

So, to my list of risk factors that may give rise to increased prevalence of sleep apnoea in PD patients would be fluid overload.

So, I just want to conclude here that sleep apnoea is prevalent among uremic patients. Fluid control indeed plays a very important role in causing sleep apnoea although other factors may also operate. This is in agreement with the fact that our CAPD patients may be fluid overloaded, as already alluded to by Doctor Krediet and Doctor Van Biesen. Therefore, optimal fluid control is of paramount importance in the therapy for sleep apnoea in PD patients.
In this regard nocturnal PD might be better than CAPD in correcting sleep apnoea. I use the word ‘might’ be because the number of patients indeed we’ve shown is small and also the number of studies in the literature is also scarce and therefore, further studies such as randomised studies or studies with proper crossover design will be needed to address this issue.

So hopefully with better fluid control our PD patients would not need to become too sleepy during the daytime.

I just want to close by acknowledging my clinical colleagues, colleagues in the sleep laboratory and renal nurses for putting this data together. I thank you very much for your attention.

Question: -- from Egypt. Congratulations for this excellent presentation. My query about the great difference between the nocturnal patients, the nocturnal peritoneal dialysis patients and the CAPD patients as regards to the sleep changes and sleep apnoea. As you mentioned that the causes are multifactorial and among these are uremic toxins as you mentioned. The peptides and the hormones frequently encountered there have a nocturnal reason, for example. Could this participate in the great changes encountered between these two categories of patients?

Question: Could the difference be attributed to the diurnal changes of the endocrinal factors and the hormonal factors and peptides namely or – play an important role in such sleep disorders?

Prof. Tang: Yes, thank you very much for your question. Well, I think if the variation in hormones should play a role that would affect both CAPD as well as NPD subjects. Am I correct? Also in our fixed sequence interventional data we showed that the CAPD and the NPD were performed in the same subjects when they were receiving different modalities of PD. So the subject was serviced there on control, so if there is any contribution from hormonal variation that should have been corrected.

Question: The clearance of such hormones during night and the nocturnal patients may be more than the other category of patients.

Prof. Tang: So you think the nocturnal would clear more of these hormones during PD? Well, I think that’s a good idea. I think we will probably look into that but I think one of the important things that we have shown is that NPD per se would remove more water during sleep than CAPD and we’ve shown it on our BIA measurements.

Question: But the question to differentiate NPD and CAPD in terms of influencing the final results is that the syndrome is not central but obstructive, so it’s very difficult to establish a relationship between an obstructive process and a central-mediated process such as the hormones could be mediated. I’m not sure that it is a correct plan to look at the influences of hormonal systems in what is mediated specifically by compression or by physical effects. Let me say something because I think it’s very, very important what pneumologists have introduced in the sleep apnoea syndrome which is the volume of the mediastinal fat and I was thinking that probably the difference between CPAD and NPD is the sustained intra-abdominal pressure that represents the NPD over the night of these patients when NPD patients release from this pressure at least 4-5 times per night. This indeed could influence what has not been included in this study. When I read your study I missed this part of the analysis. I congratulate you for your study but I missed this part because probably this sustained intra-abdominal pressure sustains some degree of mediastinal hydration or overhydration maybe by lymphatics or in some way but the other question is that probably the content of fat, of this mediastinal and neck content of fat is very, very influenced.

Prof. Tang: Yes, I agree with you and also the other factors maybe pulmonary mechanics with continuous intra-abdominal pressure rather than intermittent, there may be some changes in pulmonary mechanics which may favour sleep apnoea in these patients. We have actually performed a spirometry in all the subjects but of course, one of the short comings of performing spirometry is that you do it in the awake patients and also in the upright or sitting posture, whereas during sleep it’s completely different. So we found actually no difference in pulmonary mechanics using standard spirometry but that may not reflect the true situation during sleep in the recombinant posture. Your point about the neck, the amount of fat, well I think that’s also a very important point because the amount of fat would also influence the airway resistance. In our study we have not been able to demonstrate a difference in neck circumference in the subjects before and after conversion from NPD to CAPD but I think that the measurement itself may not be sensitive enough you know if you just measure the neck circumference a very subtle difference may not be picked up and minor differences may not be able to allow you to conclude that it was due to a difference in neck circumference. Doug Bradley’s studies showed that by applying lower body positive pressure there was an increase in pharyngeal resistance and once again this may imply that in our patients, I mean if we just measure the neck circumference that may not be sensitive enough to pick up the subtle increase in phareangyl resistance.

Question: Alan -- from Australia. The easiest way to prove or disprove your theory would be to look at 3 times a week intermittent dialysis patients. The night before dialysis and the night after dialysis they have a 3-4 L, my patients anyway, a 3-4 L difference in their volume. Do you know whether that’s been done?

Prof. Tang: Well, I think you’re referring to the nocturnal haemodialysis study.

Question: No, if you just look at the ordinary patients on 3 times a week 4-hour haemodialysis the night before their dialysis they have 3 L more than the night after their dialysis. If your theory is correct you’d expect them to have a lot more sleep apnoea the night before dialysis than the night afterwards.

Prof. Tang: Yes because of the larger amount of fluid. Well, I’m not aware of any data in the literature on this but I think that’s a good point.

Chairman: Ok thank you very much for the contribution to all and to all speakers and to the audience. Thank you.