EUROANESTHESIA 2008 Copenhagen, Denmark, 31 May - 3 June RC3

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1 RENAL REPLACEMENT THERAPY: STATE OF THE ART EUROANESTHESIA 2008 Copenhagen, Denmark, 31 May - 3 June RC3 WILFRED DRUML Department of Medicine, Division of Nephrology Medical University of Vienna Vienna, Austria Saturday, May 31, :00-15:45 Room C1-M3 Many intensivists believe that acute renal failure (ARF) is a rather harmless complication, because usually it is assumed that renal function can be easily, and practically indefinitely, replaced by modern renal replacement modalities. This view of ARF must be challenged as our understanding of ARF has fundamentally changed over the last few years. A paradigm shift in the perception of ARF has taken place; ARF is no longer seen as a mono-organ problem but a multi-system disorder [1, 2]. Several investigations have underlined that ARF is a condition which exerts a fundamental impact on the course of disease, on the evolution of associated complications and on the prognosis - independent of the type and severity of the underlying disease [3]. It must be stressed that ARF is not a problem confined to the kidneys, but that the acutely uraemic state has negative consequences for practically all physiologic functions and for all organ systems (see Table 1). TABLE 1. PATHOPHYSIOLOGICAL CONSEQUENCES OF ACUTE RENAL FAILURE (FROM [1]) This novel understanding of the importance of ARF in ICU patients has several crucial clinical implications [1]. The first clinical consequence must be that the prevention of ARF is of the utmost importance. In patient groups at risk of developing ARF preventive measures must be initiated early and systematically to avoid the evolution of renal dysfunction. The sacrifice of kidney function in favour of other organ systems, especially pulmonary function to improve gas exchange in critically ill patients - not unusual in some ICUs is questionable. More importantly, if ARF has become manifest we have to try to optimise renal replacement therapy (RRT) in a way that the negative repercussions of the acutely uraemic state are mitigated. In this respect the type, timing and dosage of extracorporeal renal replacement therapies have been shown to play an essential role. During recent years several controversies have arisen concerning RRT in critically ill patients with ARF (see Table 2). In this refresher course lecture I will discuss some of these controversies in the light of several recent publications. TABLE 2. CONTROVERSIES IN RENAL REPLACEMENT THERAPY IN THE CRITICALLY ILL

2 CONTINUOUS RENAL REPLACEMENTS THERAPY VS. INTERMITTENT HAEMODIALYSIS Since the introduction of continuous renal replacement therapies (CRRTs) into critical care medicine there has been an ongoing, and sometimes emotional, controversy about whether these treatment modalities are superior to conventional intermittent haemodialysis (HD). In fact, none of the controlled studies performed up to now with survival as an end-point, have been able to demonstrate an improved prognosis during CRRT. Because of an allocation bias with more severely ill patients usually being treated by CRRT the prognosis was worse with CRRT in several investigations. A meta-analysis by Kellum in 2002 was unable to identify a survival advantage of CRRT [ 4 ]. R e c e n t l y, Vinconneau and co-workers reported a French multi-centre study in which conventional HD (of very high quality) was compared with CRRT in critically ill patients [5]. Survival was identical between the two treatment modalities. Is CRRT no longer indicated in ICU patients? Certainly not! Advantages of CRRT are manifold and besides organisational factors and its availability in all units, there is a series of beneficial points relevant for the practical care of critically ill patients, such as haemodynamic stability, volume modulation etc (see Table 3). However, there is also a novel further aspect, which favours CRRT in the ICU patient described below. TABLE 3. ADVANTAGES OF CONTINUOUS VS. INTERMITTENT RENAL REPLACEMENT THERAPIES IN CRITICALLY ILL PATIENTS WITH ARF no osmolality shifts haemodynamic stability no cellular dysfunction no cellular oedema (brain oedema) no dysequilibrium syndrome lesser impairment of regional perfusion (for example, intestines, kidney) intracellular detoxification smooth and constant detoxification higher middle molecule clearance (mediators, cytokines) steady compensation of acid base balance free regulation of volume state and balance improvement in renal prognosis RECOVERY OF RENAL FUNCTION U s u a l l y, we assume that if a patient who has acquired ARF survives the acute illness, renal function will more or less completely normalise within one year. Recently, a series of investigations have shown, unfortunately, that this is not true. Depending on the study and the specific patient populations investigated % of patients have an incomplete recovery and many patients remain dialysis-dependent [6]. ARF has become an important cause of chronic kidney disease. Studies have indicated that the percentage of patients with persisting renal failure is also dependent on the type of RRT provided during the ICU stay. Bell and co-workers from Sweden and, recently, Uchino for the BEST K i d n e y investigators have clearly demonstrated that the evolution of dialysis-dependent chronic renal failure is much less frequent in surviving ARF patients who were treated by CRRT compared with intermittent HD [7, 8]. CO N V E N T I O NA L (I N T E R M I T T E N T) H A E M O D I A LY S I S At present most patients with ARF are treated with conventional HD. But these mostly non-critically ill patients with mono-organ failure are cared for on general wards and are haemodynamically stable. If experienced dialysis personnel are available to perform intermittent therapy on the ICU, critically ill patients can be treated with HD. Usually this is performed with adaptations of HD with lower blood flow and extended treatment periods up to 12 h (SLED, sustained low-efficiency dialysis). This semi-continuous type of RRT for critically ill patients with ARF recently received much attention with the use of the GENIUS-system [9]. When available, this system is an appropriate RRT for critically ill patients. PE R I TO N E A L D I A LY S I S Peritoneal dialysis would be an attractive RRT modality for certain ICU patient groups. However, hypermetabolic patients with sepsis and/or multi-organ dysfunction syndrome (MODS) cannot be adequately treated be peritoneal dialysis. In the elderly patients with congestive heart failure or those with liver failure, peritoneal dialysis can offer a soft, haemodynamically stable and semi-continuous type of RRT [10]. Obstacles to this quite attractive type of RRT are mostly organisational. These limitations can be easily overcome since the placement of peritoneal catheters is possible at the bedside in the ICU using a Seldinger technique, and automated cycling machines can guarantee an effective solute removal

3 Despite the considerations described above, CRRT remains the preferred type of RRT used in critically ill patients. In the ICU community there is a broad consensus that the more severely ill the patients are, the more they should be treated with continuous treatment modalities. The issues discussed below are relevant to any type of RRT in critically ill patients, but are described mainly in relation to CRRT. THE TIMING OF START OF EXTRACORPOREAL THERAPY Until recently the criteria for initiation of RRT in a patient with ARF were similar to those employed in patients with chronic renal failure. However, this practice is far from appropriate for patients with ARF. RRT has to be initiated earlier to avoid the development of an acute uraemic intoxication with many associated sideeffects. Unfortunately, only a few investigations have systematically assessed this in patients with ARF. In a retrospective study in patients on CRRT it was suggested that early starters (mean BUN 43 mg/dl) had an improved survival compared with late starters (mean BUN 95 mg/dl, 20% vs. 39%, p < 0.041) [11]. Similarly, in a study by Ronco et al on the optimal dose of continuous haemofiltration (CVVH), patients in whom therapy was started early (as assessed by urea concentration at the start of therapy) had a better survival rate [12]. The same group, in a more recent study, have shown that early haemofiltration improved haemodynamics, pulmonary function and survival in patients with sepsis [13]. The control group in this trial, however, was historical, which renders firm conclusions impossible. In contrast, a study published in 2002 by Bouman and co-workers did not confirm a beneficial effect of early initiation of RRT. However, survival in the patients investigated was excellent (70 % or more), so patient selection probably did not reflect the usual casemix in ICU [14]. It is reasonable to assume that RRT should be initiated before acute uraemic intoxication has evolved and multiple systemic side-effects are present. Certainly, we should start earlier than previously assumed and as has often been practiced analogous to practice in patients with chronic renal failure. It must be stressed that the decision to start CRRT must be individualised and should integrate various aspects of the patient s condition, the volume state, haemodynamic and respiratory situation, and not be based only on laboratory parameters such as urea or creatinine. Usually, the sicker the patient, the earlier CRRT should be started. TREATMENT DOSE The dose of extracorporeal treatment in ARF must be adjusted so that the systemic consequences are mitigated. Again, previous practice mirrored that in chronic renal failure. Generation of uraemic toxins in the hypercatabolic patient with ARF must be assumed to be several times greater than in a metabolically stable patient with chronic renal failure. In patients with ARF there is an additional problem. They often do not receive the (insufficient) therapy dose prescribed because of problems encountered in critically ill subjects such as catheter problems, haemodynamic instability, the need to perform diagnostic procedures, and surgery [15]. So, many or even most patients with ARF on continuous therapy receive a lower treatment dose than that prescribed. In a study of intermittent HD in patients with ARF, Schiffl et al convincingly demonstrated that an increase in dialysis dose has a major impact on morbidity and mortality [16]. A protocol of three times a week haemodialysis (as is routine in many institutions) was compared with daily haemodialysis. The higher dialysis dose was associated with a lower frequency of complications, such as oliguric ARF, SIRS/ sepsis, respiratory insufficiency, coma, gastrointestinal haemorrhage, with a more rapid restoration of renal function, and with a remarkable improvement in prognosis. Similarly, Ronco and co-workers have shown that using continuous haemofiltration an increase in dose of therapy (the filtration volume) from 20 ml/kg/h (~ 1.3 l/h) to 35 ml/kg/h (~ 2.3 l/h) resulted in improved survival [12]. Interestingly, a further increase in filtration volume to 45 ml/kg/min did not have any additional benefit. However, this finding has not been uniformly confirmed in other studies. In the study performed by Bouman and colleagues described above [14] there was no significant influence of the filtration volume (48 vs. ~ 20 ml/kg/h) on survival; however, there was a tendency to a worse prognosis in patients on early low volume filtration. In a further study by Brause and co-workers there was no survival advantage in a group with higher filtration rates [17]. Filtration volumes were inadequately low (1 vs. 1.5 l/h only) in both groups, so a clear-cut difference in outcome was not expected. Recently, Saudan and colleagues have conducted a study in which ARF patients treated with continuous haemofiltration (CVVH, effective dose ~ 21 ml/kg/h) were compared with a group in which dialysis was added to the continuous haemofiltration (CVVHDF, effective dose 35 ml/kg/h) [18]. The three month survival rate was markedly improved by the increase in treatment dose. To summarise this point, pathophysiologic considerations and quite convincing clinical evidence support the concept that treatment dose does matter, that it has an impact on morbidity and mortality and that a higher dose compared with that used for chronic renal failure should be prescribed

4 HIGH-VOLUME, HIGH-CUT-OFF MEMBRANES, NON RENAL INDICATIONS Since the introduction of CRRT there has been an ongoing discussion about whether these treatment modalities can eliminate not only conventional uraemic toxins, but also mediators and cytokines involved in the pathophysiology of sepsis, ARDS and MODS. To increase the efficiency of the potential elimination of such mediators, high-volume therapy (> 3 l/h) and / or the use of super-flux membranes (with a higher molecular cut-off, enabling elimination of molecules up to 50 kd molecular size) have been advocated. At present these newer treatment modalities have to be regarded as experimental and their use beyond clinical studies can not be recommended. RRTs have also been proposed for non-renal indications in patients with sepsis, ARDS, MODS, pancreatitis etc. even in the presence of normal renal function. Again, these indications are purely experimental. There is increasing evidence that the use of RRT is not justified in these indications, and might even be detrimental. ANTICOAGULATION From a clinical point of view probably the most relevant obstacle and limitation of CRRT in ICU patient is the need for continuous anticoagulation. Filter clotting remains a rather annoying aspect of these therapeutic modalities. On the other hand, bleeding complications continue to be relevant for patients at risk of haemorrhage which is very often the case in ICU patients. HEPARINS Standard anticoagulation in Europe continues to be unfractionated heparin. However, conventional heparin is associated with relevant side-effects, especially high antithrombin-iii consumption and the activation of cellular blood elements such as leukocytes and thombocytes. Thus, many workers prefer fractionated heparin (LMWH), but the data to support their use was scarce. Recently, Joannidis et al have shown that LMWH are superior with respect to filter patency and - because of a longer filter life - are also cheaper [19]. CITRATE Citrate is a promising anticoagulant. It has been used for intermitted HD for many years, and is widely used for CRRT in the US. In recent years it has gained popularity for CRRT in Europe. The advantages of citrate (see Table 4) are that it provides better anticoagulation resulting in a longer filter life, and it can allow regional anticoagulation exclusively in the extracorporeal circuit without any anticoagulant effects in the systemic circulation and the elimination of any risk of bleeding complications. There is, however, a further important advantage - calcium is required for activation of cellular elements of the blood, such as leucocytes and thrombocytes. During citrate-induced hypocalcaemia these cellular elements are not activated in the extracorporeal circuit. Finally, citrate anticoagulation is associated with a dramatic improvement of the biocompatibility of the extracorporeal circuit. TABLE 4. ADVANTAGES OF CITRATE ANTICOAGULATION perfect quality of anticoagulation (longer filter life) exclusively regional, extracorporeal anticoagulation with no systemic anticoagulation excellent biocompatibility - inhibition of cellular components, inhibition of plasmatic cascade systems low complication rate effective antidote (calcium) easy performance and monitoring At a recent European Intensive Care Congress in Berlin, Oudemans from Amsterdam presented the preliminary results of a large study comparing LMW-heparin and citrate for CRRT. Unexpectedly, there was a significant improvement in survival in the citrate group, most pronounced in patients with the highest severity of disease. Potential complications of citrate anticoagulation include hypocalcaemia - if calcium is not adequately substituted, metabolic alkalosis, a positive sodium balance and hypomagnesaemia (because citrate also forms complexes with magnesium). A further disadvantage is the need for tight monitoring of ionised calcium and the acid-base balance of the patient. This should not present a problem for most ICUs as most modern blood gas analysers also measure ionised calcium. Are there limitations to use citrate in certain patient groups? Clearance of citrate is impaired in presence of hepatic dysfunction but not in other ICU patients without hepatic failure [20]. Thus, accumulation (which can be detected by an increasing gap between total and ionised calcium concentration) should be monitored but usually does not present a problem in the absence of severe impairment of hepatic function

5 TECHNICAL DEVELOPMENTS OF CRRT MACHINES The intensity of therapy required to meet current dose recommendations and the need for safe and automated systems for citrate anticoagulation have had a considerable impact on the development of new CRRT machines for critically ill patients. Modern machines for CRRT should enable blood flow rates up to 300 ml/min to achieve the required fluid turnover rates while maintaining an acceptable filtration fraction. Optimally, modern machines should be adapted for citrate anticoagulation and the pumps for blood and substitution fluids should be electronically coupled (changes in blood flow should be paralleled by automatic adaptations in the infusion rate of the citrate based substitution fluid). At least three types of machines are available which meet these criteria. In the future, on-line calcium measurements should become available to facilitate the monitoring of citrate anticoagulation. CONCLUSIONS Several types of modern RRT are available for patients with ARF in the ICU. Many roads lead to Rome and there can be no doubt that most of these modern techniques can be safely used in critically ill patients. Which type of therapy is used on a particular ICU is very much influenced by local specifics, traditions, experience, and the availability of well-trained personnel. Even if superiority in patient outcome has not been confirmed in controlled studies there is some agreement in the ICU community that CRRTs are the treatment modality of choice for the sickest and most haemodynamically unstable patients. Moreover, and this is a very relevant and novel aspect, recovery of renal function is better with CRRT and fewer patients remain dialysis-dependent. Nevertheless, with modifications of HD, intermittent therapies can be safely performed in ICU. Sustained lowefficiency dialysis (SLED) with low blood flow rates and an extended treatment time of 12 h/ day ( semi-continuous ) can be used in ICU patients. For some patient groups peritoneal dialysis might offer advantages. Citrate anticoagulation has become an attractive modality. Citrate offers perfect, exclusively extracorporeal anticoagulation combined with a superb biocompatibility because cellular blood components are inhibited. Unconfirmed results from a recent study suggest that citrate may improve outcome of critically ill patients with ARF. KEY LEARNING POINTS Acute renal failure cannot be viewed as a harmless mono-organ complication but is a multi-system disorder with a negative impact on all biologic functions and organ systems (especially the lung) and which exerts a profound negative independent effect on survival. Prevention and, when present, the optimal therapy (regarding type of renal replacement therapy, timing and treatment dose) of acute renal failure are of crucial to mitigate untoward side-effects. With the required expertise and training most modern types of renal replacement therapy can safely be used in the ICU. Haemodynamically stable patients can be treated with conventional intermittent haemodialysis therapy. Although an improvement of survival has not been documented there is some consensus in the ICU community that the sicker the patient and the more haemodynamically unstable, the greater the indication for a continuous renal replacement therapy modalities. There is some evidence that renal recovery is improved when using continuous renal replacement therapies. Advanced semi-continuous technologies such as sustained low-efficiency dialysis might present an alternative to currently used continuous therapies. Citrate has become a promising mode of anticoagulation, especially for patients at risk of bleeding, providing an optimal exclusively extracorporeal anticoagulation, and improved biocompatibility of therapy and, potentially, a beneficial effect on prognosis

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