SLED VS CRRT VS IHD IN SEPSIS

Achim Jörres, Berlin, Germany

Chair: Norbert Lameire, Ghent, Belgium

Mehmet Sukru Sever, Istanbul, Turkey

Prof Achim JörresDepartment of Nephrology and Medical Intens ive C are

C harité Univers ity Hospital

C ampus V irchow-Klinikum

Berlin, Germany

Slide 1

Before we start discussing the pros and cons of the various modalities, I’d ask you to sit back for a second andconsider what actually are the drivers of the decision to use one or the other in the real world. I think much of thatdecision has to do with local availability of course but also in the real world much of it has to do with the localconvictions or preferences and persuasions.

Slide 2

So because we don’t know really what our colleagues think about these topics, we did a survey last year in Germanywhere with the help of the German Intensive Care Society and the German Sepsis Society we sent out a detailed 4page questionnaire to more than 2.000 ICUs in the country and requested their answers on many questions roundtheir set up of acute dialysis and how they make their decisions. I’d like to share with you 2 of the answers we got. One question was, who actually decides on the type and modalityand start of acute renal replacement therapy? What we heard was that more than half of the decisions were made by anaesthetists and only 21.5% of the decisionsto start dialysis and which type of modality to use are being made by nephrologists. If you look closer to those 21%of nephrologists, it was a little over half in-house staff but already 40% were just collaborating nephrologists runninga private dialysis unit on the premises of the hospital. So at the end of the day apparently,the focus of treatingacute patients is shifting more and more away from nephrology to intensivists.

Slide 3

If we asked them ‘what is your preference, do you have a standard modality for treating acute patients?’ Then 3 outof 4 answered, yes this is continuous treatment, one of the continuous modalities, and only 22% answered, yes ourstandard treatment is intermittent dialysis and again this was nearly exclusively related to the smallest hospitals andthese will mainly be collaborating with a private dialysis doctor on the premises. So the set up and the local circumstances will actually guide or decide what therapy is being used.

Slide 4

Now what is the reason why intensivists seem to believe that a sick patient in ICU can only be treated with acontinuous therapy?

Slide 5

Well, I think if we all sit here and consider that if we do intermittent dialysis, we will inevitably produce that type ofsawtooth pattern response in our patients and this will not only be true for the composition of the plot for ureaconcentrations and so forth which go up and down.

Slide 6

This of course, will also be the case for fluid. Intuitively we probably will all agree that it might make more sense in avery unstable patient that you have a slower onset of your effect of fluid removal but then eventually you will reach asteady state and that will give you more stability.

Slide 7

Intuitively I think we agree but the thing is that in the literature there is effectively only one prospective randomisedstudy that actually looked at the question if fluid balance is better and organ perfusion and hypertension is betterconserved with continuous treatment

Slide 8

and that’s the study you see here on the slide. It’s a study from Cleveland from Emil Paganini’s group, a prospectiverandomised trial in 80 patients performed in the second half of the 90s. Whilst there was no significant differenceregarding overall survival, renal recovery or ICU treatment days, they reported a significant drop of mean arterialpressure in patients during intermittent dialysis but not in patients with continuous hemodialysis. This paper is what you always find being cited in review articles, book chapters and so forth. But when you look at it,the difference they found was really quite small. This is the graph from the paper and the actual significant drop in the intermittent dialysis group was from 77.6 to75.0 whilst there was no significant change in the continuous group. You will probably agree that this might be a classic case of statistical significance versus clinical significance but thisis all we have.

Slide 9

There is a more recent and a much bigger trial from France that was published in 2006 in the Lancet from ChristopheVinsonneau. 360 patients studied in 21 ICUs in France. What they did they had guidelines for optimal hemodynamictolerance

Slide 10

and the guidelines were: use defined blood flow, use a defined dialysate flow, increase your dialysate sodium, loweryour dialysate temperature and do an isovolemic connection

Slide 11

and with these measures you can see here there was no difference in outcome. Survival at day 28, 60, and 90 wasequal and there was also no difference in terms of duration of renal replacement therapy or length of stay in the ICUand in hospital. Interestingly there were only 6 switches from intermittent dialysis to continuous treatment because of hemodynamicinstability but there were 31 switches from continuous to intermittent mostly because of filter clotting problems,insufficient dialysis and so forth.

Slide 12

If you look at the meta-analyses of all the trials that have been performed comparing intermittent versus continuoustreatments and looking at survival, you can see here that there is basically no preference to be seen between one ofthe modalities. Specifically the more recent and bigger trials did not find any systematic advantage for one of themodalities. Because that is so, many people have in the meantime adopted the view that well, if continuous is notbetter than intermittent, why should we not do something in between? And that is basically the underlying idea ofSLEDD or slow extended dialysis.

Slide 13

The concept is not really very new. This chap Willem Kolff, one of the fathers of dialysis did the first recorded acutetreatment back in 1945 in a 69 year old female with hepato-renal syndrome in Holland and he used basically whatwe use as SLEDD today, long hours at a lower efficiency, at a lower blood pump speed and that patient apparentlywoke from her uremic coma and was able at least to initially survive.

Slide 14

Nowadays, of course, we have more modern technology and specifically in Europe there is an increasing spread of thebatch dialysis marketed under the name of Genius which you see here which is a dialysate tank in the first version 70L and in the newer version it’s 90 L, which is very mobile and also can be brought to the intensive care patient’s bed. There is however a large variety of what we find in the literature under the heading of SLEDD and there are evendifferent acronyms available for the same thing.

Slide 15

If you look at that slide from a paper published 6 years ago in KI, there are different treatment names: extendeddaily dialysis, sustained low efficiency dialysis, sustained low efficiency daily dialysis and filtration, there are variabletreatment times anything between 7.5 and 12 hours or even longer, different blood pump speeds and so forth, whichmakes it virtually impossible to compare the various publications in the area.

Slide 16

What is a common denominator of these studies is that SLEDD is substantially cheaper than CRRT and that isbasically because the solution bags we have to buy for replacement fluids and dialysates for the CRRT are soexpensive. So if your set up is that your ICU staff will do all the various modalities, then the running costs will becheaper with SLEDD and this has made this procedure much more popular of course, with the hospital administrators.

Slide 17

There is very limited clinical data available of people using SLEDD in the ICU. This is one of the first reports byGerard Lonnemann from Hannover who studied 20 patients with multi-organ failure with the Genius system with avery low blood flow over 18 hours of treatment. You can see here they could extract quite a substantial amount ofexcess volume from these patients, 2.5, 3 L and at the same time cardiovascular stability was excellent.

Slide 18

There’s only one prospective randomised trial comparing CRRT and SLEDD and that’s the small study by Kielsteinand colleagues. 39 critically ill patients on mechanical ventilation, 85 of which had sepsis comparing CVVH withGenius for 12 hours. They didn’t look for survival in that small cohort but they reported similar efficacy in terms ofurea removal rate and faster correction of acidosis with the SLEDD and less need for heparin similar to the previousspeaker, this is an advantage of course, of the SLEDD procedure.

Slide 19

There is one recent report where people have retrospectively analysed their survival data in two cohorts that weretreated in the older days with CRRT only and in the newer days with SLEDD only.Mark Marshall is a guy from theMiddlemore hospital which is in the vicinity of Auckland. Then there is one hospital in Australia and one in Parma,Italy and looking at a large cohort 1300 patients they call it long prolonged intermittent renal replacement therapyand the switch from continuous to this prolonged intermittent treatment apparently has not been associated with anychange in outcome. Still what they find is that their observed mortality is below their expected mortality according toscores and that has not changed. So that is basically the database we have, there is no more in the literature.

Slide 20

We have been talking about patient survival so far but there of course, are some other aspects we need to consider.So in the early days when I was a young nephrologist we tended to believe that the patient with AKI does not diebecause of acute kidney failure, he dies with acute kidney failure. Then he survives the acute kidney failure when hesurvives the underlying disease, and then the kidney will recover. We know now that both assumptions are not true. As you can see here from this very recent meta-analysis, there is a substantial proportion of patients who developchronic after acute kidney disease. A meta-analysis of these 8 studies shows clearly that there is a significant excessrisk to develop chronic kidney disease and even ESRD if patients have developed an episode of AKI.

Slide 21

Also survival is poorer in those patients with AKI compared to a control group of patients who did not have AKI. So asignificantly increased mortality risk. So this would be another important clinical endpoint to study if we compare thedifferent methodologies.

Slide 22

Even in patients who did not have any sort of kidney functional disturbance before their hospital admission, thereyou have the same phenomenon. This is a retrospective analysis of 1600 patients from the Geisinger Medical Centrein Pennsylvania looking at AKI that resolved within 90 days matched to 3500 control patients. All patients had normalkidney function before they were hospitalised. Mean follow-up was over 3 years and you can see that the proportionof patients without chronic kidney failure was substantial in the patients without AKI but it was much higher, twice ashigh in patients who had one episode of AKI. So this is a relevant endpoint.

Slide 23

The interpretation of these data was well, the risk factors that predispose a patient to develop AKI, the AKI will thenpredispose the patient to develop chronic kidney disease and chronic kidney disease is apparently a risk for excessmortality.

So the question that comes up here is can we change something of the transition from AKI to chronic kidney diseaseby the choice of the modality?

Slide 24

We do have a limited number of mostly retrospective cohort studies that try to tackle the problem. This is a retrospective study from Canada. 116 patients many of whom were treated for AKI at the University ofAlberta hospital and what you can see here is whilst there was no difference in ICU or hospital survival, there was amassive difference in the probability of renal recovery in the patients who were treated with CRRT 87% recoveredcompared to only 33% in the intermittent group.

Slide 25

Similar data were reported from a big Swedish study from the SWING study, a retrospective analysis of morethan2000 patients treated for ARRT at 32 Swedish hospitals and the dialysis dependence after 3 months was alsosignificantly higher in patients who had been treated with intermittent dialysis as compared to continuous.

Slide 26

Also the BEST kidney investigators in a big study of 54 centres and 23 countries. 1000 patients treated withcontinuous versus 200 with intermittent. What they found was a higher mortality in patients with continuoustreatment but also the continuous patients were a poorer selection, they had higher need for mechanical ventilationand inotropic support

Slide 27

but that second group of patients apparently had a better chance to recover kidney function at hospital dischargeand that was highly significant. The problem with this data however, is that the patients who were treated first withintermittent treatment had a higher proportion of premorbid kidney dysfunction and if you look at it, the differencethat seems very dramatic over the course of the 100 days of survey is already present at the beginning. If you lookhere, apparently a substantial proportion of the continuous patients already recovered kidney function within a fewdays so you might argue that this was not acute tubular necrosis, this was just a pre-renal condition. Indeed thestudy reports that there were a much higher proportion of patients going on CRRT because of fluid overload as in thegroup with intermittent.

Slide 28

Similar data from a more recent study which comes from Taiwan. This is 342 patients with post-operative AKI. Againa similar pattern to the BEST study and again, the difference is already there within the first few days. So maybewe’re also looking here at a lot of patients in the continuous group who did not have really acute tubular necrosis andtherefore, of course a different probability of recovery.

Slide 29

If you do a meta-analysis of all this again, whilst there is no survival difference between CRRT and intermittentdialysis, there is also a similar expectation of recovery of renal function with both modalities. There seems to be abetter stability of blood pressure in the continuous treatment but on the other hand you buy that with a higher riskfor filter clotting, that’s the result of that Cochrane collaboration study.

Slide 30

So the guidelines that are very current and came out from the KDIGO group in March, they tell us that there aresome large observational studies indicating that CRRT might give you a better recovery of kidney function but thedata is insufficient to really form this into a recommendation and what we need is appropriately planned prospectivetrials.

Slide 31

It might well be that the same risk factors that drive AKI are also driving the development of chronic kidney diseaseand are also driving excess mortality and therefore, interventions come in here, i.e. the dialysis treatment, willmaybe not be so successful.

Slide 32

At the end of the day as clinicians standing in front of the patient we should have in our minds a checklist of thingsto consider, which therapy we should give the individual patient. Of course, between the modalities there are thingssuch as hemodynamic tolerance, hyperhydration control, and lower risk for disequilibrium which are of course,strongly advocating a continuous or semi-continuous technique. But of course if you do have an emergency situationsuch as acute hyperkalaemia then the gold standard would be an acute intermittent treatment. Then another aspect of course is anticoagulation. With the emergence of citrate this might be not that big of anargument anymore. Finally the patient with continuous treatment is less available for interventions and less available for mobilization.We get more freedom of movement with a SLEDD or an intermittent procedure there.

Slide 33

What the guidelines say is that the choice of modality should be guided by the individual patient’s clinical status ormedical nursing expertise and of course, the availability of modality

Slide 34

and as we see it these procedures are not competing they are complementary. The way we start treatment is often inthe sickest patient with a CRRT procedure, and when the patient improves, we might then step down to SLEDD or tointermittent.

Slide 35

That is also reflected in the recent KDIGO guidelines. They recommend to use continuous and intermittent therapiesas complementary but they suggest, it’s not a recommendation, it’s a suggestion to use CRRT rather than standardRRT for unstable patients and also for patients with brain injury who are at the risk of generalised brain oedema.With that I’d like to close and thank you for your attention.