Back to the future: extended dialysis for treatment of acute kidney injury in the intensive care unit

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1 THOROUGH CRITICAL APPRAISAL JN EPHROL 23( 2010; 05) : Back to the future: extended dialysis for treatment of acute kidney injury in the intensive care unit Jan T. Kielstein, Mario Schiffer, Carsten Hafer Division of Nephrology and Hypertension, Department of Internal Medicine, Medical School Hannover, Hannover - Germany Ab s t r a c t On September 11, 1945, Maria Schafstaat was the first patient who successfully underwent a dialysis treatment for acute kidney injury (AKI). The ingenious design of the first dialysis machine, made of cellophane tubing wrapped around a cylinder that rotated in a bath of fluid, together with the brave determination to treat patients with AKI, enabled the Dutch physician W.J. Kolff to save the life of the 67-year-old woman. By treating her for 690 minutes (i.e., 11.5 hours) with a blood flow rate of 116 ml/min, Kolff also set the coordinates of a renal replacement therapy that has enjoyed an unsurpassed renaissance over the last decade for treatment of severely ill patients with AKI in the intensive care unit (ICU). Prolonged dialysis time with low flow rates these days, called extended dialysis (ED) combines several advantages of both intermittent and continuous techniques, which makes it an ideal treatment method for ICU patients with AKI. This review summarizes our knowledge of this method, which is increasingly used in many centers worldwide. We reflect on prospective controlled studies in critically ill patients that have documented that small-solute clearance with ED is comparable with that of intermittent hemodialysis and continuous venovenous hemofiltration, as well as on studies showing that patients cardiovascular stability during ED is similar to that with continuous renal replacement therapy. Furthermore, we report on logistic and economic advantages of this method. We share our view on how extended dialysis offers ample opportunity for a collaborative interaction between nephrologists and intensivists as the nephrology staff, enabling optimal treatment of complex critically ill patients by using the skill and knowledge of 2 indispensable specialties in the ICU. Lastly, we address the problem of ED intensity, which does not seem to have an impact on survival at higher doses, a finding that might be caused by the fact that we still adhere to dosing guidelines for antibiotics which are at best ineffectual but might also lead to potentially dangerous underdosing of these life-saving drugs. Key words: Acute kidney injury, Continuous renal replacement therapy, Extended dialysis, Intensive care unit, Intermittent hemodialysis Ac u t e k i d n e y i n j u r y is n o t a c u t e i n j u r y! Acute kidney injury (AKI) in the intensive care unit (ICU) is increasing dramatically worldwide, making the need for renal replacement therapy (RRT) greater than ever. From 1980 to 2005, the number of patients discharged with the diagnosis of AKI from US hospitals increased from 1.8/10,000 to 36.5/10,000 discharges (1). According to results of a recently published large prospective observational study of 29,000 ICU patients in 23 countries, up to 60% of patients with AKI die during their hospital stay (2). Despite considerable progress in the field of critical care and despite the advent of new technology for RRT, patient outcomes in AKI have not improved over the last few decades. This can be explained by the ever-expanding comorbid conditions of ICU patients intensifying the severity of illness (2, 3). In this patient population, AKI is generally 1 feature of a multiple organ dysfunction syndrome (MODS), which develops in response to major surgery, cardiogenic shock or sepsis. Hence, the de Società Italiana di Nefrologia - ISSN

2 JNEPHROL 2010; 23( 05) : velopment of AKI is thought to be an independent risk factor for in-hospital death (4), mid-term (6-month) survival (5) and a major cause of chronic kidney disease if survived (6). Wh a t is t h e m e t h o d o f c h o i c e t o t r e a t patients with AKI? For decades, continuous renal replacement therapies (CR- RTs) such as continuous venovenous hemofiltration (CVVH) were thought to offer better cardiovascular stability, resulting in better survival, in critically ill patients than conventional intermittent hemodialysis (IHD). This opinion has been challenged by observations that if IHD is performed with low blood flow and ultrafiltration rates at the start of the treatment, reduced dialysate temperature along with other measures, procedural morbidity with IHD is comparable with that of CRRT (7). Furthermore, controlled studies (8) and a meta-analysis (9) have not revealed a definitive advantage in terms of patient survival for CRRT as compared with IHD. Hence, outside of rare natural catastrophes (10), the method for RRT should be based on the clinical situation, physician proficiency with the available techniques and logistical capacity of the ICU and dialysis personnel. Both conventional IHD and CRRTs have certain advantages, but also several disadvantages, which are summarized in Table I. While IHD is the domain of nephrologists, CRRTs have been performed in ICUs mostly without the involvement of nephrologists. Consequently, the choice of RRT may also be TABLE I COMPARISON OF CONTINUOUS RENAL REPLACEMENT THERAPY (CRRT), INTERMITTENT HEMODIALYSIS (IHD) AND EXTENDED DIALYSIS (ED) CRRT IHD ED Elimination of uremic toxins Convective Diffusive Diffusive Membranes High-flux Low-flux / high-flux Low-flux / high-flux Dialysate flow Low High Low Ultrafiltration and solute elimination Continuous (in theory) Intermittent (3-5 hours) Intermittent (8-18 hours) Anticoagulation Continuous Intermittent (3-5 hours) Intermittent (8-12 hours) Citrate anticoagulation Yes Yes Yes Dialysis nursing staff Not required Required Required Required nursing time High Requires 1 nurse Low Mobilization/diagnostic procedures Not possible Possible Possible Operating costs High (mostly for sterile filtration fluid) Low Low Physical workload/lifting High Low Low Risk of microbial contamination High Low Low Use of standard dialysis machines No Yes Yes Hemodynamic stability Excellent Poor (in some centers) Excellent Proven survival benefit compared to other methods No No No 495

3 Kielstein et al: Renaissance of extended dialysis seen as a statement of who should care for the patients and thereby represents a source of tension between medical specialties. In an extreme approach to this issue, some ICUs have become closed units managed by intensivists, with other specialists, such as nephrologists, having a restricted supportive role. What do we need a nephrologist for? What do we need an intensivist for? These questions reflect the rather hostile environment in which the Latin motto Salus aegroti suprema lex (the well-being of the patient is the most important law) is given no more than lip-service. It also neglects the simple fact that both specialties require several years of training with only partially overlapping content, hence the intensivist never has the knowledge of the nephrologist and vice versa. In this regard it is of interest that the timing of a nephrology consultation may affect the patient s survival in the ICU. A prospective study in 4 US teaching hospitals revealed that delayed consultation of the nephrology service was associated with a trend toward increased mortality and morbidity, whether or not dialysis was ultimately required (11). Most ICUs are run by physicians specialized in intensive care medicine, and nephrologists are not always consulted to provide optimal care including the best possible extracorporeal RRT for critically ill patients. No t o n l y f o r c a r s t h e h y b r i d approach According to Wikipedia, a hybrid is the combination of 2 or more different things, aimed at achieving a particular objective or goal. In the ICU, the goal for patients with AKI is to provide the optimal RRT for the patient in a way that is cost-effective and easy to handle. This goal has lead to the renaissance of the original way to treat AKI i.e., extended dialysis (ED). It combines advantages of both intermittent and continuous RRTs, with morbidity and mortality rates that are not inferior to those of both classical ways of treating AKI. This hybrid RRT utilizes equipment originally designed for treatment of patients with chronic renal failure and therefore does not require expensive industrially produced substitution fluid. The term ED is most widely used. An alternative term is sustained low-efficiency dialysis (SLED). The devices used for ED are modified standard dialysis machines (12-18). ED offers ample opportunity for a collaborative interaction between nephrologists and intensivists as the nephrology staff is responsible for the prescription, provision and initiation of the treatment, while responsibilities for monitoring, variation of ultrafiltration, troubleshooting and discontinuation are shared. This cooperative approach may also promote close collaboration between the 2 distinct specialties, with opportunities for setting joint therapeutic standards and research programs. Cl i n i ca l e x p e r i e n c e w i t h EDD t h e r a p y of critically ill patients with AKI Several controlled studies and accounts of long-term experience have been published by groups that use ED to treat ICU patients with AKI (12-22) (Tab. II). Marshall et al (17, 25) used a 2008H machine at a reduced dialysate flow rate of 100 ml/min to treat critically ill patients in whom IHD had repeatedly failed due to intradialytic hypotension, and patients in whom prescribed solute control goals were not achieved despite daily IHD. Under those circumstances, the authors achieved ultrafiltration goals and adequate solute removal in most of their 37 treated patients. The in-hospital mortality rate of 62% was not significantly different from expected mortality determined from the APACHE II score. Also, formal training to operate the machines was undertaken by all full-time ICU nurses at the time of the hybrid therapy program inception, consisting of a brief instructional video and a 2-hour hands-on training session. Inservice was offered on an as-needed basis, and has been incorporated into nephrology and ICU nursing orientation programs and quarterly skills updates. Two months after the introduction of ED, satisfaction of ICU nurses was formally assessed. When compared with that for CRRT, all felt that ED was technically easier and all preferred the hybrid technique to CRRT (30). Another US center compared ED with standard CVVH in a prospective study. Twenty-five critically ill patients were treated with ED, and 17 were treated with CVVH (14). Median daily treatment time was 7.5 hours for ED and 19.5 hours for CVVH. No differences in mean arterial blood pressure or use of catecholamines were observed between the treatment groups, despite similar median net daily ultrafiltration rates (3,000 vs. 3,028 ml/day). By contrast, requirement for anticoagulation was significantly less in patients treated with ED (median heparin dose 4,000 U/ day, vs. 21,100 U/day with CVVH). The authors also published an account of their long-term experience with ED (15). They concluded that this technique is well-tolerated and offers many of the benefits of continuous techniques, but is technically much simpler to perform. In this program, the nephrology nurse is always in-house with a response time of less than 5 minutes to the bedside, and he or she can be responsible for 2 concurrent treatments at a given time. ICU nursing satisfaction with hybrid therapy was assessed as at least equal to that with CVVH (15). We use the Genius single-pass dialysis system (Fresenius Medical Care Germany, Bad Homburg, Germany) to treat patients with AKI in the ICU, which is currently available in Europe and South America. The technical principle under- 496

4 JNEPHROL 2010; 23( 05) : lying this standard IHD machine is based on the very first dialysis systems, the tank or batch devices (the technical features are described in detail elsewhere (19)). This simple yet highly efficient treatment modality fulfills all ICU requirements: it offers immediate, highly effective dialysis therapy for acute hyperkalemia, whereas for less urgent indications, treatment durations can be extended up to 24 hours. In a prospective randomized controlled study in ventilated critically ill patients suffering from oliguric AKI, we could demonstrate that 12-hour ED treatments performed with this machine achieve urea reduction rates comparable to those achieved with 24 hours of CVVH, even though a substitution fluid exchange rate of at least 3 l per hour was used with the latter (19). These data are in line with other studies (12) supporting kinetic models, which indicate that both CVVH and ED provide very effective control of azotemia in hypercatabolic AKI patients (31). Moreover, cardiovascular parameters assessed online via invasive monitoring were not significantly different during CVVH and ED despite comparable ultrafiltration volumes. An advantage of ED over CVVH is, in our view, the absent of any need for frequent changes of bags with the substitution fluid. Aside from a considerable work load that is associated with the manual transport of these bags, the repeated opening of the circuit is a main cause for the frequent breaches of microbial integrity in industry-standard, bicarbonate-based substitution fluid (32). Thus ED, especially the Genius system, avoids by its very nature an added microbiological risk to the vulnerable, critically ill patient. In our institution, the intensive care nephrology fellow discusses the required dialysis prescription on his/her twice-daily rounds in the 12 ICUs. Provision, initiation and discontinuation of hybrid treatments is always done by the nephrology nurse, while hourly monitoring variation of ultrafiltration, troubleshooting and other responsibilities are shared. Taken together, a growing body of evidence suggests that ED, at absolutely equivalent hemodynamic stability, is as efficacious as classical CVVH. The significantly reduced need for heparin with ED can be a decisive advantage, especially in patients at high risk of bleeding (19, 25). Another consideration in favor of ED is the closed system. The 40 and more times a CRRT system is opened to connect a bag TABLE II REPORTS ON ED EXPERIENCE* Authors (Reference) Dialysis Blood / dialysate Treatment Nocturnal machine flow rates (ml/min) time (hours) treatment Berbece et al (12) Not reported 200 / No Czock et al (23) Genius / Yes Fiaccadori et al (13) AK200 Ultra 200 / No Kielstein et al (19) Genius 200 / Yes Kielstein et al (24) Genius / Yes Kumar et al (14) 2008H* 200 / No Lonnemann et al (20) Genius 70 / Not reported Marshall et al (25) 2008H* 200 / Yes Marshall et al (17) 2008H* 200 / Not reported Marshall et al (26) 4008S ArRT-Plus / No Morgera et al (27) Genius / No Naka et al (21) Not reported 100 / Not reported Ratanarat et al (22) Not reported / Not reported Schneider et al (28) Genius / Not reported Schlaeper et al (18) 2008H * / Yes Swoboda et al (29) Genius / Yes ED = extended dialysis. *Modified for ED treatment. 497

5 Kielstein et al: Renaissance of extended dialysis Fig. 1 - Survival from day 0 to 28 after initiation of renal replacement therapy, shown by Kaplan Meier curves. No significant differences were detected in the survival proportions. Survival at day 14 was 70.4% in the intensified extended dialysis (IED) group versus 70.7% in the standard extended dialysis (SED) group (p=0.97). Survival at day 28 was 61.3% in the SED group versus 55.6% in the IED group (p=0.47). Reprinted with permission from Faulhaber- Walter et al (35). of replacement fluid and discard the used filtrate (given a substitution rate of 37.5 ml/kg per hour in a 100-kg patient) represent a considerable risk of bacterial contamination, especially if bicarbonate-based buffers are used (32). ED of any kind does not involve this risk. Finally, nocturnal ED allows unrestricted access of the ICU staff to patients for daytime procedures, thereby minimizing disruption of ICU activities by RRT (19, 25). In general, there are no practical differences with respect to performing daytime and nighttime ED. After appropriate training, ICU personnel are solely responsible for supervising machines during the overnight shift, but a dialysis nurse is usually available on-call for advice and troubleshooting. Su r v i v a l a n d d o s e o f ED A review of several recent trials shows that the relationship between dose of RRT and survival is not a linear one (33). In contrast to earlier studies, recent multicenter trials could not confirm a survival benefit for an increased dose of RRT (34). We addressed this issue in the Hannover Dialysis Outcome (HANDOUT) study, in which intensive extended dialysis (IED) treatment (urea levels 15 mmol/l) was compared to standard extended dialysis (SED) (urea levels between 20 and 25 mmol/l). No differences between intensified and standard treatment were seen for survival by day 14 or day 28 (Fig. 1) or for renal recovery among the survivors by day 28 (35). Technical modifications An important modification of the ED technique is the use of regional citrate anticoagulation. Schneider et al (28) have used the Genius system together with a low-calcium dialysate concentration (1 mmol/l) infusing a 4% sodium citrate solution into the arterial line of the extracorporal circuit, and adjusted the citrate dose according to the postfilter ionized calcium concentration (target value: mmol/l) without routine calcium substitution. They observed no significant untoward effects on blood levels of calcium and sodium, and acid base values remained equilibrated during citrate anticoagulation. Excellent filter patency and cardiovascular stability of patients were maintained. Filtering o u t t h e b a d a n d t h e g o o d The ED technique has been further extended by introduction of sustained low-efficiency daily diafiltration (SLEDD-f), which combines diffusive and convective solute transport to improve clearance of putative middle-molecule inflammatory mediators (26). However, considerable removal of larger molecules has also been reported for standard ED with high-flux dialyzers (19). Encouraged by the efficient solute elimination, physicians increasingly use ED to treat intoxications. The advantages of ED for this indication include fewer complications (especially in comparison with charcoal perfusion) and use of regular dialysis machines thus minimizing staff work load. Many case reports of standard dialysis followed by ED to prevent rebound of the offending toxin have been published (36, 37), but the issue merits further study. Highly efficient methods of RRT eliminate potentially lifesaving drugs such as antibiotics to a larger extent than they did 1 or 2 decades ago (38). This also holds true for the nutritional support of these patients, as increasing the dose of RRT also enhances the elimination of nutrients 498

6 JNEPHROL 2010; 23( 05) : (39). Due to the efficient removal of small solutes by ED, attention must be paid to vital electrolytes such as phosphate (19). As such, in institutions that perform ED on a daily basis, phosphate supplementation is part of the treatment protocol ( mmol/kg per day) (15, 26). Still, in the ATN study, hypophosphatemia developed in 17.6% of patients in the intensive-therapy group as compared with 10.9% in the group undergoing less-intensive therapy (1). In the RENAL trial the rate of hypophosphatemia was even 65% (40). The obvious failure to adapt phosphate supplementation to the increased dialysis dose suggests that the dosing of antibiotics, which in many instances have to be increased considerably in parallel with intensified renal support, was altered even more than it was the case for phosphate levels, leading to underdosing of these important drugs. This is aggravated by the fact that therapeutic drug monitoring is only available for a few antibiotics. As pointed out by Mueller and colleagues, the growth of higher delivered doses of RRTs in critically ill patients with AKI has rendered old dosing guidelines for antibiotics ineffectual and, potentially dangerous (41). Indeed, results from several clinical studies have confirmed that there are significant differences in rates of drug removal by ED compared with IHD and CRRT (42-45). Thus, dosing recommendations for patients with AKI in the ICU treated with EDD (and other efficient techniques) must be developed if increased mortality due to underdosing of life-saving medications is to be avoided. Meanwhile, therapeutic drug monitoring should be performed whenever possible. The dilemma of underdosing antibiotics could in part explain why septic patients in particular i.e., those patients in whom therapeutic drug levels of antibiotics are of vital importance tended to have an even higher mortality with intensive renal support in the ATN trial. Hence, pharmacokinetic data in intensive care patients with an increased volume of distribution and low albumin concentration are of utter importance to guide dosing in these patients. Increasingly relevant are economic evaluations that have proven ED to be less expensive than CRRT, both within the setting of the US health care reimbursement scheme and within a more widely applicable nationalized health care system (12, 46). Moreover, the equipment used for ED can also be used for chronic RRT in the same hospital. In fact, all centers offering ED use various standard IHD machines without substantial changes in software or hardware. Flexible treatment modalities allow the same machine to be used for daytime IHD sessions and overnight ED treatment. This dual usage has been recognized by major manufacturers of dialysis equipment, which frequently has a built-in option for EDD in the startup menu. In summary, ED, the original way to treat AKI, is a safe, cost-effective and logistically less demanding alternative to standard intermittent and continuous RRTs for critically ill patients with AKI. ED has been proven in many centers to be an excellent area of collaboration between nephrologists and intensivists to provide the best possible treatment to critically ill patients. The high level of satisfaction of all who are involved in its use proves this to be a prudent approach. As with hybrid vehicles, the hybrid ED will neither completely replace other means of RRT in the ICU nor make the development of alternatives unnecessary, yet it will become the method of choice to treat patients with AKI in the decades to come. Financial support: This work was supported by a grant from the Else Kröner Fresenius Foundation (P63/06 // EKMS 06/03) to J.T.K. Conflict of interest statement: None of the authors declares any conflict of interest. Ou t l o o k ED is an increasingly popular RRT in critically ill patients with AKI in the ICU. It can also be employed as prolonged high-volume treatment of severely ill patients, such as highly catabolic patients with sepsis, because normalization of indicators of uremic intoxication is achieved in even shorter times than with CVVH (19). Survival outcome of patients treated with ED does not differ from that of those treated with state-of-the-art CVVH. An important aspect of ED is its ease of use for the ICU staff and its high degree of flexibility. Address for correspondence: Jan T. Kielstein Department of Internal Medicine Division of Nephrology and Hypertension Medical School Hannover Carl-Neuberg-Strasse 1 DE Hannover, Germany Kielstein@yahoo.com 499

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