Dose of Dialysis in Acute Renal Failure
Zaccaria Ricci,* Rinaldo Bellomo,† and Claudio Ronco‡
*Department of Anesthesiology and Intensive Care, University of Rome “La Sapienza,” Rome, Italy; †Department of Intensive Care, Austin Hospital, Melbourne, Australia; and ‡Department of Nephrology, Dialysis and Transplantation, San Bortolo Hospital, Vicenza, Italy
Clin J Am Soc Nephrol 1: 380 –388, 2006. doi: 10.2215/CJN.00520705
ne to 25% of critically ill patients who are admitted to intensive care unit (ICU) develop acute renal failure (ARF), depending on the definition used (1). ARF has a significant impact on morbidity and represents an independent risk factor for mortality. The mortality rate for severe ARF exceeded 50% over the past three decades (2– 6). The wide range of incidence in the literature depends on the lack of a reliable definition of the syndrome. On the basis of the most recent RIFLE classification (an acronym indicating Risk of renal dysfunction, Injury to the kidney, Failure of kidney function, Loss of kidney function, and ESRD) (7), ARF can be stratified for severity, and different outcomes depend on the degree of severity as assessed by the extent of GFR loss. Current management depends on the level of severity and includes optimization of hemodynamics and fluid status, avoidance of further renal insults, optimization of nutrition, and, when appropriate, the application of renal replacement therapy (RRT). Indications for RRT generally are clear for patients with the most severe of conditions (e.g., anuria with severe hyperkalemia in the setting of septic shock), whereas they can be a matter of controversy and require individualized assessment in less severe situations (e.g., polyuric ARF in a patient who has previous chronic renal dysfunction and is otherwise well 2 d after cardiac surgery). Optimal strategies to improve patient outcome in ARF may include optimization of delivered RRT dose (8 –15). This review focuses on RRT dose and its measurement and prescription in the ICU and on the current evidence concerning the relationship between RRT dose and outcome.
What Is RRT Dose, and How Is It Measured?
The conventional view of RRT dose is that it is a measure of the quantity of blood purification achieved by means of extracorporeal techniques. As this broad concept is too difficult to measure and quantify, the operative view of RRT dose is that it is a measure of the quantity of a representative marker solute that is removed from a patient. This marker solute is taken to be reasonably representative of similar solutes, which require removal for blood purification to be considered adequate. This
Published online ahead of print. Publication date available at www.cjasn.org. Address correspondence to: Dr. Claudio Ronco, Department of Nephrology, Dialysis, and Transplantation, San Bortolo Hospital, Viale Rodolfi 36100, Vicenza, Italy. Phone: 39-0444-993869; Fax: 39-0444-993949; E-mail: email@example.com Copyright © 2006 by the American Society of Nephrology
premise has several major flaws: the marker solute cannot and does not represent all of the solutes that accumulate in renal failure. Its kinetics and volume of distribution are also different from such solutes. Finally, its removal during RRT is not representative of the removal of other solutes. This is true for both end-stage renal failure and acute renal failure. However, a significant body of data in the end-stage renal failure literature (16 –21) suggests that, despite all of the above major limitations, single solute marker assessment of dose of dialysis seems to have a clinically meaningful relationship with patient outcome and, therefore, clinical utility. Nevertheless, the HEMO study, examining the effect of intermittent hemodialysis (IHD) doses, failed to confirm the intuition that “more dialysis (than recommended by current guidelines) is better” (21). Thus, if this premise that seems useful in end-stage renal failure is accepted to be potentially useful in ARF for operative purposes, then the amount (measure) of delivered dose of RRT can be described by various terms: efficiency, intensity, frequency, and clinical efficacy. Each is discussed below. Efficiency of RRT is represented by the concept of clearance (K), i.e., the volume of blood cleared of a given solute over a given time. K does not reflect the overall solute removal rate (mass transfer) but rather its value normalized by the serum concentration. Even when K remains stable over time, the removal rate will vary if the blood levels of the reference molecule change. K depends on solute molecular size, transport modality (diffusion or convection), and circuit operational characteristics (blood flow rate, dialysate flow rate, ultrafiltration rate, hemodialyzer type, and size). K can be normally used to compare the treatment dose during each dialysis session, but it cannot be used as an absolute dose measure to compare treatments with different time schedules. For example, K is typically higher in IHD than in continuous renal replacement therapy (CRRT) and sustained low efficiency daily dialysis (SLEDD). This is not surprising, because K represents only the instantaneous efficiency of the system. However, mass removal may be greater during SLEDD or CRRT. For this reason, the information about the time span during which K is delivered is fundamental to describe the effective dose of dialysis. Intensity of RRT can be defined by the product “clearance time” (Kt). Kt is more useful than K in comparing various RRT. A further step in assessing dose must include frequency of the Kt application over a particular period (e.g., 1 wk). This additional dimension is given by the product of intensity freISSN: 1555-9041/103-0380
As such. which seem easier to be achieved without formal modeling. To evaluate VUREA in patients with ARF. the effect of compartmentalization of solutes is minimized. Kt/V is an established maker of adequacy of dialysis for small solute correlating with medium term (several years) survival in chronic hemodialysis patients (21). and a singlepool Kt/volume of distribution of urea (VUREA) of at least 1. It must be acknowledged. but it also is of the urea generation rate (G) from protein intake. The time-averaged blood urea concentration (TACUREA) is the area under the saw tooth curve produced by intermittent dialysis sessions. single-pool kinetics can be applied (spKt/V) with a reasonable chance of approximating true solute behavior. and VUREA.Clin J Am Soc Nephrol 1: 380 –388. Finally. A modification of this equation was described by Gotch and colleagues (24 –26) as standardized Kt/V (stdKt/V). membrane clotting. labile fluid volumes. G likely is extremely variable from day to day in patients with ARF. Furthermore. is simply statistically incorrect.
. To study the use of spKt/VUREA as a feasible method for the measurement of CRRT dose and to standardize disparate prescriptions. it is not a good indicator of RRT dose per se. then EKRc can be calculated by the ratio of total urea removal (equal to G at steady state) and TACUREA. However. daily. from a theoretical point of view. 2006
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quency (Kt treatment days/wk Kt d/w).6 versus 55. determination of TBW by different
Figure 1. If G and TACUREA are known. This concept of Kt d/w offers the possibility to compare disparate treatment schedules (intermittent. Furthermore. nonetheless. after some days of CRRT. that the final spKt/VUREA value was approximated considering VUREA as a function of total body weight (TBW) (see below). and TACUREA calculations are less immediate than K. less so during SLEDD. the concept of MPC. respectively). which changes dynamically during the course of treatment. and possible residual renal function.2 or 61. and it is calculated as the ratio of G and mean weekly urea pretreatment concentrations (MPC) normalized for VUREA. MPC. we recently tested a software called “Adequacy Calculator for ARF” (22).2 is currently recommended. It can be described by a fractional clearance of a given solute (Kt/V). Efficacy of RRT represents the effective solute removal outcome that results from the administration of a given treatment to a given patient. it does not take into account the size of the pool of solute that needs to be cleared. Difference between KCALC and KDEL tends to increase for mean KCALC–KDEL values 60 ml/min. Urea is typically used as a marker molecule in end-stage kidney disease to guide treatment dose. poor blood flows with temporary venous catheters. This difference is the result of patients’ urea levels approaching a real steady state. delivery of prescribed dose in ARF can be limited by technical problems such as access recirculation. Kt d/w is superior to Kt because it offers information beyond a single treatment: patients with ARF typically require more than one treatment. many concerns have been raised because problems that are intrinsic to ARF can hinder accuracy and meaning of such dose measurement. The average KCALC-KDEL value for each treatment is presented on the x axis. a high protein catabolic rate. These formulas would allow comparisons among the dose measurement of disparate therapies and different frequencies of RRT. In fact.2 13. the value of clearance predicted by the calculator correlated significantly to the value obtained from direct blood and dialysate determination during the first 24 treatment hours. This is a simple Microsoft Excel-based program (23) that calculates urea clearance and estimates fractional clearance and Kt/VUREA for all RRT modalities. in a pilot evaluation of a small cohort of patients.3 12. uncertainty about the VUREA. However. Adapted from (21). TACUREA is a function of dialysis dose. Finally. and. Furthermore. These include the lack of a metabolic steady state. irrespective of the renal replacement modality
used (Figure 1). because the therapy is applied continuously. where V is the volume of distribution of the marker molecule in the body. the difference between both methods is shown on the y axis. in patients who might receive only three or four sessions of IHD. G. We found that. These aspects are particularly evident during IHD. Access recirculation is also an issue of lesser impact during low efficiency continuous techniques. and machine malfunction. Furthermore. However. difference of 16 and 11%. Bland-Altman analysis illustrates correlation between urea clearance obtained by the two methods: Urea clearance calculated with the described software (KCALC) and urea clearance obtained by direct measure on prefilter blood and effluent samples (KDEL). and even less so during CRRT. Other dose measurement methods have been used in patients with end-stage renal failure but have not been investigated sufficiently in the setting of ARF. This requires the dimension of efficacy. continuous). (27) undertook a systematic study in a cohort of 28 patients with ARF. Parallel lines indicate 95% limit of agreement. The calculator works on the assumption that urea sieving coefficient is 1 for convective therapies and that complete saturation of spent dialysate occurs during continuous dialysis. Emerging evidence from patients with end-stage renal failure suggests the importance of using equivalent renal clearance (EKRc).9 19. although the application of Kt/V to the assessment of dose in ARF is theoretically intriguing. Himmelfarb et al. alternate day. VUREA is also dynamic and not as easily estimated using anthropometric calculations. Kt/VUREA application to patients with ARF has not been validated rigorously.9 L. They found that VUREA estimated by double-pool Kt/V and by equilibrated Kt/V was statistically significantly higher than VUREA determined by single-pool Kt/V (67. which would require a parametric distribution of values. t. clinical issues such as hypotension and vasopressor requirements can be responsible for solute disequilibrium within tissues and organs.
In a patient who has right ventricular failure. In these patients.0 or TACUREA 45 mg/dl was associated with increased survival. These observations highlight the gross inadequacies of applying end-stage renal failure paradigms to patients with ARF. and cerebral edema. However. 2006
approaches to anthropometric measurements (Watson. Several reports exist in the literature dealing with this issue. Hume-Weyer. RRT dose is all about lowering the temperature without any tonicity shifts that might increase intracranial pressure. Finally and more important. found that higher Kt/V values (0. 10 units of cryoprecipitate. respectively). 43. This is likely due to evidence from ESRD. magnesium control.0 L. Chertow. and rapidly rising serum potassium already at 7 mmol/L. and 10 units of platelets to be administered rapidly without inducing fluid overload (because 1 to 1. (28). and whose cerebral edema. who is worsening because of fever.1 11. Brause et al.6 7. extravascular volume control. Dose of RRT is about prophylactic volume control.
who is awaiting urgent liver transplantation. using continuous venovenous hemofiltration (CVVH). and acute respiratory distress syndrome (ARDS) who is receiving lungprotective ventilation with permissive hypercapnia. sepsis. ischemic hepatitis. to begin with. intravascular volume control. These investigators inevitably concluded that estimates of TBW cannot be used as a surrogate for VUREA in patients with ARF.5 L of ultrafiltrate is removed in 1 h) than for Kt/V to be any particular value at all. In the critically ill patient. and who has acidemia inducing a further life-threatening deterioration in pulmonary vascular resistance. Solute removal is just a by-product of fluid control. This study. in the setting of coagulopathic bleeding after cardiac surgery) for 10 units of fresh-frozen plasma. it is much more important (e.5 7.g. 42. More subtle adjustments such as prescribing a calculated Kt/V of 1 versus 1. of course. is all about controlling kalemia. dialysis dose. Although each and every aspect of this broader understanding of dose is difficult to measure. in a patient with pulmonary edema after an ischemic ventricular septal defect that required emergency surgery. not one dimension picked because of a similarity with end-stage renal failure: there is no evidence in the acute field that such solute control data are more relevant to clinical outcomes than volume control or acid-base control or tonicity control. changing from second daily to daily dialysis while prescribing the same Kt/V) can be reasonably believed truly to deliver a “different” dose in the setting of ARF. The validity of these observations remains highly questionable.
Prescribed Dose of Solute Removal: How Much?
Despite all of the uncertainty surrounding its meaning and the gross shortcomings related to its accuracy in patients with ARF. rhabdomyolysis.10) retrospectively evaluated 844 patients who had ARF and required CRRT or IHD over a 7-yr period. the therapeutic needs that can/need to be affected by the “dose” of RRT are many more than the simple control of small solutes as represented by urea. In a patient who has fulminant liver failure.382
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Clin J Am Soc Nephrol 1: 380 –388. ARF.3 L.6 and 51.. The view that it would still be sufficient to alter clinical outcomes remains somewhat optimistic. They also indicate that. only major changes in the application of dose (e.
Critique of the Traditional Concept of Dose
The major shortcoming of the traditional solute marker– based approach to dialysis dose in ARF lies well beyond any methodologic critique of single-solute kinetics-based thinking similar to that offered in the preceding paragraphs. the “dose” component of RRT that matters immediately is acid-base control and normalization of pH 24 h/d. tonicity control. and the avoidance of unwanted side effects associated with the delivery of solute control. Nonetheless.2 thrice weekly is indicated as standard (21).8 8. the majority of whom are in intensive care. the benefits of greater Kt/V accrue over years of therapy. a restrictive (solute-based only) concept of dialysis dose seems grossly inappropriate.2 can easily be criticized as being within the calculation error around each prescription and not necessarily representing a reliable change in dose delivery. These aspects of dose must be considered explicitly when discussing the dose of RRT in ARF. In patients with ARF. the idea that there might be an optimal dose of solute removal continues to have a powerful hold in the literature.1 13. any difference in dose would apply for days to weeks. the hypothesis that higher doses of dialysis may be beneficial in critically ill patients with ARF must be considered by analogy and investigated. RRT dose is all about removing fluid gently and safely so that the extravascular volume falls while the intravascular volume remains optimal. No clinically important outcome was affected. A mean Kt/V 1. In a young man with trauma. Finally. ARF. ARF. Daily hemodialysis resulted in significantly improved survival
. potassium control. for which a minimum Kt/V of 1. Daily IHD compared with alternate-day dialysis also seemed to be associated with improved outcome in a recent trial (29). The Kt/V (or any other solutocentric concept of dose) is almost just a by-product of such dose delivery. was retrospective with a clear post hoc selection bias. and the need for inotropic and intraaortic balloon counterpulsation support. Investigators from the Cleveland Clinic (9. dialysis dose did not affect outcome in patients with very high or very low scores but did correlate with survival in patients with intermediate degrees of illness.g. 46.53) were correlated with improved uremic control and acid-base balance. They found that when patients were stratified for disease severity.1 L) yielded significantly lower measures compared with TBW determined by physiologic formulas and by bioimpedance (51. calcium and phosphate control. They include acid-base control. temperature control. clinically relevant assessment of dose in critically ill patients with ARF should include all dimensions of such dose. unlike in the field of chronic hemodialysis. This would be expected.1 L.. all measures of VUREA by blood-based kinetics exceeded TBW measurements by any method (7 to 50% difference). because it is likely that patients die more often from incorrect “dose” delivery of this kind than incorrect dose delivery of the Kt/V kind. In ARF.8 versus 0.
Another prospective. male gender.or 90-d mortality typically used in ICU trials. controlled trial of CRRT dose. that the incidence of sepsis was low compared with the typical populations reported to develop ARF in the world (31).01).2. second-daily dialysis was associated with significant differences in fluid removal and dialysis-associated hypotension. better control of uremia. prescribed doses were not standardized by weight. The use of the “calculator” allowed us to monitor strictly our treatments during the study period. randomized trial conducted by Bouman et al. however.
. Unfortunately. patients receive only 67% of prescribed CRRT therapy. 2006
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(72 versus 54%. according to reported mean TACUREA. we conducted a survey on aspects of ARF. only patients who achieved 85% of the prescribed dose were included: to obtain this goal. making the study insufficiently powered and the incidence of sepsis low compared with the typical populations reported to develop ARF in the world. All of these studies must be seen. alarms troubleshooting. Italy. to an operative treatment time that was shorter than prescribed (during bag substitution. early low-volume hemofiltration (24 to 36 L/24 h). when compared with prescribed dose (22). They include filter clotting. and 75% of responders did not monitor RRT delivered dose (Figure 2). can make it difficult. to apply such strict protocol by pure postdilution hemofiltration.2. however. These investigators found no difference in terms of renal recovery or 28-d mortality. as is true for antibiotic blood levels during severe infections. although a clear understanding of the adequate dose of RRT has not yet been achieved. and low blood flow were limiting factors that affect RRT administration and that approximately 70% of dialysis delivered a Kt/V of 1. Equally important is the observation that this study was conducted over 6 yr in a single center. including treatment prescription. P 0. and that its final outcome was not the accepted 28. it is also true.7% (P 0.
Figure 2.05) reduction of delivery of therapy. These observations underline that RRT prescriptions for patients who have ARF and are in the ICU should be monitored closely if one wishes to ensure adequate delivery of the prescribed dose. radiologic procedures. the number of patients was small. (34) also showed that. Many technical and/or clinical problems. and filter change. Applying the Kt/V dose assessment method to CVVH at a dose of 35 ml/kg per h in a 70-kg patient who is treated for 24 h. that the study was unblinded and therefore potentially subject to a Hawthorne effect. CVVH at 35 ml/kg per h would still provide an effective daily delivery of 1. Furthermore. high filtration fraction in the presence of access dysfunction and fluctuations in blood flow.4 also applied daily. making the potential variability in RRT dose large. in the CVVH dose trial (14). this delivery reduction was sometimes due to calculator overestimation and. several limitations affected this study: sicker. hemodynamically unstable patients were excluded and underwent CRRT instead. fewer hypotensive episodes. In addition. it seems that patients who received conventional IHD were underdialyzed. that uremic control was not reported. a treatment day would be equivalent to a Kt/V of 1. this study was single center in nature with all of the inherent limitations with regard to external validity and also the source of an inquiry by a university committee and serious questioning concerning scientific rigor and propriety (30). Participants’ view about dialysis efficiency targets (K) for urea during the third International Course on Critical Care Nephrology held in Vicenza. Italy. These observations suggest that further studies should be undertaken to assess the effect of dose of IHD on outcome. (32) assigned patients to three intensity groups: Early high-volume hemofiltration (72 to 96 L/24 h). However. In fact. similarly. and late low-volume hemofiltration (24 to 36 L/24 h). Of note. In our population. more often. Furthermore. the external validity of this study remains untested. in the light of an absolute lack of any previous attempt to adjust ARF treatment dose to specific target levels. (33). During the third International
Course on Critical Care Nephrology held in Vicenza. Despite uncertainty regarding the calculation of VUREA. among approximately 550 participants (equally distributed between nephrologists and intensivists) from approximately 500 different centers (unpublished data). suggesting that other aspects of “dose” beyond solute control (inadequate and episodic volume control) might have explained the findings. In a randomized. Thus. A retrospective study by Venkatarman et al. We found that more than one third of responders reported not prescribing any specific RRT dose for patients with ARF. that adequate prescription should be followed by adequate administration. and circuit down time during surgery. even in the presence of an underestimation of VUREA by 20%. and we found an average 10. The differences between delivered and prescribed dose in patients who had ARF and underwent IHD were analyzed by Evanson et al. continuous venovenous postdilution hemofiltration (CVVH) at 35 or 45 ml/kg per h was associated with improved survival when compared with 20 ml/kg per h in 425 critically ill patients with ARF (14). The authors found that a high patient weight.Clin J Am Soc Nephrol 1: 380 –388. Furthermore. CRRT is not administered). and more rapid resolution of ARF. compensation for interruptions in treatment as a result of ICU procedures was made by increasing effluent flow rates in the subsequent hours. in routine practice. and filter changes.
This study will assume a conservative 90-d mortality rate of 60% in the control group. multicenter study conducted in ICU. This study will also assume a conservative estimate for the reduction in mortality in patients of only half that reported by Ronco et al. controlled trials that assess the impact of RRT dose in ARF will be available to better inform clinical practice. sophisticated dialysis machinery. For example. unpublished data) found that very few units had adopted the intensive CRRT regimen proposed by Ronco et al. tailored dialysate composition. The Australian and New Zealand Intensive Care Group has also recently been funded to conduct a multicenter. whereas current practice in Australia includes a variety of techniques in addition to CVVH. it is likely that. Patients will be included in the study if the following criteria are fulfilled: the clinician believes that the patient requires RRT for ARF. and the treating clinician anticipates treating the patient with CRRT for at least 72 h. clinically significant organ edema in the setting of ARF. However. (14). randomized. The primary aim is to study the delivered dose of dialysis.38). in the study conducted by Ronco et al. in the near future. creatinine 300 mol/L secondary to ARF.20) in the setting of ARF. RRT prescription occurs in closed ICU under Intensivist control in almost 100% of cases and is almost exclusively in the form of CRRT (37. In addition to the benefits that pertain specifically to the kinetics of solute removal. whereas unstable patients receive either CRRT or SLED.5%). ICU length of stay. the practice of a higher intensity CRRT has not been widely adopted into routine ICU practice.
Dose Delivery: Continuously or Intermittently?
Clearance-based dose quantification methods may not be adequate to compare effectiveness. severe acidemia (pH 7.5% absolute reduction from a 90-d mortality of 60 to 51. Thus. Patients will be randomized to one of two dosing strategies for RRT. (i. In November 2003. controlled trial of CRRT dose in critically ill patients with ARF. despite the development of new membranes. and continuous dialysis therapies.90 to detect a reduction in mortality from 55 to 45% on the basis of RRT dose (36).5 mmol/L). (14). It is hoped that this international collaboration will provide a clearer picture of how RRT is chosen. which then will be compared with ICU mortality. traditionally providing less urea clearance per week than IHD. 28-d mortality. hospital mortality. Data from such Australian units showed that the vast majority prescribe a standard CRRT intensity of 2 L/h of effluent to all patients irrespective of weight. an acceptable mean blood urea nitrogen level of 60 mg/dl. Because current practice for RRT in ICU remain poorly defined. hemodynamically stable patients receive IHD. A recent study (31) also showed marked variability worldwide. Finally. 2006
Are New Studies Needed?
The practice of CRRT seems not to have changed in recent years.e.384
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Clin J Am Soc Nephrol 1: 380 –388. a relationship between delivery of RRT continuously instead of intermittently has not been fully established. in the high-dose arm. Again. two large. The avoidance of volume swings related to rapid ultrafiltration rates may also represent another dimension of dose for which comparability is difficult. The planned total enrollment is 1164 patients at 27 institutions during 3 yr to achieve a power of 0. In the low-dose arm. the DOse REsponse Multicenter International collaboration (DO-RE-MI) (35) is currently seeking to address the issue of how practice patterns are currently chosen and performed. Most recently. If we consider that the median body weight for Australian patients is approximately 80 kg. A survey of several units in the Australian and New Zealand Intensive Care Society Clinical Trials Group (Bellomo R. and number of days of mechanical ventilation.5% ( 0. prospective. when the critical parameter is metabolic control. prescribed. patients receive IHD and SLED on a 6 /wk schedule or CVVHDF with an effluent flow rate of 35 ml/kg per h. given these two large studies that are either under way or about to start. we can assume that the median prescribed CRRT dose in Australia is approximately 25 ml/kg per h. the patient fulfils one of the following clinical criteria for initiating RRT: oliguria (urine output 100 ml/6 h) unresponsive to fluid resuscitation measures. current practice in CRRT even within a single country is extremely varied. parallelgroup trial (ATN Study) of an intensive-dose strategy versus a conventional-dose strategy of RRT for the treatment of ARF caused by acute tubular necrosis in critically ill patients. hyperkalemia ([K ] 6. an absolute reduction of 8.05). This design is intended to deliver data on both a comparison between intermittent therapy and CRRT and one between “low” and “high” dose of RRT. has been shown to be very difficult to reach even by intensive IHD regimens (40). urea concentration 25 mmol/L secondary to ARF. randomized. the Acute Renal Failure Trial Network initiated a multicenter. Thus. The reason for this difference may be that urea is less compartmentalized than other solutes and equivalent amounts of urea removal where one therapy is intermittent rather than continuous do not represent equivalent therapies for a broader range of solutes. has comparable patient outcomes. easily obtainable in a 100-kg patient with a 2-L/h CVVH. the technique of CRRT was CVVH with postdilution. patients receive IHD and SLED on a 3 /wk schedule or CVVHDF with an effluent flow rate of 20 ml/kg per h. peritoneal dialysis (PD). randomized.. irrespective of treatment modality. in both strategies. In Australia.. Despite a strong rationale and positive findings of some prospective trials. this study is projected to have 90% power of detecting an 8. such as CVVHD and CVVHDF. in a computer-based simulation. The treatment effect observed in the previous dose of CRRT study was a reduction in mortality from 59 to 42% (29% relative risk reduction and 17% absolute risk reduction). and delivered and how such delivery may affect outcome. The study will randomize 1500 patients in 35 Australian and New Zealand ICU to receive either postdilution CVVHDF
at 25 or at 40 ml/kg per h of effluent. DO-RE-MI is an observational. the Surviving Sepsis Campaign guidelines for management of severe sepsis and
. Even when EKRc is used to compare intermittent and continuous therapies. On the basis of these figures. increased RRT frequency results in decreased ultrafiltration requirements per treatment. it does not seem to be equivalent in terms of outcome (39).
Just like stereotyped approaches to ventilation are anachronistic and inappropriately try to fit the patient into a fixed therapy rather than tailoring the therapy to the patient. Theoretically speaking. the choices now are almost limitless: should it be 3 or 4 h of IHD with standard settings? Or should it be CRRT at 35 ml/kg per h effluent flow rate? Or should it be SLEDD at blood and dialysate flow rates of 150 ml/min for 8 h during the day? Or should we apply SLEDD for 12 h overnight? Or she we add a convective component to SLEDD and make it SLEDDf? Or should we combine CRRT for the first 2 or 3 d when the patient is in the hyperacute phase.2 versus CRRT at an effluent flow rate of 35 ml/kg per h. Initial case series have shown the feasibility and high clearances that potentially are associated with such approaches
. A meta-analysis of 13 studies conducted by Kellum et al. Thus. on the basis of actual scientific evidence. people then might consider compromise solutions. which concluded that. 2006
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septic shock (41) concluded that. had significantly greater severity of illness scores. randomized clinical trial should be undertaken (44). A single short-term. If IHD were found to be inferior. CRRT had increased mortality. So. in greater amounts. reduced ultrafiltration rate with hemodynamic stability. efficiency of resource use. from the point of view of the intensivist. when similar patients were compared. so should RRT be adjusted to fulfill the needs of the individual and his or her illness. and. then the immediate question would be whether the difference was dependent on the nature of the therapy (intermittent or continuous) or the “dose” of solute removal. despite randomization. Thus. the modes of RRT are beginning to resemble the modes of mechanical ventilation. relatively fixed approaches must be chosen. The authors found that the CRRT population. the dispute simply might be insoluble. One major problem with all of these comparisons remains that for the purpose of randomized. Similarly.” Can we make RRT equal to the metabolic challenge that we might face in different patients? ARF in the critically ill patient is frequently part of multiple organ failure (MOF) and sepsis. then the protagonists of IHD then simply would say that it all would be just a matter of increasing the time or the frequency and hence the overall weekly dose of IHD and the outcome difference would disappear.48). controlled trials. It is logical to hypothesize that the blood purification dose needed in patients with uncomplicated ARF would be very different from that needed in patients with ARF in the setting of septic MOF. during ARF. despite better control of azotemia and a greater likelihood of achieving the desired fluid balance. and patients. if effluent flow rates were increased to 45 ml/kg per h. like in a computerized drop-down menu. then the protagonists of continuous therapy simply would say that it all was a matter of prescribing the right CRRT dose. (44). intended as a hypothetical therapy that would closely mimic the features of the native kidney in this setting and perhaps enhance them (51).Clin J Am Soc Nephrol 1: 380 –388. single-center trial comparing hybrid therapies with CRRT has shown satisfying results in terms of dose delivery and hemodynamic stability (49). with ventilator settings seamlessly being changed to fit into the therapeutic goals and patient needs and phases of illness. extended daily dialysis. low anticoagulant needs. The largest comparative trial so far conducted randomly assigned 166 critically ill patients with ARF to either CRRT or IHD (42). beyond “adequate” RRT dose for ARF.
(47. One can now easily use technology in ICU to generate ultrapure replacement fluid and administer it like in CRRT but at lower cost. optimized delivered-to-prescribed ratio. Hence. Thus. such as SLEDD. and improved patient mobility. The authors confirmed that a large. whereas the excess of one over the other might be responsible for the
Hybrid techniques have been given a variety of names. A more recent smaller trial by the Cleveland Clinic group (43) also failed to find a difference in outcome between one therapy and another. patients may be randomly assigned to an IHD at a calculated Kt/V of 1. CVVH and IHD should be considered equivalent. the difference in outcome again would disappear. Given this kind of impasse. the purpose of such therapy would be the optimization of the advantages offered by either CRRT and IHD. If one approach was found superior. another meta-analysis (45) found no difference between the two techniques. the 9 to 5 maximum staff availability period or the nighttime period. or simply extended dialysis (46 – 49).
Is There Adequacy Beyond Adequacy?
“Ad equatum” is a Latin expression that means “equal to. One such solution might be represented by hybrid techniques such SLEDD. depending on variations in schedule and type of solute removal (convective or diffusive). if CRRT were found to be inferior. the same might happen with RRT. with SLEDD thereafter as recovery takes place? Indeed. after stratification of 1400 patients according to disease severity. These mediators normally exist in a state of immune homeostasis. The arrival of technology that can be used in the ICU by ICU nurses to deliver SLEDD with convective components offers further options from a therapeutic point of view. independent from other comorbidities and despite technical improvements in RRT delivery. CRRT was associated with a significant decrease in the risk for death. there may be a role for an “adequate” RRT dose for ARF with sepsis. prolonged intermittent daily RRT. for example. are still dying of ARF (50): it is evident that absence of kidney function accounts for some specific and independent risk factor for poor prognosis of unknown magnitude. diminished cost of therapy delivery. including efficient solute removal with minimum solute disequilibrium. it remains uncertain whether the choice of RRT modality (intermittent or continuous) actually matters to patient outcome. and for shorter periods of time or combine such hemofiltration with diffusion or use pure diffusion at any chosen clearance for a period of time that can encompass a given nursing shift. carefully controlled. It was hypothesized further recently that the peak concentration of either the proand anti-inflammatory mediators in plasma might be responsible for some of the ill effects of sepsis (52). Just like the concept of showing that one mode of ventilation is better than another seems a lost cause. However. Furthermore.
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technology that is available and frequent multidisciplinary setting of physiologic and clinical goals would dictate therapeutic choices that are adapted to the patient and his or her illness rather than the other way around. 1994 9. dynamic clinical judgments and knowledge of the
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