CME Slides Forum - J. Kielstein

EXTENDED DAILY DIALYSIS FOR TREATMENT OF ARF IN THE ICU

Jan Kielstein, Hannover, Germany

Chair: Josep M. Grinyo, Barcelona, Spain

Cengiz Utas, Kayseri, Turkey

kielstein

Dr. Jan T. Kielstein
Department of Nephrology
Medical School Hannover
Hannover, Germany

Mr Chairman, Ladies and Gentlemen, first I would like to thank the organisers for giving me the opportunity to speak on a very nice but still evolving subject, namely the subject of extended daily dialysis in the ICU.

So after a short prelude I would like to explain to you the rationale why it’s useful to think about a third treatment alternative in the ICU and then present to you the data on CVVH versus extended dialysis as scarce as they may be and after pointing out specifics of the system we are using in Hanover and that is widely used all over Europe I would like to summarise our knowledge.

So, we have a 70-year old woman that is admitted to the surgery department and of course, she has a painful distended abdomen, jaundice, people think about maybe hepatorenal syndrome, we’re having a high fever. On urine analysis we find red brown urine, albuminuria, erythrocytes, leukocytes and even casts and of course, the patient was treated with antibiotics and then at a rather late time point during the course of staying in the surgical department we get a BUN of 396 mg/dL.

So what do we do? So, there are a lot of meta-analyses comparing intermittent versus continuous renal replacement therapies and although you can argue about the quality of the trials that went into this meta-analysis, overall I think the agreement in most parts of the world is that there’s no conclusive benefit of either continuous or intermittent therapies.

Well, the rationale actually stands from this landmark study by Ronco and I’m sure this is the most presented slide during this conference again, as every year because it’s so important. Ronco and colleagues pointed out that dose does matter up to a certain degree. So if you have patients with acute renal failure and treat them with a high dose of renal replacement therapy being 35 or 45 ml/hour/kg you have much, much better survival than in the group treated with a low dose of renal replacement therapy. It might be worth while to point out because this point was raised during the discussion already there might be a point beyond which it’s not useful and beneficial to increase the dose although you have a huge increase in mortality between group 1 and 2, it seems that between group 2 and 3 the difference in survival is vanishing.

So, Ronco tells us based on our results that an average 70 kg patient with acute renal failure and multiorgan failure in the ICU we recommend a starting dose of haemofiltration of 2 L/hour and more. So unfortunately, our average patient at least in Hannover is not 70 kg.

So if we take 120 kg patient, we calculate about 3.6 L/hour and more so this is quite an enormous amount of sterile expensive replacement fluid.

Just to give you a vivid idea of how much that is, so you would have to have all these boxes of sterile haemofiltration fluid to treat a patient like the one shown in the slide before. The uniform reply and reaction of our ICU nurses is this; because our ICU nurses have a lot of responsibilities and duties and they’re really overwhelmed by tasks and if they have two patients on CVVH with such a high dose, they spend most of their day changing bags in the CVVH machine.

So in 2000 Lonnemann and co-workers from Hannover published the first study that pointed out that extended daily dialysis might be a way to a third treatment way for patients with acute renal failure. What he did was that he put a patient or several patients on an 18-hour dialysis with very slow blood and dialysate flow rates and a low ultrafiltration volume and he could see that the hallmark of continuous therapies, namely stable blood pressure could be approved in these patients.

So although he could ultrafiltrate quite a lot of fluid, the blood pressure did not drop during treatment. 2 years later Van Holder from Belgium speculated that the main advantage of CRT blood pressure stability and high efficiency in terms of eliminating uremic toxins could be actually reached by employing extended daily dialysis.

Well, maybe this was a little bit premature to say that in 2001 what is the evidence supporting this?

In 2000 Kumar and colleagues from California did a very nice study where they randomised patients to either CVVH therapy or extended daily dialysis. They looked at blood pressure before the treatment, in the middle of the treatment, at the end of the treatment. As you can see, there’s no difference between the two groups and then of course, all the colleagues working in the ICU say well, this is no problem at all because I can artificially elevate the blood pressure to whatever level you wish to have it using inotropes but if you look at the number of inotropes there was no difference between the two groups as well. So suggesting that indeed the blood pressure stability could be reached by extended daily dialysis that was not inferior to continuous renal replacement therapies.

We did a study directly comparing extended daily dialysis and CVVH with a high dose as recommended by Ronco and looking at two things, blood pressure stability and detoxification. As you can see, these are severely ill patients as indicated by the APACHE score and we had a high presence of sepsis cases in that study, about 80% and most of the patients were on the respirator.

So what you see now is the comparison between 24-hour CVVH treatment and 12-hour extended daily dialysis. This is important to keep that in mind. As you can see, the urea level here was no different at the start of the therapy and after 12 hours of extended daily dialysis we did quite a reduction of the urea level which was comparable to 24 hours of CVVH treatment. The same you can see for creatinine levels and for phosphate levels. This is important because it tells you one hallmark of modern renal replacement therapy no matter whether you do high dose CVVH or SLED therapy, you deprive a patient of very important minerals and drugs. As you can see here, after 12 or 24 hours of high dose treatment we had to supplement phosphate in those patients.

So looking at pH and bicarbonate you can see pretty much the same picture. We started with acidotic patients acidosis was corrected within 12 hours and again, extended daily dialysis did a very good job that was comparable to 24 hours of CVVH treatment and the same is true for bicarbonate. We were able to deliver enough bicarbonate over the course of the treatment even though it was only 12 hours. Then as probably markers of intensity like Kt/V are a little bit problematic in long-term or even continuous treatments, we thought it would be the best idea to collect all the dialysate and all the haemofiltrate that was used and pool that and then measure the amount of urea and creatinine removed during the whole treatment. So these are data derived from 50, 60, 70 L.

So as you can see here, 24-hour CVVH treatment eliminated in the urea amount that was comparable to 12 hours of extended daily dialysis and the same was true for creatinine. Of course, there is a benefit of haemofiltration in terms of markers. You can see here that CVVH eliminated much more β2M as compared to extended daily dialysis. Whether this has any clinical significance remains to be proven.

So the second endpoint and aim of the study was to look at cardiovascular stability and so we used invasively measured blood pressure and had a pico catheter in those patients to also measure cardiac output and systemic vascular resistance. What you can see here, 12 hour treatment with extended daily dialysis the blood pressure was comparable with the treatment during 24-hour CVVH. So to make it really comparable we had to ultrafiltrate much more during the 12 hours. So here in 12 hours we eliminated almost 3L of ultrafiltration fluid and in 24 hours CVVH we eliminated a little bit more than 3 L however the difference was not statically significant. What about pressure support? So the norepinephrine dose at 0 hours was comparable in the 2 groups and at 12 hours there was no significant difference between extended daily dialysis and CVVH. So indeed, we can have cardiovascular stability in those patients without sacrificing the ultrafiltration volume or without needing more pressure support.

The same graph as the previous one is seen in cardiac output and here I continued the line because sometimes people say oh what is it after you stop the treatment?. So even there you don’t see a difference between the two groups.
Why is blood pressure stability important? Well, we don’t want to hit the kidney a second time because we have about a 40-50% chance that if the patients survive, they need their kidney function and one way to make sure that they have a high chance to regain their kidney function is to stabilise their blood pressure under renal replacement therapy.

Here’s a very nice study by Augustine saying that the mean arterial pressure after initiation of dialysis therapy predicts renal recovery and survival time. So it’s really important if you treat patients with acute renal failure, that you have a stable blood pressure.

What about in terms of hard outcome data? So up to this point there are no head to head comparative studies in terms of outcome. What we do have is a publication in abstract form by Marshall and colleagues and what they did was they looked at two hospitals where they switched from CVVH to SLED therapy either from one day to the other or in a more gradual manner and they looked at health related mortality in the hospital. As you can see here, so this is before the switch from CVVH to SLED was done and the health related mortality has its usual ups and downs and then after the abrupt switch from one mode to the other you see that there’s no difference. I was assured that statisticians know how to interpret these curves.

And you can see the same thing in the hospital death had a gradual switch from CVVH to SLED therapy even there and this was involving almost 5000 patients in this hospital there was no change in health related mortality no matter which method you employed. This is not a prospective randomised trial. So we still need those data but it think it’s rather indicative that you do not harm your patients employing this treatment mode.

What are the specifics of the GENIUS system that is used in European and even South America?

Well, maybe it’s the only system that would come close to the Pope, if he suffered from acute renal failure because it’s in the Gemelli clinic in Rome and Claudio Ronco says well, if this were an Italian pope, we would have a CVVH machine there. Well, let’s wait to see how this will develop in the future. But there’s more scientific data on the benefits rather than being approved by the Pope.

One benefit of the system is that since this is pre-filled, the dialysate cools down over time and especially in septic patients it’s important because you can see a drop in the core temperature over time. Shifting them to a more normal temperature region which I think contributes to the cardiovascular stability of those patients.

Another aspect which I mentioned already before high dose of renal replacement therapy means high elimination of potential beneficial substances. Doctor Fiaccadori did a very elegant study in Critical Care Medicine on – showing that high doses on renal replacement therapy remove drugs much more rapidly and we could show this for vancomycin. So if you give a patient in the ICU vancomycin, 1g, you can see the median drop in the drug level over time. If you start 8 hours of extended daily dialysis, you get a huge drop in vancomycin levels and in the tank of the GENIUS system you can measure the amount of the substance removed and we removed more than 30% of the vancomycin given. So this is just to caution you, don’t trust old books that give you a dose recommendation on antibiotics. They are some books still around saying 1 g of vancomycin a week is enough. It’s clearly not enough in patients treated with high doses of renal replacement therapy.

Another point is that if you change bags quite a lot in CVVH, this is always a possibility for bacteria contamination and this hasn’t been properly examined. So far wee just have one paper, a preliminary study looking at all the different access points in a CVVH circuit and opening the circuit several times might do harm to our patients by inoculating bacteria and you don’t have this problem if you use a machine that operates continuously for 12-18 hours without changing it.

extended daily dialysis is a therapy that combines excellent detoxification and cardiovascular stability. You can use a pre-existing dialysis equipment and you have a very high flexibility in terms of treatment times and of course, the cost is much cheaper than using sterile filtration fluids. It is definitely a third very popular choice in the ICU in terms of treating acute renal failure.

So when we come back to the case, what did we do in this woman? Or better she was treated by a colleague of ours, so the renal replacement therapy was initiated and of course, a therapy of 11.5 hours meaning a SLED therapy was employed with a rather low blood flow of 116 ml/minute and eventually the patient survived her acute illness and left the hospital.

I would like to introduce to you the doctor who did that treatment and he ’s Professor Kolff.

So, the case I showed you was the first successful SLED therapy or haemodialysis therapy by Professor Kolff and so it’s very nice that after decades we come back to the original treatment of how to treat acute renal failure.

And as nicely summarised by Doctor Himmelfar and Ikizler it’s uncanny how much the first successful dialysis treatment resembles the SLED therapy or to close with the words of Winston Churchill; the longer you can look backward, the further you can look forward. Thank you very much for your attention.

Chairman: Thank you Doctor Kielstein for this very interesting presentation. We have a question.

Question: Thank you very much for this illustrative talk but actually you have terrified me because in the beginning you said that the BUN is 396 and I don’t think we should allow patients to be kept in the ICU for these very high levels. You didn’t say urea you said BUN and BUN means that the blood urea was exceeding 800. Yes we could accept that at the time of Colf but we cannot accept it now and this has disturbed all over the lecture. I was not able to concentrate because I was terrified how in Germany you can keep the patient with such a level in 2007.

Dr. Kielstein: Well, I’m sorry I teased you for the entire talk but unfortunately I cannot change the case description by the original case by Colf. But that’s the way his first successful dialysis patient presented and of course, you are right that this is not the standard of care neither in Germany nor in other countries today. Maybe this gave already a way of the origin of those data.

Question: Are you aware, can you tell us direct comparisons between CVVHD versus SLED?

Dr. Kielstein: No, there’s no direct comparison of CVVHD and SLED. So there are a couple of studies underway comparing SLED with CVVH and we have to wait for the outcome of those studies. Although I’m rather sceptical given the whole history of comparison between intermittent haemodialysis and continuous therapies, it’s like you know competing religions and I think Jonathan Himmelfar did a calculation that it would need a study with about 40,000 patients to have definitive answers that would satisfy either side and I think even with big trials coming up I’m very sceptic whether everybody would accept the answers of those trials because you never have all the subgroups included, you always have restriction by entrance criteria, exclusion criteria, so I think this discussion will go on for the next decades.

Question: But don’t you think if we give diffusion along with CVVH, it would be more useful for the removal of middle molecules in an extended duration of ICU state?

Dr. Kielstein: I don’t know whether it’s the middle molecules I’m very sceptic about that but there are data that if you add or compare CVVH with CVVHD, that this is beneficial, adding a dose is beneficial. We have those data, I think it’s published in Kidney International but I had to add a comparison of extended daily dialysis versus CVVHD at that. I mean extended daily dialysis is in a way continuous venovenous haemodialysis. So whatever term you use whether it’s beneficial to add more filtration to that treatment I don’t know.

Question: What kind of anticoagulation regimen do you use in your EDD patients, if they are at high risk of bleeding?

Dr. Kielstein: Well, thank you for your question. So, so far we used very small doses of heparin but we now switch to citrate anticoagulation after Moghera and colleagues from Berlin published that it’s very easily durable with the GENIUS system we’re using currently. I think that’s another advantage because you don’t need 24 hour anticoagulation, you just need 8 or 12 hours anticoagulation and then you can transfer the patient to diagnostic procedures or try to mobilise the patients, if they are destined to leave the ICU. So in our hands this is a very useful approach to treat acute renal failure. Especially we still do a little bit of continuous treatments but they are continuous in theory and not in everyday life because you have to interrupt therapy because the patient has to go to a CT scan, so it’s never or very rarely a continuous therapy.

Question: Over here. I agree that hybrid therapy is a very important tool in the ICU but in every meeting the speakers on hybrid therapies are usually from the developed countries etc. Particularly in Europe you people have the advantage of having ultra pure water or volumetric machines. I guess one comment in these international meetings there are people from underdeveloped countries and I think it’s very important to emphasise that when we do these hybrid therapies that we have to pay attention to the machines we are using are they volumetric and the quality of our water because it’s possible that that part is sort of under emphasised and people think it’s just prolonging dialysis duration.

Dr. Kielstein: That’s a very good point and I thank you for raising it but especially with that in mind it’s hard for me to understand why your first choice in a developing country would be CVVH with enormous costs of sterile filtration bags. I think, I know there are groups in India that just use ordinary dialysis machines and turn down the dialysate and the blood flow and use this for extended daily dialysis and I think that that it is a very prudent way to go if you don’t have the resources to buy 90 L of sterile filtration fluid a day. Of course, peritoneal dialysis is still one important part of therapy in acute renal failure in developing countries. We should not forget that, thank you for raising that point.

Dr. Kielstein: Well, we have dialysate and blood flow rates between 90-180 depending on the time. So we were kind of limited by our 75 or 90 L tank. We can play around a little bit because we have tubing that allows us either a 1:1 ratio of blood and dialysate flow because we have only one pump in this machine or a 2:1 ratio of blood and dialysate flow but that’s it so there are fancy gadgets and no fancy alarms in that machine. So it’s a very simple one pump counter current flow machine which increases the acceptance in the ICU, if you involve other departments because it’s very easy to understand how this machine works.