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Crit Care Clin 18 (2002) 223 ­ 247

Dialysis modalities in the intensive care unit

Omaran Abdeen, MD, Ravindra L. Mehta, MD*

Division of Nephrology and Hypertension, University of California, San Diego Medical Center, 8342, 200 West Arbor Drive, San Diego, CA, 92103, USA

During the past decade, a number of advances have been made in the field of renal replacement therapy. Clinicians have gained a better appreciation of the need for early and aggressive management of patients with renal failure in the intensive care unit (ICU) [12]. Although a number of treatment modalities exist, there seems to be continued controversy about selection of the most appropriate modality for each individual patient. This article discusses the clinical spectrum of renal failure in the ICU, indications for the initiation of dialysis, principles of dialysis therapy, and unique features, advantages, disadvantages, and usefulness of the various renal replacement modalities available.

Diversity of clinical renal failure in the ICU Appropriate modality selection requires an understanding of the clinical spectrum of renal failure in the ICU. Uncomplicated acute renal failure (ARF) refers to an acute and transient decline in glomerular filtration rate without clinically apparent complications. Dialytic support often is not required in patients with uncomplicated ARF or may be performed for a single indication, such as hyperkalemia. In complicated ARF, however, multiple metabolic and volume status perturbations are present, the patient is often oliguric, and the renal failure may be present in association with multiorgan failure (MOF). The threshold for initiation of dialysis and the choice of dialytic modality differ depending on the associated complications and comorbid conditions.

Indications for initiation of dialysis Although there has been an increased appreciation for the need for early and aggressive management of ARF in the ICU, there are no standards for initiation of

* Corresponding author. E-mail address: [email protected] (R.L. Mehta). 0749-0704/02/$ - see front matter D 2002, Elsevier Science (USA). All rights reserved. PII: S 0 7 4 9 - 0 7 0 4 ( 0 1 ) 0 0 0 0 7 - 0

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dialysis, and many nephrologists avoid dialysis initiation for as long as possible. Two major factors contribute to the tendency to delay dialysis. One factor is that the dialysis procedure itself has associated risks. Hypotension, arrhythmias, and complications of vascular access placement are common [46,90]. A second factor is concern that dialysis may delay recovery of renal function [17,78]. This contention is supported by animal data in which hypotension resulted in recurrent renal ischemia [31] and by human studies that showed a decline in the glomerular filtration rate (GFR) during and after the intermittent hemodialysis session [44]. Several factors need to be considered when making the decision to provide renal replacement therapy. It is important to recognize that for patients in the ICU, ARF usually does not occur in isolation from other organ-system dysfunction. Consequently, providing dialysis can be viewed as a form of renal support for multiorgan dysfunction rather than renal replacement [50]. In the presence of oliguric renal failure, administration of large volumes of fluid to patients with MOF may lead to impaired oxygenation. In such a setting, early intervention with extracorporeal therapies for management of fluid balance significantly may impact the function of other organs, even in the absence of traditional indices of renal failure such as marked azotemia. In general, indications for dialysis fall into one of three broad categories: (1) solute indications such as marked azotemia, (2) volume indications such as in fluid overload, or (3) both. The indication for initiation influences outcome. The authors showed in a randomized, controlled trial comparing intermittent therapies with continuous therapies that patients dialyzed for solute control had a better outcome than those dialyzed for volume control [53]. Patients dialyzed for solute and volume control had the worst outcome. It seems that volume overload tends to confer a poorer prognosis. This notion is supported by a number of observational studies. Mukau et al. [1] showed that 95% of their patients with postoperative ARF had fluid excesses of more than 10 L at initiation of dialysis [63]. Studies have suggested that achieving a negative fluid balance in the first 3 days of admission for septic shock is a predictor of better survival. Consequently, fluid regulation should be an important consideration when deciding to initiate dialysis in ICU patients with ARF. Such renal support provides volume space that permits for the administration of adequate nutritional support without limitations [88]. In addition to volume overload, solute disturbances such as hyperkalemia may predispose to life-threatening arrhythmias, and uncontrolled uremia may lead to a variety of serious complications. Maintaining electrolyte, acid-base, and solute homeostasis is another important factor when considering initiation of dialysis (Table 1).

Principles of dialysis Overview Dialysis is a process in which molecules in solution A (blood) diffuse across a semipermeable membrane into solution B (dialysate) [90]. The transfer of solute

O. Abdeen, R.L. Mehta / Crit Care Clin 18 (2002) 223­247 Table 1 Indications and timing of dialysis for acute renal failure: renal replacement vs. renal support Renal replacement Purpose Timing of intervention Indications for dialysis Dialysis dose Replace renal function Based on level of biochemical markers Narrow Extrapolated from ESRD Renal support

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Support other organs Based on individualized need Broad Targeted for overall support

ESRD = end-stage renal disease. Adapted from Mehta RL. Supportive therapies: intermittent hemodialysis, continuous renal replacement therapies, and peritoneal dialysis. In: Schrier RW, editor. Atlas of diseases of the kidney, Current Medicine, Philadelphia: Blackwell Science; 1998; with permission.

across the membrane is determined by membrane characteristics and the solute concentration on the two sides of the membrane. Diffusive clearance denotes the movement of small-molecular-weight solutes from blood to dialysate under the driving force of an electrochemical gradient. Convective clearance (ultrafiltration) occurs when water is driven across the membrane by a hydrostatic or an osmotic force. Solutes that can pass through the membrane pores move along with the water (solute drag).

Determinants of diffusive clearance Membrane characteristics have a major role in determining the efficacy of diffusive clearance. Membranes with larger pores, larger surface area, and a specific geometric configuration have greater permeability to smalland middle-molecular-weight solutes than membranes with smaller pores and smaller surface area. Most hemodialysis membranes are synthetic and are more permeable than older, cellulose-based membranes. The flow rates of blood and dialysate and the dialysis time are the principal determinants of diffusive solute clearance. Direction of blood and dialysate flow is also a major determinant of solute diffusion capacity. All hemodialysis modalities employ a countercurrent mechanism in which the direction of dialysate flow is opposite that of blood flow. Countercurrent flow serves to maximize the concentration gradient between the blood and dialysate throughout the length of the membrane [90]. Determinants of convective clearance Because convective clearance is achieved mainly by solute drag during ultrafiltration, the rate at which ultrafiltration occurs is the major determinant of convective clearance. Ultrafiltration rate, in turn, is determined by transmembrane pressure, water permeability, pore size, surface area, and membrane geometry and thickness. Enhanced blood flow rates increase ultrafiltration rates, because higher blood flow rates prevent the stagnant accumulation of proteins that cannot cross membranes at the surface of ultrafiltration. As the transmembrane pressure difference increases, more fluid and accompanying solute are

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removed. The maximum transmembrane pressure that can be applied is limited by the tensile strength of the membrane. The size of solutes that can be dragged during convection is determined in large part by the size selectivity of the membrane. In general, convection is more efficient than diffusion at removing middle- and large-molecular-weight solutes [90]. Vascular access In order for blood to be removed from the patient, circulated through the dialyzer, and then returned to the patient, access to the vasculature is required. Although arteriovenous fistulas and grafts are used in chronic-dialysis patients, it is more common to use a catheter for vascular access in the acute setting. When arteriovenous acute dialysis commonly was used, patients would receive one catheter in a major artery and another in a major vein. This type of vascular access has fallen out of favor because of the multitude of complications that arise from the use of chronic indwelling arterial catheters. Currently, most patients who require acute dialysis receive a dual-lumen venous catheter placed in the femoral, jugular, or subclavian vein. The design of these catheters allows blood to be withdrawn from a proximal opening and returned to a more distal opening. Because of this design, some of the blood that is returned to the vein recirculates into the withdrawing port and into the hemofilter again, reducing the efficiency of dialysis. Recirculation has been shown to be worse in femoral catheters (16%) when compared with that of subclavian catheters (4% P = 0.0001) [39]. Anticoagulation To avoid clotting of the blood in the dialysis membrane or circuit tubing or at the vascular access, patients who receive dialysis generally require anticoagulation. Although a variety of anticoagulants have been used (including lowmolecular-weight heparin, prostacyclin, and nafamostat), systemic unfractionated heparin anticoagulation, regional citrate anticoagulation, and frequent saline flushing of the system are the most commonly used methods [48]. Heparin anticoagulation is easy to use but has the disadvantage of necessitating anticoagulation of the entire patient. At the authors' institution, they have favored the use of regional citrate anticoagulation [86,87]. The use of protocol-driven monitoring and adjustment of anticoagulation has improved the efficiency of the nursing staff and the physicians. The authors have been able to provide dialysis to patients at high risk for bleeding, with minimal complications.

Definition of terms Intermittent therapy An intermittent therapy is defined as any extracorporeal dialysis therapy in which the patient is treated for less than 24 hours. Included in this category are

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patients treated with intermittent hemodialysis (IHD), sorbent IHD, intermittent hemodiafiltration (IHF), intermittent ultrafiltration (IUF), extended daily dialysis (EDD), and slow, low-efficiency dialysis (SLED), also termed slow, continuous dialysis (SCD) (Table 2) [51]. Continuous therapy A continuous therapy is defined as any extracorporeal dialysis therapy in which the patient is treated for 24 hours or longer. Included in this category are a number of modalities that are defined in this section (see Table 2). Continuous arteriovenous hemofiltration Continuous arteriovenous hemofiltration (CAVH) is a form of continuous renal replacement therapy (CRRT) in which blood is driven by the patient's blood pressure through a filter containing a highly permeable membrane by way of an extracorporeal circuit originating from an artery and terminating in a vein. The ultrafiltrate produced is replaced in part or completely with appropriate replacement solution to achieve blood purification and volume control (Fig. 1) [9,11]. Continuous venovenous hemofiltration Continuous venovenous hemofiltration (CVVH) is a form of CRRT in which blood is driven through a highly permeable membrane by a peristaltic pump by way of an extracorporeal circuit originating from a vein and terminating in a vein. The ultrafiltrate that is produced is replaced in part or completely with appropriate replacement solution to achieve blood purification and volume control (see Fig. 1) [9,11]. Slow, continuous ultrafiltration Slow, continuous ultrafiltration (SCUF) is a form of CAVH or CVVH that is not associated with fluid replacement and often is used in the management of

Table 2 Dialysis modalities for acute renal failure Intermittent therapies Hemodialysis Single pass Sorbent based Hemodiafiltration Ultrafiltration Extended daily dialysis Slow continuous dialysis Continuous therapies Peritoneal dialysis Ultrafiltration (SCUF) Hemofiltration (CAVH, CVVH) Hemodialysis (CAVHD, CVVHD) Hemodiafiltration (CAVHDF, CVVHDF)

Adapted from Mehta RL. Supportive therapies: intermittent hemodialysis, continuous renal replacement therapies, and peritoneal dialysis. In Schrier RW, editor. Atlas of diseases of the kidney, Current Medicine, Philadelphia: Blackwell Science; 1998; with permission.

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Fig. 1. CRRT techniques: CAVH and CVVH. A = artery; V = vein; Uf = ultrafiltrate; R = replacement fluid; P = peristaltic pump; Qb = blood flow; Qf = ultrafiltration rate; TMP = transmembrane pressure. (Adapted from Bellomo R, Ronco C, Mehta RI. Nomenclature for continuous renal replacement therapies. Am J Kidney Dis 1996;28(5)S3:2 ­ 7; with permission.)

refractory edema with or without renal failure. Its primary goal is fluid removal (Fig. 2) [9,11]. Continuous arteriovenous hemodialysis Continuous arteriovenous hemodialysis (CAVHD) is a form of CRRT in which the extracorporeal circuit includes slow, countercurrent dialysate flow into the ultrafiltrate-dialysate compartment of the hemofilter. Blood flow through the blood compartment of the membrane is driven by the patient's blood pressure through a circuit beginning in an artery and terminating in a vein. Fluid replacement is not administered routinely, and solute clearance is mostly diffusive (Fig. 3) [9,11]. Continuous venovenous hemodialysis Continuous venovenous hemodialysis (CVVHD) is a form of CRRT in which the extracorporeal circuit includes slow, countercurrent dialysate flow into the ultrafiltrate-dialysate compartment of the hemofilter. Blood flow through the blood compartment of the membrane is driven by a peristaltic pump through a circuit beginning and terminating in a vein. Fluid replacement is not administered routinely, and solute clearance is mostly diffusive (see Fig. 3) [9,11]. Continuous arteriovenous hemodiafiltration Continuous arteriovenous hemodiafiltration (CAVHDF) is a form of CRRT in which the CAVH circuit is modified by the addition of slow, countercurrent

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Fig. 2. CRRT techniques: SCUF. A = artery; V = vein; Uf = ultrafiltrate; P = peristaltic pump; Qb = blood flow; Qf = ultrafiltration rate; TMP = transmembrane pressure; UFC = ultrafiltration control system. (Adapted from Bellomo R, Ronco C, Mehta RI. Nomenclature for continuous renal replacement therapies. Am J Kidney Dis 1996;28(5)S3:2 ­ 7; with permission.)

dialysate flow into the ultrafiltrate-dialysate compartment of the hemofilter. Ultrafiltration volumes are optimized to exceed the desired weight loss to take advantage of convection. Fluid replacement is administered routinely as clinically

Fig. 3. CRRT techniques: CAVHD and CVVHD. A = artery; V = vein; P = peristaltic pump; Qb = blood flow; Qf = ultrafiltration rate; TMP = transmembrane pressure; in = dialyzer inlet; Out = dialyzer outlet; Dial. = dialysate; Qd = dialysate flow rate. (Adapted from Bellomo R, Ronco C, Mehta RI. Nomenclature for continuous renal replacement therapies. Am J Kidney Dis 1996; 28(5)S3:2 ­ 7; with permission.)

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Fig. 4. CRRT techniques: CAVHDF and CVVHDF. A = artery; V = vein; Uf = ultrafiltrate; R = replacement fluid; P = peristaltic pump; Qb = blood flow; Qf = ultrafiltration rate; TMP = transmembrane pressure; in = dialyzer inlet; Out = dialyzer outlet; Dial. = dialysate; Qd = dialysate flow rate. (Adapted from Bellomo R, Ronco C, Mehta RI. Nomenclature for continuous renal replacement therapies. Am J Kidney Dis 1996;28(5)S3:2 ­ 7; with permission.)

indicated to replace fluid losses either in part or completely. Solute removal is diffusive and convective (Fig. 4) [9,11]. Continuous venovenous hemodiafiltration Continuous venovenous hemodiafiltration (CVVHDF) is a form of CRRT in which the CVVH circuit is modified by the addition of slow, countercurrent dialysate flow into the ultrafiltrate-dialysate compartment of the hemofilter. Ultrafiltration volumes are optimized to exceed the desired weight loss to take advantage of convection. Fluid replacement is administered routinely as clinically indicated to replace fluid losses in part or completely. Solute removal is diffusive and convective (see Fig. 4) [9,11].

Dialysis modalities in the ICU Intermittent therapies Intermittent hemodialys Intermittent hemodialysis has been widely used over the past 4 decades in patients with end-stage renal disease (ESRD) and patients with ARF [38]. The vast majority of IHD is performed using a single pass of dialysate at flow rates greater than that of blood. Several important technologic advances have made the procedure safer and more suited for patients with ARF. The availability of variable sodium concentrations in the dialysate, biocompatible membranes, bicarbonate-

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based dialysate, and volumetrically controlled ultrafiltration offer certain advantages that are suited to patients with ARF [20,30]. Nevertheless, most medical centers use a fairly standard regimen for administration of the therapy. Because of limitations imposed by the use of dual-lumen catheters for vascular access, only moderate blood flow rates (200 ­ 300 mL/min) can be achieved. The standard dialysate flow rates are 500 mL/min. IHD offers the advantage of providing for rapid correction of electrolyte and acid-base disturbances. A major disadvantage is its limited time (usually 3­ 4 hours) of total therapy per day. As a result, patients remain without renal support for most of the day, during which fluid regulation, acid-base balance, and electrolyte homeostasis are not possible. Another important disadvantage of IHD is that patients with hemodynamic instability may not tolerate the higher blood flow rates needed to achieve an adequate level of diffusive clearance in the limited duration of the treatment. More importantly, intradialytic hypotension may contribute to delayed renal recovery [17,78]. Schortgen et al. [73] showed that implementation of strict guidelines for the management and prevention of intradialytic hypotension helped reduce the incidence of such episodes but did not affect overall mortality. Sorbent system IHD is a system that regenerates dialysate by passing it through a sorbent cartridge that contains five distinct layers [66,74]. The first layer contains activated carbon, the second layer contains urease, which converts urea to ammonium carbonate, and the third layer contains zirconium phosphate in which cations such as potassium, calcium, and magnesium are adsorbed and exchanged for hydrogen and sodium ions. The fourth layer of the cartridge contains hydrated zirconium oxide through which phosphate and fluoride are adsorbed and exchanged for acetate. The fifth layer contains activated carbon that removes creatinine and other waste products. Although this system is used infrequently, it obviates the need for a source of pure water and provides a system that is highly portable. Because of the unique characteristics of the regenerating system, sorbent IHD allows for greater flexibility in custom tailoring the dialysate. The biggest disadvantage of the sorbent system is that it is less efficient than singlepass IHD. The slower flow rate of dialysate and the overall adsorptive capacity of the sorbent cartridge are the main efficiency limitations of diffusive clearance. Intermittent hemodiafiltration Intermittent hemodiafiltration uses convective clearance for solute removal. The main disadvantage of IHF is the need for large volumes of sterile replacement fluid. The expense associated with IHF has limited its use in the United States. Proponents of the therapy claim that it offers greater hemodynamic stability and improved middle molecule clearance, compared with IHD. Because of these advantages, IHF has been used extensively in Europe [13,51]. Intermittent ultrafiltration Intermittent ultrafiltration uses the same device used for IHD but differs in that the main use of IUF is fluid removal. Typically, the procedure is used for treatment of pulmonary edema or severe cardiomyopathy with resistant fluid overload.

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Because the same machine that is used for IHD also is used for IUF, some medical centers use a combination of IUF and IHD in series. This approach provides greater hemodynamic stability and the ability to quickly treat volume overload. A major disadvantage is the loss of time available for diffusive solute clearance. Extended daily dialysis Extended daily dialysis has been described by Kumar et al. [37] who treated 25 patients with daily IHD for a duration of 6 ­ 8 hours during daylight hours at a blood flow rate of 200 mL/min and a dialysate flow rate of 100 ­ 300 mL/min. In comparison with a similar group of patients treated with CVVH, they demonstrated that less total daily heparin was needed and less intensive nursing commitments were required. No outcome measures such as survival or renal recovery were assessed. In 1999, Schlaeper et al. [72] reported the use of SCD in which blood flow rates were 100 ­200 mL/min and dialysate flow rates were also 100 ­300 mL/min. Patients were treated for 12 hours during the day or evening. The procedure was believed to be safe, efficient, and relatively simple to use. Lornoy et al. showed similar results [43]. Continuous therapies Peritoneal dialysis Peritoneal dialysis (PD) was the first continuous form of dialysis therapy used in the acute setting. In PD, the patient's peritoneum acts as the semipermeable dialysis membrane. Dialysate consists of a sterile, lactate-based solution inserted through a peritoneal catheter into the abdominal cavity. Diffusion occurs from the blood perfusing the peritoneum to the fluid in the abdominal cavity across the peritoneum. Once the dialysate becomes saturated (3 ­ 4 hours), it is removed and fresh dialysate is instilled. Fluid removal is achieved by using an osmotic pressure mechanism in which varying dextrose concentrations in the dialysate provide an osmotic gradient for water flow from the patient's blood to the peritoneum. The process of dialysate instillation and removal can be automated with a device known as a cycler. The main advantages of PD are that it is less labor intensive than hemodialysis, does not require anticoagulation, and may be better tolerated hemodynamically than IHD. Its major disadvantage is that dialysis is relatively inefficient, because total solute removal is limited by total peritoneal effluent. Transfer across the peritoneum is highly influenced by the anatomy of the peritoneum and the underlying hemodynamic status of the patient. Another major disadvantage is that the procedure requires the placement of a peritoneal catheter into the abdominal cavity, which may add to the morbidity of the already compromised ICU patient [35]. Continuous renal replacement therapies Over the last decade, a number of continuous renal replacement therapies (CRRTs) have emerged. The definitions of the various therapies were provided

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earlier. All types of CRRT use membranes that are highly permeable to water and low-molecular-weight solutes. The various forms of CRRT differ in how the vasculature is accessed and in the mechanism by which solute clearance is achieved. The use of continuous arteriovenous modalities has fallen out of favor largely because of the complications associated with indwelling arterial catheters. The various venovenous modalities differ primarily by their mechanisms of solute removal. In SCUF, there is minimal solute removal, whereas in CVVH, removal is primarily by convection. In CVVHD, solute removal is primarily by diffusion, and in CVVHDF, removal is by diffusive and convective mechanisms. Continuous renal replacement therapy mechanisms have a number of operational characteristics that distinguish them from those of IHD. The blood flow rate (100 ­ 200 mL/min) and dialysate flow rate (1 ­2 L/h or 17 ­ 34 mL/min) are usually lower. Because of the lower dialysate flow rate, the dialysate becomes saturated quickly and is a limiting factor in diffusive clearance capacity. Because continuous ultrafiltration results in the loss of significant volumes of plasma water (often 1 L/h), administration of replacement fluids is necessary. The composition of the replacement solution can be varied depending on the needs of the patient. CRRT is unique in that solute removal is dissociated from fluid removal. Varying the composition of the dialysate or replacement fluid allows for accurate control of solute balance, and fluid removal can be manipulated independently by varying the amount of replacement fluid administered. Net fluid removal during a given time period (e.g., each hour) is equal to the ultrafiltrate volume during that time period less the amount of replacement fluid administered. Another unique feature of CRRT is that the time available for either solute or fluid management is no longer a limiting factor (Table 3) [49,51].

Table 3 Continuous renal replacement therapy: comparison of techniques SCUF CAVH CVVH CAVHD CAVHDF CVVHD CVVHDF PD Access Pump Filtrate (mL/h) Dialysate flow (L/h) Replacement fluid (L/d) Urea clearance (mL/min) Simplicity b Cost b A-V No 100 0 0 1.7 1 1 A-V No 600 0 12 10 2 2 V-V Yes 1000 0 21.6 16.7 3 4 A-V No 300 1 4.8 21.7 2 3 A-V No 600 1 12 26.7 2 3 V-V Yes 300 1 4.8 21.7 3 4 V-V Yes 800 1 16.8 30 3 4 Peritoneal catheter Noa 500 2.0 0 8.5 2 3

A-V = arteriovenous; V-V = venovenous. Adapted from Mehta RL. Supportive therapies: Intermittent hemodialysis, continuous renal replacement therapies, and peritoneal dialysis. In: Schrier RW, editor. Atlas of diseases of the kidney, Current Medicine, Philadelphia: Blackwell Science; 1998; with permission. a Cycler can be used to automate exchanges; adds to the cost and complexity of 2.0-L exchanges. b 1 = most simple and least expensive; 4 = most difficult and most expensive.

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Potential advantages of CRRT Hemodynamic stability Hypotensive patients may not tolerate the rapid solute shifts associated with the higher blood flow rates required for IHD. Approximately 10% of all patients with ARF who require dialysis cannot be treated with IHD because of hemodynamic instability [8,19,29,44,46,57]. Paganini et al. [64] were the first investigators to show that 23 patients who were too unstable to tolerate IHD could be dialyzed with CRRT. Davenport et al. [18] showed that CRRT was superior to IHD in maintaining hemodynamic stability. Manns et al. [46] and Bellomo et al. [5] showed similar results. Data from Misset et al., however, showed no difference between CRRT and IHD with regard to hemodynamic stability [57]. Because of the continuous nature of CRRT, lower blood and dialysate flow rates can be used to achieve blood purification without hemodynamic compromise. Slower electrolyte and fluid shifts Rapid alterations in sodium and fluid status have been shown to occur in IHD. Such alterations are implicated as a cause for the cerebral edema that can be observed with IHD. Such fluctuations are avoided in CRRT, because electrolyte and fluid changes are more gradual [18]. Dialysis adequacy Dialysis dosing is discussed in greater detail later in this article, but a major advantage of CRRT is its more efficient removal of middle- and large-molecularweight solutes. Such solutes are removed inefficiently with IHD, which uses primarily diffusive clearance, but can be cleared more effectively by CRRT modalities, which incorporate convective clearance [16,51]. Provision of volume space Because fluid balance can be managed on an hour-by-hour basis, CRRT allows the administration of large volumes of fluids. Of particular importance is the ability to administer adequate parenteral nutrition to critically ill patients without concern about exacerbating fluid overload. It is well established that the increased catabolism seen in critically ill patients requires more aggressive nutrition management [61]. Several studies have shown that CRRT allows patients with MOF to benefit from adequate nutritional support [7,88]. Several studies also have shown that intermittent procedures often necessitate suboptimal nutrition because of fear of interdialytic volume overload (Table 4) [61]. Potential disadvantages of CRRT A number of disadvantages exist for performing CRRT. The required nursing support and cost of CRRT may be greater than that needed for intermittent techniques. CRRT requires continuous anticoagulation; if heparin is chosen as the method of choice, the patient, by necessity, is exposed to anticoagulant for a

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Table 4 Relative advantages (+) and disadvantages (À) of continuous renal replacement therapy and intermittent hemodialysis Parameter Continuous renal replacement Hemodynamic stability Fluid balance easily achieved Unlimited nutritional supplementation Superior metabolic control Continuous removal of potential toxins Relatively simple to perform Rapid removal of poisons, electrolytes Limited Anticoagulation ICU nursing support Hemodialysis nursing support Patient mobility CRRT + ++ + ++ + + + À À ++ + À IHD À + À À À À À + + À ++ +

Adapted from Mehta RL. Supportive therapies: Intermittent hemodialysis, continuous renal replacement therapies, and peritoneal dialysis. In: Schrier RW, editor. Atlas of diseases of the kidney, Current Medicine, Philadelphia: Blackwell Science; 1998; with permission.

prolonged period of time. Consequently, the authors have found that the use of regional citrate anticoagulation is more advantageous in certain patients at high risk for bleeding complications; however, citrate anticoagulation requires careful attention to acid-base balance and serum calcium levels and requires the preparation of specialized solutions, which may not be available in all medical centers [48,86,87]. Although frequent saline flushes have been used in CRRT, the filter life under such circumstances is markedly reduced.

Selection of dialysis modality In general, the goal of dialysis is to provide adequate renal replacement or support while minimizing complications of the therapy. Unfortunately, there is no consensus regarding the timing, duration, frequency, and amount of dialysis to be administered for patients with ARF in the ICU. In practice, the modality choice is dictated by the experience of the provider and the availability of various modalities. In a survey of nephrologists from the United States, IHD was used most commonly for ARF in the ICU, followed by CRRT and PD [52]. Of the nephrologists who used IHD most often, familiarity with the procedure, efficacy, and ease of use were cited as the main reasons for choosing IHD. CRRT techniques were reserved, in large part, for patients with hemodynamic instability or for patients in need of aggressive nutritional support. The few nephrologists who preferred PD believed that it offered several unique advantages. Most notably, it provides dialysis with remarkable hemodynamic stability and does not require the use of anticoagulation. It is clear that the choice of modality must be tailored to the needs of each patient. The factors that influence the selection of dialysis modality can be divided into three main categories: (1) those specific to

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the patient, (2) those specific to the modality, and (3) those specific to the practice environment. Patient factors Indication for renal replacement therapy The indications for dialysis in the ICU are diverse and prone to modification over the course of the disease. Consequently, the indications for initiating dialysis influence the type of modality selected. Certain modalities are more efficient at solute control, whereas others are more efficient at controlling fluid balance. If the main indication for initiation of dialysis in a hemodynamically stable patient is hyperkalemia, then IHD is the modality of choice. Conversely, if volume overload is the main indication for dialysis, particularly in the setting of hemodynamic instability, CRRT may be the preferred modality [8,18,44, 57,66]. In many cases, however, the indications are multiple and often include solute and fluid components. In such cases, the time course of the desired response influences the choice of modality. It is important to recognize that indications and modality selection influence outcome. In the authors' randomized, controlled trial comparing CRRT to IHD, patients dialyzed for solute control had a better outcome than patients dialyzed predominantly for volume control [53]. Patients dialyzed for solute and volume controls had the worst outcome. The use of protocol-driven, hour-by-hour fluid balance management in CRRT affords more sustained and predictable control of volume status. Bellomo et al. showed that CVVHDF was superior to IHD in controlling azotemia 24 hours after initiation of renal replacement therapy in ICU patients with ARF [6]. Presence of other organ failure The presence of nonrenal organ failure concomitantly with ARF has a major impact on outcome. Data from the European Dialysis and Transplant Association (EDTA) have shown that patients with isolated ARF experienced a mortality of only 8% [89]. Several investigators have shown that the greater the number of failing organ systems, the greater the mortality. Lohr et al. described a clinical index to predict survival in patients with ARF who are undergoing dialysis [41]. These investigators found that the presence of associated organ-system failure worsened mortality. Thus, the presence of other organ failure in the setting of ARF can influence the choice of modality selection. Patients with an abdominal surgery, such as an abdominal aortic aneurysm repair, are not candidates for PD. Patients with severe hypotension are not likely to tolerate IHD. The impact of anticoagulation is an important consideration. Peritoneal dialysis and IHD can be performed without anticoagulation; however, CRRT usually requires some form of anticoagulation [48]. The influence of the therapy itself on the function of other compromised organs is another important consideration. IHD, but not CRRT, often is associated with changes in intracranial pressure [18]. Continuous therapies generally do not compromise hemodynamic stability; however, if not monitored closely, volume depletion can ensue from lack of adequate replace-

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ment fluid administration. Peritoneal dialysis may contribute to worsening hypoalbuminemia in patients with liver disease and may not be the modality of choice in that patient population [35]. Peritoneal dialysis often is associated with the enhanced removal of albumin-bound drugs, a problem not encountered in hemodialysis [35]. Vascular access The ability to obtain appropriate vascular access is one of the most important factors affecting the ability to provide adequate dialysis therapy. The use of arterial vascular access catheters has fallen out of favor because of the many complications encountered with these catheters. A number of complications can limit the ability to use a venous catheter adequately. Clotting or malpositioning of the catheter in the vein can lead to unforeseen reductions in blood flow rate. Currently used peristaltic blood pumps usually are set to withdraw blood from the access at a certain rate. In the presence of partial clotting, however, the pump may not be able to actually draw the dialed rate; such a complication may go unnoticed for many hours. Another important complication is the presence of recirculation in which a portion of clean blood that is returned to the patient from the dialyzer is redrawn by the peristaltic pump before it enters the patient's overall blood pool [39]. Such recirculation limits the efficacy of dialysis, because the same portion of blood is being dialyzed repeatedly. Mobility In cases in which a patient needs to moved from the bedside for radiographic studies, surgery, or other procedures, it may difficult to perform CRRT. It is usually not possible to transfer CRRT equipment along with the patient because most current CRRT machines are not equipped with a battery-operated module. Disconnecting patients from CRRT deprive them of important dialysis and ultrafiltration time, lowering the efficacy of the treatment. Because of the need for more intensive nursing monitoring with CRRT, patients who are not in the ICU (i.e., where there is no one-to-one nursing) are not candidates for CRRT. Dialysis modality factors Membrane choice There are two factors to consider when choosing the type of membrane used for dialysis. The first issue is membrane biocompatibility [15,68]. Complement activation and neutrophil sequestration are known to occur in IHD with the use of certain membranes. Because the patient's blood is exposed to the membrane for a prolonged time in CRRT, the issue of membrane interactions becomes of paramount importance. Polysulfone and polyacrylonitrile membranes do not seem to activate complement and often are used in CRRT [15]. Biocompatible membranes seem to be associated with improved renal recovery [24,26,45, 69,71]. The second issue concerning membrane selection is that membranes

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differ in their capacity to clear certain cytokines such as tumor necrosis factor a (TNF-a), interleukin-1b (IL-1b), and IL-6. Conceivably, removal of these cytokines at a critical stage of disease progression may influence outcome. An in vitro model of CAVHD showed that a polyacrylonitrile membrane was two- to three-fold more efficient at removing TNF-a when compared with a polysulfone or polyamide membrane [14]. Nevertheless, human studies have shown the ability to remove cytokines in CRRT, but blood levels of cytokines remain unchanged [25,42,75,76]. Although cytokine removal remains an active area of research, it is not an important factor in modality selection. Dose of dialysis Unfortunately, there are no standard methods for the assessment of dialysis dose in ARF [40]. In patients with ESRD, dialysis dose is assessed using urea kinetic modeling. In such a model, the basic elements measured are the urea level before and after dialysis. Many formulas exist that incorporate weight, ultrafiltration, time, and change in blood urea nitrogen (BUN) for assessment of dialysis dose. A main assumption of these models is that patients with ESRD have a relatively constant urea generation rate and are at a steady state. Because of this assumption, the method of dialysis-dose determination used in patients with ESRD is not directly applicable to patients with ARF. Patients with ARF tend to have fluctuating body fluid composition and varying urea generation rates. Nevertheless, a number of factors are related to the dialysis dose delivered. In intermittent therapies, higher blood flow rates and longer durations of therapy are associated with an increased dose of dialysis delivered. In some studies, changes in BUN have been used as a surrogate for dose intensity. Clark et al. compared IHD with CRRT using a computer model to determine the number of IHD sessions that would be required to achieve equivalent control of uremia [16]. They found that for a 50-kg man, an average of 4.4 sessions of IHD per week were required to achieve the same uremic control obtained with CRRT. In patients with a weight greater than 90 kg, equivalent uremic control could not be achieved, even with daily IHD. Bellomo et al. showed that in similar critically ill patients, CRRT was more effective at control of azotemia than was IHD [6]. Although it is difficult to measure dose per se, many investigators have studied the factors that influence dose and their effects on outcomes. In hemofiltration techniques, the amount of ultrafiltrate generated per kilogram of body weight per unit time is associated with dose. Ronco et al. have shown that in patients treated with hemofiltration techniques, a filtration rate of 35 mL/h/kg was associated with improved 15-day survival [67]. Honore et al. showed that short-term highvolume hemofiltration (35 L in the first 4 hours) improved survival in patients with septic shock. Schiffl et al. retrospectively compared daily hemodialysis with every-other-day treatments. They showed an improvement in survival among patients on daily hemodialysis (15% versus 22%; P < 0.05) [70]. Paganini et al. showed that approximately 65% of patients with IHD received a dialysis dose, as measured by urea kinetic modeling, that was lower than prescribed [65]. The

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nonsurvivors in that group had a significantly lower actual dose compared with that of survivors. Intermittent versus continuous therapies Because of the heterogeneity of patients with ARF with respect to illness severity and comorbidities, it is difficult to adequately assess the effect of a particular renal replacement modality on survival. A number of studies have compared IHD with CRRT in an effort to delineate whether one modality is superior to another with regard to survival. Several retrospective analyses in the early 1990s showed that it was likely that CRRT offered a survival advantage when compared with IHD [10,23,47,77,85]. In 1986, Mauritz et al. compared IHD to either CAVH or CVVH and found no difference in survival between the groups [47]. In 1992, Bellomo et al. compared survival in 84 critically ill patients treated with conventional dialysis with 83 patients matched for age, APACHE II score, and number of failing organs who were treated with CAVHDF or CVVHDF [7]. Overall survival was 30% in the conventional-dialysis group and 41% in the CRRT group ( P = NS). In a second study, the same investigators compared a prospectively treated group with their initial conventional-dialysis control group. Patients treated with CVVHDF had better survival if they had two, three, or four organs failing or an APACHE II score of 24 to 29, when compared with patients treated with conventional dialysis [4]. At the extremes of illness severity, survival was not different. This study is difficult to interpret in view of the use of a retrospective control group. In 1993, Kruczynski et al reported a retrospective analysis of 12 patients treated with CAVH versus 23 patients treated with conventional hemodialysis [36]. Survival was better in the CAVH group compared with the conventional dialysis group (25% versus 82%; P < 0.001); however, patients in the conventional-dialysis group were significantly older. In 1991, Kierdorf retrospectively compared 73 patients treated with CVVH with 73 age-matched controls treated with IHD and found a significant survival advantage in the CVVH group [32]. In 1995, van Bommel et al. retrospectively compared 34 patients treated with IHD with 60 patients treated with CAVHDF [84]. The CAVHDF group had higher APACHE II scores, but survival was not different between the two groups. The data from retrospective analyses conflict with some studies that show a survival advantage and others studies that show CRRT has no advantages over conventional dialysis. A comprehensive review of multiple studies showed that no survival advantage was conferred with the use of continuous therapies [28]. There are two prospective, randomized trials comparing IHD with CRRT. The study by Kierdorf and Sieberth had a target enrollment of 400 patients [33]. An interim analysis of 100 patients showed a survival of 39.6% in the CVVH group and 34.1% in the IHD group. Five patients in the IHD group were excluded from the analysis because they failed to complete the therapy because of ``hemodynamic instability.'' In the authors' study, 166 patients with ARF requiring dialysis were randomized to CRRT (n = 84) or IHD (n = 82) [53]. Patients with a mean arterial pressure (MAP) of less than 70 were excluded. Patients in the two groups were similar except that there

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were more males in the CRRT group than the IHD group, and the APACHE II and III scores were higher in the CRRT group. ICU (59% versus 41%; P = 0.02) and hospital (65% versus 47%; P = 0.02) motalities were worse in the CRRT group compared with those of the IHD group. Subgroup analysis showed that renal recovery improved in survivors of CRRT when compared with survivors of IHD (92% versus 59%; P = 0.01). One of the main limitations of this study is that patients with a mean arterial pressure (MAP) of less than 70, a group that may benefit the most from CRRT, were excluded. Although there is no definitive evidence that CRRT is superior to IHD, it inherently may be invalid to make such a broad comparison. It might be more appropriate to categorize patients into subgroups. Patients with heart failure may have different outcomes with CRRT than patients with sepsis or trauma. Similarly, patients with end-stage liver disease who do not receive a transplant have a grave outcome irrespective of the treatment modality used [22]. Selection of modality based on the anticipated duration of therapy is better judged by the needs of the patients at the time of initiation. In hemodynamically unstable patients in whom fluid control is the main indication, it may be more appropriate to initiate CRRT, whereas trauma patients with hyperkalemia may be better treated with an intermittent modality. Logistic factors Cost It remains unclear whether CRRT is more expensive than IHD [27]. Some studies have suggested that CRRT may be slightly more expensive [54,62]. The higher cost of CRRT can be attributed to the higher price of hemofilters, which are generally different than the hemofilters used for IHD. The filters used for IHD are cheaper because they are purchased in bulk for use in the ESRD population. This disparity in cost may be reduced if CRRT is used more frequently and if filter life is extended by adequate anticoagulation. Physician time spent per patient is higher for patients with CRRT compared with that for patients with IHD; however, this can be reduced as the physician gains familiarity with the procedure. At the authors' institutions, standardized protocols for fluid, electrolyte, and anticoagulation management markedly have reduced the time spent monitoring and adjusting the CRRT prescription. Nursing expertise and other support Unlike IHD and PD, CRRT requires active participation of the critical care nurse in caring for the patient. Consequently, nurses who are unfamiliar with CRRT may have difficulty managing the accurate fluid and electrolyte monitoring that is required to minimize complications [3]. The availability of simple, easy-to-understand flow sheets, instructional booklets, and backup support minimize errors related to nursing involvement [2]. One of the main advantages of CRRT is the ability to provide patients with improved nutrition. As a result, involvement of clinical nutrition personnel becomes essential. Preparation of custom dialysate and replacement fluid and drug dosing adjustment require the

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involvement of skilled pharmacists who are familiar with the pharmacokinetics associated with the different dialysis modalities. Modality selection summary A number of factors have roles in the process of deciding which dialysis modality is most appropriate for a particular clinical situation. Consequently, it is important for the intensivist to become familiar with the various modalities and to gain some understanding of the differences between the modalities and their relative advantages and disadvantages. Table 5 summarizes recommendations regarding the choice of dialysis modality in common clinical circumstances.

Emerging dialysis techniques Continuous coupled plasma filtration and adsorption The possibility that removal of inflammatory mediators might improve outcome from sepsis and the systemic inflammatory response syndrome has led to the development of devices in which plasma is first separated from the formed elements of the blood and then passed directly over activated charcoal and an anion exchanger [21,82,83]. The cleansed plasma is reconstituted with the formed elements before reinfusion into the patient. Such systems have shown promise in animal studies. A phase I trial in 10 critically ill patients showed marked hemodynamic benefits. Liver support systems In the past few years a number of newer extracorporeal therapies have become available for the management of patients with end-stage liver disease. The

Table 5 Recommendation for initial choice of dialysis modality for acute renal failure Indication Uncomplicated ARF Fluid removal Uremia Increased intracranial pressure Shock Nutrition Poisons Electrolyte abnormalities ARF in pregnancy Clinical condition Antibiotic nephrotoxicity Cardiogenic shock, CP bypass Complicated ARF in ICU Subarachnoid hemorrhage, hepatorenal syndrome Sepsis, ARDS Burns Theophylline, barbiturates Marked hyperkalemia Uremia in 2nd, 3rd trimesters Preferred therapy IHD, PD SCUF, CAVH CVVHDF, CAVHDF, IHD CVVHD, CAVHD CVVH, CVVHDF, CAVHDF CVVHDF, CAVHDF, CVVH IHD, CVVHDF IHD, CVVHDF PD

CP = Cardiopulmonary; ARDS = Acute Respiratory Distress Syndrome. Adapted from Mehta RL. Supportive therapies: intermittent hemodialysis, continuous renal replacement therapies, and peritoneal dialysis. In: Schrier RW, editor. Atlas of diseases of the kidney, Current Medicine, Philadelphia: Blackwell Science; 1998; with permission.

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appropriate use of such therapies requires a multidisciplinary approach in which the intensivist coordinates closely with the hepatologist, who has knowledge of the disease process, and the nephrologist, who has experience with extracorporeal therapies. The authors present an overview of the various techniques that are or will be available for the management of this complex subset of critically ill patients. At this stage of development, most of these therapies are aimed at bridging the patient to transplantation. Some liver support devices are cell based, whereas others are not. The concepts of each modality and their preliminary clinical results are reviewed. HepatAssist System The HepatAssist System (Circle Biomedical Inc., Lexington, MA) is a cellbased liver-assist device in which porcine hepatocytes are cryopreserved in hollow fiber cartridges. The patient's blood is passed through a plasma separator and then is passed over a charcoal column. The plasma is pumped into a cartridge containing the porcine hepatocytes and reconstituted with the cellular elements of the blood before being returned to the patient [81]. In phase I and II trials, the treatment of 39 patients showed significant improvements in transaminases, bilirubin, intracranial pressure, and Glasgow Coma Scale score (data presented at the Sixth International Conference on Continuous Renal Replacement Therapies, San Diego, CA, March 2001). Phase III trials are in progress. Extracorporeal Liver Assist Device The Extracorporeal Liver Assist Device (VitaGen Inc., La Jolla, CA) is similar in concept to the HepatAssist system except that a human, immortalized hepatoblastoma cell line, C3A, is used instead of porcine hepatocytes [55,56]. Phase II trials are in progress. HemoTherapies Unit The HemoTherapies Unit (HemoTherapies Inc., San Diego, CA) is a sorbent system that uses finely powdered charcoal. The patient's blood is pumped using a back-and-forth mechanism that enables contact with the charcoal so that toxins, including bilirubin, are adsorbed by the charcoal. Ten of 31 patients treated with the device had some form of hepatic recovery or received a transplant. These outcomes were not different than the 8 of 26 controls treated with conventional treatment who also demonstrated recovery or received a transplant [34]. A prospective randomized trial is underway. Molecular Adsorbent Recycling System The Molecular Adsorbent Recycling System (MARS) (Teraklin AG, Rostock, Germany) is an extracorporeal therapy in which the patient's blood is passed through a hemofilter with an albumin-containing dialysate. The presence of albumin in the dialysate has been shown to remove bilirubin and bile acids from the patient's blood. Because of the high cost of albumin, the dialysate is in a closed circuit and is recycled by passage through a charcoal filter, an anion

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exchanger, and a hemofilter through which standard bicarbonate dialysate is circulated in the dialysate compartment. Over 100 patients have been treated with this modality. A limited number of studies using this modality have shown improvements in encephalopathy scores, hospital survival, and renal function [58 ­ 60,79,80]. A randomized clinical trial is under way to further assess MARS.

Summary Acute renal failure in the ICU is a clinically diverse entity. Consequently, the indications for initiation of dialysis therapy are varied. In general, the indications are solute control, volume control, or both. A variety of dialysis modalities are available; however, there is no consensus as to the optimal modality for any particular group of patients. A careful understanding of the particular benefits, limitations, and potential complications of each modality coupled with a thorough assessment of the individual patient's need formulate the basis for dialysis modality selection. In certain circumstances, the more conventional intermittent therapies are sufficient, whereas in other settings, CRRT techniques are advantageous. The impact of modality selection on outcome remains an area of significant controversy. Future studies in which more uniformity within specific subgroups of patients with ARF is sought may shed light on the optimal modality for a particular patient group. Newer therapies aimed at more optimal and more specific blood purification may prove promising in the management of complex critically ill patients with ARF and other comorbid conditions.

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