Dialytic Management of Acute Kidney Injury and Intensive Care Unit Nephrology

C H A P T E R

70

 

Dialytic Management of Acute Kidney Injury and Intensive Care Unit Nephrology Mark R. Marshall

Intensive care unit nephrology can be defined as a subspecialty that focuses on abnormalities of fluid, electrolyte, and pH homeostasis in intensive care unit (ICU) patients and the prevention and management of acute kidney injury (AKI). By use of the RIFLE (risk, injury, failure, loss, and end stage) criteria (see Fig. 68.1), up to 65% of ICU patients have evidence of AKI, an independent risk factor for death. The nondialytic therapy for AKI is discussed in Chapter 69. Approximately 5% of ICU patients receive acute renal replacement therapy (ARRT). Mortality in this population appears to be gradually improving over time despite a higher degree of illness severity, although it remains high in absolute terms.1 Death attributable to AKI appears to be due to nonresolving infection, hemorrhage, or nonresolving shock, despite optimal care. Such conditions may therefore comprise an acute uremic syndrome that is specific to AKI and a possible target for modulation with ARRT as opposed to the traditional uremic syndrome of end-stage renal disease (ESRD).

ORGANIZATIONAL ASPECTS OF ACUTE RENAL REPLACEMENT THERAPY PROGRAMS ICUs can be referred to as open (patient care remains under the attending physician of record), closed (patient care is transferred to an intensivist), or co-managed (an open ICU in which patients receive mandatory consultation from an intensivist). Most ICUs in the United States are open, whereas most in Australia and New Zealand are closed. Those in Europe are approximately equally split. In considering AKI and ARRT, advantages of intensivist-based management include immediate availability of service, cost containment, and decreased fragmentation of care. This model of care is supported by ecological studies suggesting improved patient outcomes in health care systems with closed ICUs, although these studies often lack internal validity because of important residual confounding. Alternatively, advantages of nephrology-based management include greater understanding of dialysis dosing and membrane design and of the processes underlying AKI and their implications. This model of care is supported by studies showing improved outcomes in ICU patients with AKI associated with earlier consultation to nephrology, although these studies often lack external validity in health care systems with closed ICUs where expertise is “in-house.” Clinical governance over ARRT is therefore likely to remain a point of con­ tention between intensivists and nephrologists in the future, although the individual expertise of staff providing care probably influences patient outcomes more than the specialty to which

they belong. Specific training in ICU nephrology with exposure to ARRT is inadequate in many critical care and nephrology training fellowships, and it should be a component of both core curriculums. In many parts of the world, all modalities of ARRT are now delivered by ICU nursing staff; in other countries, support from nephrology staff is still sought. As machinery platforms are becoming universal for continuous renal replacement therapy and intermittent hemodialysis, it is likely that ICU expertise in all modalities of renal replacement therapy will grow, provided in-service education and support are sufficient to develop and to maintain the skill base.

OVERVIEW OF ACUTE RENAL REPLACEMENT THERAPIES The four main modalities of ARRT are acute intermittent hemodialysis (iHD); continuous renal replacement therapy (CRRT); prolonged intermittent renal replacement therapy (PIRRT), otherwise known as sustained low-efficiency dialysis (SLED); and acute peritoneal dialysis. Globally, CRRT is the most popular modality, although practice patterns vary regionally because of cost, availability of technology, and reimbursement policies. PIRRT is becoming more popular, and for reasons of cost and convenience, it may become the dominant ARRT in the future. Acute peritoneal dialysis is only occasionally used in adults and is not considered further in this chapter. Therapeutic goals for ARRT are not well defined. The usual minimum recommendation is to correct acidosis or hyperkalemia, refractory hypervolemia, and traditional uremic features such as pericarditis and coma. Serum electrolyte and bicarbonate concentrations should be maintained in the normal range. Targets for uremic solute control are discussed later in this chapter. Importantly, the process of ARRT itself should not jeopardize the patient by exacerbating hemodynamic instability, increasing end-organ damage, or delaying renal recovery. Determination of therapeutic goals with respect to the patient’s fluid status is not straightforward. Assessment itself is difficult; physical signs such as jugular venous distention are not often informative, especially for mechanically ventilated patients. Moreover, baseline values of central venous pressure, pulmonary capillary wedge pressure, and echocardiographic left ventricular diastolic dimensions may be inaccurate surrogates for intravascular volume status, especially for septic patients. More reliable approaches use the effect of therapeutic maneuvers such as fluid challenge on blood pressure, stroke volume, or vena cava 843

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collapsibility obtained by bedside echocardiography. Even once fluid status is adequately assessed, determination of the therapeutic goal is also difficult; patients with extracellular fluid excess in the absence of intravascular hypervolemia may benefit from fluid removal if they develop abdominal compartment syndrome, impairment of lung compliance and oxygenation, or poor wound healing. Patients with acute respiratory distress syndrome (ARDS, defined as low Pao2 relative to inspired oxygen, diffuse pulmonary infiltrates, and no left atrial hypertension) require a shorter period of ventilation with less fluid loading (guided by central filling pressures). However, the benefit of fluid removal in ARDS by means of ARRT has not been established. Increasingly, ARRT is being used to facilitate adsorption or clearance of unconventional uremic markers and mediators such as proinflammatory cytokines, which might contribute to the purported acute uremic syndrome by their cardiodepressant, vasodilatory, and immunomodulatory properties. Because ARRT will remove both proinflammatory and anti-inflammatory cytokines, there is the potential to inadvertently exacerbate the inflammatory milieu.2 The evolving technique of high-volume hemofiltration (HVHF) in septic shock is an area of intense study, supported by observations in septic ICU patients with AKI of improved outcomes with higher doses of hemofiltration (≥45 ml/kg per hour) and improved hemodynamic stability with HVHF (60 to 100 ml/kg per hour) applied either as a “pulse” or continuous maneuver. Presently, there are insufficient outcome data to justify routine clinical use of HVHF. Clinical trials of this approach, such as the IVOIRE (hIgh VOlume in Intensive Care) study, are under way.3 Timing of ARRT initiation remains controversial and current practices vary widely. A large multinational cohort study showed that ARRT was initiated when the median (IQR) serum creatinine and urea levels were 309 (202 to 442) µmol/l and 24 (15 to 35) µmol/l, respectively, and when urine output was 576 (192 to 1272) ml/day.4 Observational studies suggest that earlier rather than later initiation might achieve better outcomes, and none suggests that it is harmful. There is no high-quality evidence to guide practice, and the single clinical trial designed to answer the question was insufficiently powered.5 Proponents of early initiation argue that it is in the patient’s interest to prevent rather than to treat the acute uremic syndrome and recommend initiation to prevent or to minimize fluid overload and biochemical abnormalities once kidney injury or failure is present. Timing of ARRT initiation is currently the leading priority for research in AKI.6 An important determinant of modality choice is cost. More complex extracorporeal circuits and replacement fluids make CRRT generally more expensive than iHD or PIRRT. Pharmacoeconomic studies comparing ARRT modalities are all limited by wide variation in ICU cost and reimbursement structures.

ACUTE INTERMITTENT HEMODIALYSIS Acute intermittent hemodialysis (iHD) is still a widely used modality for the management of AKI when the patient has sufficient hemodynamic stability. Hemodialysis techniques and adequacy are discussed in the context of maintenance treatment of ESRD in Chapters 89 and 90.

Techniques for Acute Intermittent Hemodialysis Acute iHD is categorized according to hemodialyzer membrane and mechanism of solute removal. High-flux membranes allow

greater convective removal of middle and larger solutes, but there are only limited clinical data on high-flux dialysis in the critically ill with AKI, and these do not show obvious advantages.7 Biocompatibility defines a membrane with a low capacity for activating complement and leukocytes. After complement activation, there is stasis of leukocytes in the lungs, renal parenchyma, and other organs, and the release of products of leukocyte activation. By minimizing these processes, use of biocompatible membranes should in principle favorably affect mortality and recovery of renal function in ICU patients with AKI. Unfortunately, studies to resolve this issue have often been confounded by poor design, and meta-analyses have not clarified this issue. A reasonable recommendation can be made against the use of less biocompatible unsubstituted cuprophane membranes. Hemodiafiltration (HDF) is usually performed in the ICU as a continuous modality. However, acute intermittent HDF can be performed in this setting with standard machinery, using sterile online replacement fluid generated from ultrapure dialysate, which is then diverted by a separate pump to be infused directly into the extracorporeal blood circuit. As with high-flux dialysis, limited clinical data do not show obvious advantages. Dialysate for the single-pass machines is generated online with a proportioning system from concentrate using reverse osmosis–treated tap water. There is concern about the possibility of backfiltration of bacterial contaminants, specifically endotoxin, which could perpetuate microcirculatory insult and cytokine-mediated injury. As a minimum, dialysate for iHD should be of the same purity as that accepted for ESRD settings. Online replacement fluid for intermittent HDF is produced by cold sterilization using ultrafilters in the dialysate pathway fluid and does not differ from commercial hemofiltration (HF) solutions in terms of microbial counts, endotoxin concentration, and cytokine-inducing activity. Dialysate cold sterilization is also suggested by some for acute iHD, although there are insufficient data to support a strong recommendation.

Strategies to Reduce Intradialytic Hemodynamic Instability Hypotension is detrimental for end-organ function and recovery. Fresh ischemic lesions in kidney biopsy specimens can be found in patients with RIFLE failure stage of more than 3 weeks in duration. The relatively high ultrafiltration rate (UFR) with iHD often leads to intradialytic hypotension, which reduces residual renal function. A frequent schedule of iHD and prolonged treatment time will minimize ultrafiltration goals and rates and is the most effective measure to minimize hypotension. Bicarbonate-buffered dialysate should be used routinely in critically ill AKI patients. It is associated with less hypotension than acetate dialysate, which has a peripheral vasodilating and myocardial depressant effect. The rapid reduction in serum osmolality with iHD promotes water movement into cells, thus reducing effective circulating volume. Sodium profiling mitigates this process by promoting water flux into the vascular compartment, although the simpler approach of a high-sodium dialysate without profiling also may achieve this and needs to be tested in the ICU setting. A randomized study showed that iHD with sodium profiling (160 mmol/l initially, reducing to 140 mmol/l) combined with ultrafiltration profiling (50% of ultrafiltration volume removed in first third of treatment) improved hemodynamic stability.8 Profiling therefore seems to be safe and effective, although it should be used judiciously in the patients with dysnatremias, in which serum sodium



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70  Dialytic Management of Acute Kidney Injury and Intensive Care Unit Nephrology

concentrations should be corrected slowly to minimize the risk of neurologic complications (see Chapter 7). Relative blood volume monitoring with a biofeedback system automatically adjusts UFR and dialysate sodium content in response to a decrease in circulating blood volume. Although it is effective for ESRD patients, relative blood volume monitoring does not correlate with volumetric and hemodynamic parameters measured with transpulmonary thermodilution and does not appear useful for preventing hypotension in ICU patients.9 High dialysate calcium (1.75 mmol/l) has been used to improve hemodynamic stability during iHD in ESRD patients with cardiomyopathy. This technique is limited by the development of hypercalcemia, however, and has not been studied in ICU patients with AKI. Vasoconstriction due to lower body temperatures has been used to increase vascular resistance and to improve hemodynamic stability during iHD in ESRD. Hypothermia, however, may be undesirable in ICU patients because of adverse effects on myocardial function, end-organ perfusion, blood clotting, and probably renal recovery. With blood temperature monitoring, the patient’s blood temperature is precisely maintained at target value by a series of feedback loops controlling thermal transfer to and from the dialysate. Blood temperature monitoring is effective in ameliorating hemodynamic instability for ESRD patients. Blood temperature monitoring might conceivably allow controlled cooling in ICU patients without the risk of hypothermic damage, but it has not been evaluated in this setting. In the ESRD setting, hemodynamic stability may be better during intermittent HDF compared with conventional iHD, although prospective controlled studies are contradictory. This could theoretically be related to heat loss in the circuit, lower sodium removal, higher calcium flux, and enhanced removal of endogenous vasoactive substances leading to increased peripheral vasoconstriction. There are insufficient data in ICU patients with AKI to support a strong recommendation. Measures to reduce hemodynamic instability during iHD are summarized in Figure 70.1.10 Should these measures fail, modality change to PIRRT or CRRT is recommended.

Dosing of Acute Intermittent Hemodialysis The relationship between acute iHD dose and mortality has been clarified in several studies. A retrospective observational study

Measures to Improve Hemodynamic Stability During Intermittent HD Minimize ultrafiltration rate requirements by Increased frequency of treatments (up to daily) Increased duration of treatments (up to 6 hours), then consider PIRRT (SLED) or CRRT Bicarbonate-buffered dialysate

showed that delivered single-pool Kt/V (spKt/V; see Chapter 90) above 1.0 per treatment was associated with improved survival in patients with intermediate illness severity.11 This study did not relate outcomes to frequency of treatments. A prospective, controlled trial demonstrated that delivered spKt/V of 0.9 to 1.0 per treatment six or seven times per week improved survival compared with this dose three or four times per week. In this study, the time-averaged blood urea nitrogen (BUN) in the lower dose group (104 mg/dl) indicates underdialysis by current standards.12 Most recently, a prospective, randomized controlled trial showed that delivered spKt/V of 1.2 to 1.4 per treatment five or six times per week did not improve survival compared with this dose thrice weekly.13 Optimal iHD dose therefore appears to be related to small rather than to larger solute clearance, and there appears to be a dose above which survival becomes dose independent. This “breakpoint” in the iHD dose-response curve suggests a recommended iHD dose: delivered spKt/V of 1.2 or more per treatment at least thrice weekly. This mandates routine measurement of spKt/V for iHD treatments in ICU patients with AKI to guide appropriate adjustment of operating parameters. Delivered dose tends to be low in this population and is optimized by measures summarized in Figure 70.2.10 If delivered spKt/V of 1.2 or more per treatment cannot be achieved, dose should be maintained as high as possible and treatment frequency increased. The required number of treatments per week and dosing interval can be established from the nomogram in Figure 70.3 expressing combinations of iHD dose and treatment frequency as a continuous small-solute clearance (expressed as the corrected equivalent

Measures to Increase Intermittent Hemodialysis Dose Maximize hemodialyzer surface area (up to 2–2.2 m2) Maximize hemodialyzer porosity (high flux) Maximize blood flow rate by Maximizing internal lumen diameter of catheter (up to 2.0–2.2 mm) Titrating blood flow to maximum arterial and venous pressure (up to − and + 300–350 mm Hg, respectively) Correcting position of catheter tip in SVC and IVC as appropriate Use right-sided IJ and SC in preference to left-sided IJ and SC Minimize access recirculation by correcting position of catheter tip in superior or inferior vena cava as appropriate using internal jugular and subclavian, rather than femoral, catheters Maximize dialysate flow (up to 800–1000 ml/min) Add postdilution HDF Optimize anticoagulation to reduce hemodialyzer fiber bundle clotting

Sodium/ultrafiltration profiling

Optimize circulation to reduce compartmental urea sequestration

? Increase dialysate [Ca2+]

Increased treatment frequency (up to daily)

? Change modality from hemodialysis to hemodiafiltration

Increased treatment duration (up to 6–8 hours, then consider PIRRT (SLED) or CRRT)

? Blood temperature monitoring Figure 70.1  Measures to improve hemodynamic stability during intermittent HD. CRRT, continuous renal replacement therapy; PIRRT, prolonged intermittent renal replacement therapy; SLED, sustained lowefficiency dialysis. (Modified from reference 10.)

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Figure 70.2  Measures to increase intermittent hemodialysis dose. CRRT, continuous renal replacement therapy; HDF, hemodiafiltration;  IJ, internal jugular; IVC, inferior vena cava; PIRRT, prolonged intermittent renal replacement therapy; SC, subclavian; SLED, sustained low-efficiency dialysis; SVC, superior vena cava. (Modified from reference 10.)

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Figure 70.3  Relationship between corrected continuous renal urea clearance (weekly urea clearance/volume of distribution of urea) and singlepool Kt/V) per treatment for a frequency of three to seven treatments per week. iHD, intermittent hemodialysis. (From reference 14.)

Continuous renal urea clearance (ml/min)

Relationship Between Renal Urea Clearance and Single-Pool Kt/V 7 iHD/week

38 36 34 32 30 28 26 24 22 20 18 16 14 12 10 8 6 4 2 0

6 iHD/week

5 iHD/week 4 iHD/week Alternate-day iHD 3 iHD/week

0.4 0.5 0.6 0.7 0.8 0.9

1

1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9

2

Single-pool Kt/V (per iHD treatment)

renal urea clearance), aiming for a value of 12.6 ml/min or more.14

CONTINUOUS RENAL REPLACEMENT THERAPY CRRT involves the application of lower UFR and solute clearances for substantial periods every day. Solute removal is achieved by diffusion, convection, or a combination. CRRT is used to complement or to supplant iHD. The lower UFR provides comparatively better hemodynamic stability than with iHD, especially during ultrafiltration of large obligatory fluid loads, and the lower solute clearances result in single-pool solute kinetics despite discrepancies in regional blood flow due to pressor use. The longer treatment duration results in better and more consistent control of uremic solutes, especially for severely catabolic patients. Interruptions to CRRT because of circuit clotting or out-ofunit procedures lead to a reduction in dose from downtime as well as expense related to blood circuitry changes. Mean operating time for CRRT has been reported at 21.9 h/day.15

Techniques of Continuous Renal Replacement Therapy The Acute Dialysis Quality Initiative group (www.adqi.net) has proposed standardized classification, with nomenclature based on the type of vascular access and the method of solute removal. Arteriovenous (AV) denotes an extracorporeal blood circuit in which an arterial catheter allows blood to circulate by systemic blood pressure. A venous catheter is placed for return. AV circuits are simple but involve arterial puncture, which can lead to distal embolization, hemorrhage, and vessel damage. A blood flow (Qb) of 90 to 150 ml/min is typical in patients with mean arterial pressure above 80 mm Hg, although flow can be erratic, predisposing to clotting. Venovenous (VV) denotes a circuit with a central venous catheter, achieving more reliable and rapid Qb

of ∼250 ml/min by a mechanical pump. Pumped VV circuits have the disadvantage of potential inadvertent disconnection of lines, resulting in hemorrhage or air embolism with continued pump operation; this risk is minimized but not eliminated by monitors and alarms.

Mechanisms of Solute Removal Hemodialysis Continuous hemodialysis (HD) provides diffusive small-solute transport that can be quantified according to the degree to which dialysate is saturated with urea (expressed as the ratio of dialysate to blood urea nitrogen or DUN/BUN). Qb and dialysate flow (Qd) during CRRT are usually relatively low (100 to 200 ml/min and 1 to 2 l/h, respectively). Under these conditions, the dialysate to blood urea nitrogen ratio (DUN/BUN) is 1.0, indicating complete saturation. Urea clearance therefore equals Qd and is unaffected by Qb until it decreases to less than 50 ml/min. With increasing Qd, there are proportionally decreasing gains in small-solute clearance as the DUN/BUN progressively decreases. Figure 70.4 illustrates this principle.16 The flattening of the curves describes the conditions in which increasing Qb does not enhance clearance. At Qb of 200 ml/min, urea clearance will correspond to Qd at a rate of 2 l/h (or less) and will not increase with increased Qb. If Qd is increased to 4 l/h, this will correspond to a urea clearance of ∼3 l/h that will progressively increase with increased Qb. Hemofiltration Continuous HF provides convective transport of small and medium-sized solutes that can be similarly quantified by use of filtrate saturation with urea (FUN/BUN). An important determinant of clearance is the site of fluid replacement, which can be infused either into the arterial blood line leading to the hemofilter (predilution) or into the venous blood line leaving the hemofilter (postdilution). The standard method is postdilution.



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70  Dialytic Management of Acute Kidney Injury and Intensive Care Unit Nephrology

However, higher UFR can lead to hemoconcentration in the hemofilter, increased resistance in the blood flow pathway, reductions in Qb, and ultimately hemofilter clotting. In practice, UFR should not exceed 30% of the plasma water flow rate (i.e., filtration fraction should be <0.30). The problem can be resolved by increasing Qb to ≥200 to 250 ml/min or by diluting the blood and clotting factors with replacement fluid before it reaches the hemofilter (predilution), thereby improving filter patency and decreasing anticoagulant requirements.

The disadvantage of predilution is that filtrate is generated from blood diluted with replacement fluid and therefore contains a lower concentration of uremic solutes. Small-solute clearance is reduced by ∼15% at low UFR, although this figure increases to ∼40% with a higher UFR.17,18 Clearance of any given solute during continuous HF is K ( postdilution ) = UFR × S K ( predilution ) = UFR × S × [Qbw (Qbw + Qr )] where K is clearance (ml/min), S is the sieving coefficient of the solute, Qbw is blood water flow rate equal to the product of Qb and (1 − hematocrit), and Qr is the replacement fluid rate.

Urea Clearance During Continuous Hemodialysis

Hemodiafiltration Continuous HDF refers to a combination of the preceding techniques. With large enough membranes, the small-solute clearances obtained approach the sum of the individual techniques.17

150

Urea clearance (ml/min)

847

Qd = 250 ml/min

Specific Techniques

100 Qd = 200 ml/min Qd = 150 ml/min Qd = 100 ml/min 50

Qd = 50 ml/min

0 0

50 100 Qb (ml/min)

150

Figure 70.4  Determinants of urea clearance during continuous hemodialysis. Relationship between urea clearance, Qb (blood flow), and Qd (dialysate flow) during continuous hemodialysis. The flattening of the urea clearance curves describes the conditions in which increases in Qb do not enhance clearance. (From reference 16.)

CRRT techniques are shown in Figures 70.5 and 70.6. The choice of technique is dependent on equipment availability, clinician expertise, prospects for vascular access, and whether the primary need is for fluid or solute removal. This last factor is often the most important because each technique provides different rates of fluid and solute removal. Most clinicians avoid AV circuits because of higher vascular complication rates. The potential complications of the techniques are listed in Figure 70.7.19 For isolated fluid removal, slow continuous ultrafiltration (SCUF) can be used. Given its minimal solute clearance (equal to the UFR at generally 4 to 5 ml/min), SCUF has primarily proved useful for treatment of the cardiorenal syndrome (see Chapter 71). Most ICU patients require removal of solute in addition to that of fluid. For this, most clinicians prefer pumped VV rather than AV circuits because of higher and more reliable Qb, allowing greater solute clearance. The substantially enhanced clearance capabilities of continuous HDF combine diffusion and convection for removal of both small and medium-sized solutes

Comparison of Continuous Renal Replacement Modalities

Modality

Blood Pump

Dialysate (D) Replacement Fluid (RF)

Urea Clearance (l/day)

Urea Clearance (ml/min)

Middle Molecular Clearance

Complexity

Slow continuous ultrafiltration

Yes/no

No

1–4

1–3

+

+

Continuous arteriovenous hemofiltration

No

RF

10–15

7–10

++

+

Continuous venovenous hemofiltration

Yes

RF

22–24

15–17

+++

++

Continuous arteriovenous hemodialysis

No

D

24–30

17–21

−

+

Continuous venovenous hemodialysis

Yes

D

24–30

17–21

−

++

Continuous arteriovenous hemodiafiltration

No

RF+D

36–38

25–26

+++

+++

Continuous venovenous hemodiafiltration

Yes

RF+D

36–38

25–26

+++

+++

Figure 70.5  Comparison of different continuous renal replacement modalities. +, simplest; +++, most complex. (Modified from reference 20.)

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Continuous Renal Replacement Therapies Slow continuous ultrafiltration

Continuous hemofiltration

Continuous hemodialysis

Replacement fluids AP V

V

AP V

Ultrafiltrate

V

Continuous hemodiafiltration

Replacement Inlet fluids

Inlet AP V

Ultrafiltrate

V

Outlet

AP V

V

Outlet and ultrafiltrate

Arteriovenous (AV) or venovenous (VV)

AV or VV

AV or VV

AV or VV

AV or VV

Blood flow (ml/min)

50–100

50–200

50–200

50–200

Dialysate flow (ml/min)

–

–

10–20

10–20

Clearance (l/24 h)

–

12–36

14–36

20–40

Ultrafiltration rate (ml/min)

2–5

8–25

2–4

8–12

Blood filter

Highly permeable filter

Highly permeable filter

Low-permeability dialyzer with High-permeability dialyzer with countercurrent flow through countercurrent flow through the dialyzer compartment the dialyzer compartment

Ultrafiltrate

Corresponds exactly to the patient’s weight loss

Replaced in part or Corresponds to patient’s In excess of patient's weight completely to achieve weight loss; solute clearance loss; solute clearance by both purification and volume control by diffusion diffusion and convection

Replacement fluid

None

Yes

Efficiency

Used only for fluid control in Clearance for all solutes overhydrated states equals ultrafiltration

None

Yes, to achieve fluid balance

Limited to small molecules

Extends from small to large molecules

Figure 70.6  Continuous renal replacement therapy modalities. The pump (P) is used only in venovenous modes. (Modified from reference 21.)

Complications of Continuous Renal Replacement Therapy Technical

Clinical

Vascular access malfunction

Hemorrhage

Circuit clotting

Hematomas

Catheter and circuit kinking

Thrombosis

Line disconnections

Hypothermia

Insufficient blood flow

Allergic reactions

Air embolism

Nutrient losses

Fluid balance errors

Insufficient clearance

Loss of efficiency

Hypotension Arrhythmias

Figure 70.7  Complications of continuous renal replacement therapy. (Reproduced from reference 19.)

and can be applied to hypercatabolic and intoxicated patients. The benefit of larger solute clearance is uncertain in this population, whereas the benefits of small-solute clearance are more evident (see later discussion). The long cherished practice of treating lactic acidosis with CRRT should be discarded. Extracorporeal lactate clearance is between 10- and 100-fold lower than plasma clearance, and the only effective treatment of lactic

acidosis is improving tissue oxygenation to prevent acid production.

Dosing of Continuous Renal Replacement Therapy The relationship between CRRT dose and mortality has been established in several prospective, randomized controlled trials. The first demonstrated that an effluent volume flow rate above 35 ml/kg per hour (based on premorbid or pre-ICU weight) of postdilution continuous HF was associated with highest survival. The external validity of this study, however, is limited by the small patient size and the predominantly postsurgical causes of AKI.22 Another demonstrated that the addition of 18 ml/kg per hour of continuous HD to ∼25 ml/kg per hour of predilution continuous HF resulted in improved survival.23 Most recently, two more trials demonstrated that more than 35 ml/kg per hour of predilution continuous HDF did not improve survival compared with 20 ml/kg per hour, and another demonstrated that 40 ml/kg per hour of postdilution continuous HDF did not improve survival compared with 20 ml/kg per hour.13,24,25 Optimal CRRT dose therefore appears to be related to small as much as to larger solute clearance, and as with iHD, there appears to be a dose above which survival becomes dose independent. This breakpoint in the CRRT dose-response curve varies by study but suggests a minimum recommendation for CRRT dose: an effluent volume flow rate of 20 ml/kg per hour. As for iHD, this mandates routine measurement of dose on a regular basis.



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70  Dialytic Management of Acute Kidney Injury and Intensive Care Unit Nephrology

Technical Aspects of Continuous Renal Replacement Therapy Equipment VV CRRT requires a blood pump, a hemofilter or hemodialyzer, arterial and venous pressure monitors, an air detection system, a method for removal of air bubbles, and a system to balance dialysate inflow/replacement fluid with dialysate outflow/filtrate. Integrated machinery dedicated to CRRT is commercially available with computerized volumetric or gravimetric balancing, allowing accurate and reliable treatment delivery. Hemofilters Specific devices for CRRT are usually referred to as hemofilters. However, conventional inexpensive hemodialyzers can serve as hemofilters by occlusion of one of the dialysate ports and connection of the other to a drainage system. To achieve adequate UFR, the surface area must be large (∼2 m2) for low-flux or, alternatively, more modest (∼0.5 m2) for high-flux hemodialyzers. Some CRRT machines use a specific hemofilter because of a unique cartridge system. Sieving coefficients of small solutes are usually preserved throughout the life of all such hemofilters. A promising innovation has been the recent use of so-called superflux hemofilters with a cutoff of 100 to 150 kd. When they are used with CRRT and iHD ex vivo or in healthy volunteers, significant convective removal of cytokines can be achieved, and studies are under way to determine effects on clinical outcomes. Albumin losses may prevent prolonged use of such filters. Replacement Fluids and Dialysate CRRT requires sterile replacement fluid or dialysate for blood purification, with composition that is determined by the clinical requirements for acid-base control and electrolyte management. Fluids are available commercially or can be prepared aseptically

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in hospital pharmacies. A commonly used regimen consists of a blended mixture of 1 liter of each of four different solutions, which are kept separate until allowed to mix through a multiprong adapter just before entering the blood pathway: 1. Isotonic saline (0.9% NaCl) plus 7.5 ml 10% calcium chloride (5.2 mmol calcium). 2. Isotonic saline plus 1.6 ml 50% magnesium sulfate (3.2 mmol magnesium). 3. Half-isotonic saline. 4. Half-isotonic saline plus 150 mmol sodium bicarbonate. Options for replacement fluids are summarized in Figure 70.8. Buffer choice is between bicarbonate and lactate, which metabolizes in the liver to bicarbonate in a 1:1 ratio. Although many patients tolerate lactate solutions, bicarbonate solutions are superior in terms of acid-base control, hemodynamic stability, urea generation, cerebral dysfunction, and possibly survival in patients with a history of cardiovascular disease. Overall, bicarbonate has become the buffer of choice and is preferred in patients with lactic acidosis or liver failure. If lactate-buffered fluids are used, the development of lactate intolerance (>5 mmol/l increase in serum lactate during CRRT) may require a switch to bicarbonate-based fluid. Bicarbonate concentrations in fluid are typically 25 to 35 mmol/l; concentrations in the lower part of this range are indicated during high-dose or prolonged CRRT and during regional citrate anticoagulation therapy to prevent metabolic alkalosis. Glucose concentrations in fluids range from 0.1% in commercially prepared fluids to 1.5% to 4.25% in peritoneal dialysis fluids adapted for use with CRRT. Up to 3600 kcal/day may be derived from these latter solutions, although hyperglycemia may supervene to the detriment of patient outcomes. It is recommended that glucose intake be less than 5 g/kg per day and that glucose concentration in fluid be ∼100 to 180 mg/dl (∼5.5 to 10 mmol/l) to maintain zero glucose balance.

Replacement Fluids for CRRT Component (mmol/l)

Dialysis Machine Generated*

Lactated Peritoneal Ringer’s † Dialysis Fluid Solution

Accusol† (2.5-liter bag)

Prismasate (5-liter bag)

NxStage§ (5-liter bag)

Normocarb¶

Sodium

140

132

130

140

140

140

140

Potassium

Variable

—

4

0 or 2 or 4

0 or 2 or 4

0 or 2 or 4

0

Chloride

Variable

96

109

109.5 to 116.3

108 to 120.5

109 to 113

106

Bicarbonate

Variable

—

—

30 or 35

22 or 32

35

35

Calcium

Variable

3.5

2.7

2.8 or 3.5

0 or 2.5 or 3.5

3

0

Magnesium

1.5

0.5

—

1 or 1.5

1.0 or 1.5

1

1.5

Lactate

2

40

28

0

3

0

0

1360

—

Glucose (mg/dl)

100

—

0 or 110

0 or 110

100

Preparation method

6-liter bag via Premix membrane filtration

Premix

Two-compartment bag

Two-compartment bag or Premix

Two-compartment Vial mix added to bag or Premix 3-liter sterile water bag

Sterility

No

Yes

Yes

Yes

Yes

Yes

Yes

Figure 70.8  Replacement fluids for CRRT. Examples of replacement fluids that are suitable for CRRT. Dialysis machine–generated ultrapure dialysate and peritoneal dialysis fluid are used for continuous hemodialysis only. Lactated Ringer’s solution and commercial hemodiafiltration fluids are used for continuous hemodialysis, hemofiltration, and hemodiafiltration. *Leblanc et al.26 †Dianeal 1.5%, Baxter Healthcare Corp. ‡Gambro Renal Products. §Nxstage Medical Inc. ¶B. Braun Medical Inc.

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Intravenous phosphate supplementation is often required during CRRT and is usually administered separately because of the potential for precipitation with calcium and magnesium in dialysate or replacement fluid. This concern may have been overstated in the past, and phosphate has been safely supplemented by injection of phosphate into these solutions.

PROLONGED INTERMITTENT RENAL REPLACEMENT THERAPY PIRRT should replace alternative names such as sustained low efficiency dialysis (SLED), slow low efficiency dialysis, go slow dialysis, extended dialysis, extended daily dialysis, accelerated venovenous filtration. PIRRT uses standard iHD equipment and accessories, but with lower solute clearances and UFR maintained for prolonged periods.27 Typical operating parameters would be Qb of 200 to 300 mL/min and Qd of 300 ml/min for regimens of 8 hours or less, and Qb of 100 to 200 ml/min and Qd of 100 to 200 mL/min for regimens longer than 8 hours. The systems are fully monitored with computerized ultrafiltration control. Qd and urea clearances are higher than in conventional CRRT, which allows scheduled downtime without compromise in dialysis dose. PIRRT provides a high dose of dialysis with minimal urea disequilibrium, online bicarbonate dialysate, excellent control of electrolytes, and good tolerance to ultrafiltration. PIRRT is usually delivered as a diffusive therapy (a subgroup of PIRRT referred to as extended dialysis), although there is increasing experience with combined diffusive and convective clearance using online replacement fluid (extended diafiltration). Survival in the reported observational series has not differed from that predicted by a variety of illness severity scores. ARRT that is easiest to administer will be the most popular if all such outcomes are equivalent, and PIRRT may become the therapy of choice in this setting as it is safe, convenient, inexpensive, and effective in achieving goals for solute and fluid removal.

VASCULAR ACCESS A prerequisite for all ARRT modalities is reliable vascular access. This is usually through uncuffed, untunneled (temporary) double-lumen polyurethane or silicone catheters in the internal jugular (IJ), subclavian (SC), or femoral (FE) veins. SC catheters are associated with a higher incidence of procedural complications, venous stenosis, and thrombosis. For CRRT and PIRRT, Qb below 250 ml/min is usually sufficient. For acute iHD, higher Qb is required to provide sufficient solute clearance, and it can be safely increased until venous and arterial pressures are plus and minus 350 mm Hg, respectively, after which hemolysis can occur. Left-sided IJ and SC catheters provide flows that are more erratic and up to 100 ml/min lower than elsewhere because their tips abut the vein walls. FE and right-sided IJ or SC catheters provide the best Qb.25 Catheters with larger bore lines are preferred. Access recirculation for all sites is approximately 10% at Qb of 250 to 350 ml/min and may increase to as much as 35% at Qb above 500 ml/min. It is least in IJ catheters and highest in FE catheters shorter than 20 cm. Up to half of acute iHD treatments will require catheters to be used in reversed configuration, such that the original venous line is used as for blood inflow (relative to dialyzer), and the original arterial line for outflow. Access recirculation in this situation doubles to ∼20% at 250 to 350 ml/

min.28 Access recirculation also affects dialysis dose; in one study, the urea reduction ratio was significantly higher with SC (63%) versus FE (55%) catheters despite identical iHD operating parameters.29 Infection of temporary catheters is common. Blood stream, exit site, and distant infections occurred in one series at 6.2, 3.6, and 1.1 episodes per 1000 catheter-days.28 The risk of bacteremia is highest with FE catheters and lowest with SC catheters. Although there are generally fewer data than for tunneled catheters, both povidone and mupirocin ointments with dry gauze exit site dressings and antimicrobial locks using taurolidine or 30% trisodium citrate have been shown to reduce the risk of blood stream infection from temporary catheters. The Centers for Disease Control and Prevention recommend that temporary catheters in the ICU setting be changed when it is clinically indicated rather than routinely because the risks of the catheterization outweigh the supposed benefit of reduced infection risk.30 KDOQI (Kidney Disease Outcomes Quality Initiative) recommends that SC and IJ catheters be changed after 3 weeks and FE catheters after 5 days in the non-ICU setting because of increased infection risk.31

ANTICOAGULATION IN ACUTE RENAL REPLACEMENT THERAPY Anticoagulation during ARRT ideally should prevent clotting in the extracorporeal circuit without producing significant systemic anticoagulation. Most commonly, unfractionated heparin is infused into the most proximal part of the extracorporeal circuit, keeping the activated partial thromboplastin time in the venous blood line 1.5 to 2 times the control value and the systemic activated partial thromboplastin time below 50 seconds. This typically requires an initial bolus dose of ∼2000 U and maintenance infusion of ∼500 U/h. Low-molecular-weight heparin is theoretically advantageous because of increased antithrombotic activity and decreased hemorrhagic risk. However, disadvantages include a prolonged half-life (approximately doubled in RIFLE failure stage), incomplete reversal with protamine, and limited availability of appropriate monitoring by serial anti–factor Xa determinations. Most experience is with dalteparin, and the optimal dose appears to be an initial bolus of ∼20 to 30 U/kg (all ARRT modalities), followed by an infusion of ∼10 U/kg per hour (CRRT and PIRRT). Other systemic anticoagulants include lepirudin (recombinant hirudin, notable for its very long half-life in those with reduced renal function) and argatroban, which are direct thrombin inhibitors, and fondaparinux, which is a synthetic pentasaccharide that inhibits factor Xa by binding to antithrombin. Experience with these anticoagulants is limited, although they are the anticoagulants of choice in patients with heparin-induced thrombocytopenia who also require ARRT. For those receiving systemic anticoagulation with heparin, the incidence of significant bleeding complications is 25% to 30%, and 4% of such patients die as a result of hemorrhage. Most patients can successfully avoid any anticoagulation during iHD, but only a minority can during PIRRT or CRRT. Alternatives to systemic anticoagulation include regional citrate anti­ coagulation, regional heparin anticoagulation, and prostacyclin (epoprostenol), which is a potent inhibitor of platelet aggregation that essentially acts as a regional anticoagulant. The lowest rates of hemorrhage and greatest prolongation of filter life are associated with regional citrate anticoagulation, and it is the preferred regional technique.



CHAPTER

70  Dialytic Management of Acute Kidney Injury and Intensive Care Unit Nephrology

Regional citrate anticoagulation involves calcium chelation in the extracorporeal blood circuit with calcium reversal. For iHD and PIRRT, this most commonly involves an infusion of 4% trisodium citrate into the proximal circuit, with zero calcium dialysate and an infusion of calcium chloride into the venous blood line. A simpler approach has been described in which the trisodium citrate infusion is combined with normal calcium dialysate and no calcium infusion. The positive calcium flux through the hemodialyzer maintains calcium balance without the need for a separate infusion and provides partial chelation of the undialyzed citrate. For CRRT, regional citrate anticoagulation may be performed with 4% trisodium citrate or with ACD-A solution (anticoagulant citrate dextrose A). ACD-A is preferred to trisodium citrate as it is less hypertonic, potentially reducing complications from overinfusion and mixing errors. For continuous HD, a prefilter infusion of 3% to 7% of Qb with a postfilter infusion of calcium chloride is used. This requires dialysate that is hyponatremic and devoid of alkali because citrate metabolizes to bicarbonate in the liver in a 1:3 ratio. For continuous HF, a prefilter infusion of substitution fluid that contains no calcium but citrate as buffer can be used (Fig. 70.9). Frequent monitoring and titration of citrate dose are needed to keep the ionized calcium within a therapeutic range. The major complications of regional citrate anticoagulation are systemic hypocalcemia and metabolic alkalosis from citrate toxicity, particularly in patients with liver dysfunction. Regional heparin anticoagulation involves neutralization of heparin by infusion of protamine into the venous blood line. It

851

may be complicated by rebound bleeding, occurring when neutralization with protamine wears out faster than the anticoagulation from heparin. Furthermore, protamine may cause sudden hypotension, bradycardia, or anaphylactoid reactions. Prostacyclin is an effective alternative anticoagulant. However, it is a vasodilator, causing a variable but occasionally marked decrease in blood pressure.

MODALITY CHOICE AND OUTCOMES IN ACUTE RENAL REPLACEMENT THERAPY The prime advantage of CRRT appears to be the increased hemodynamic stability and solute control; patient survival does not appear to differ between AV and VV CRRT when dose is the same. Observational reports have previously suggested improved survival with CRRT compared with iHD, but numerous confounding variables have made definitive comparison with iHD difficult. Small randomized clinical trials and subsequent meta-analyses comparing iHD and CRRT have shown no difference in patient survival.32 The relationship between modality choice and outcomes is currently under study in specific clinical situations, such as acute lung injury, sepsis, and acute cardiac decompensation. Such studies may yet yield definitive data, but in the interim, modality choice depends on the patient’s condition and the clinical objectives. In most cases, iHD can provide safe and effective renal replacement therapy, with recourse to other therapies as the individual situation dictates. For example, CRRT will be more

Comparison of Regional Citrate Anticoagulation Protocols Modality

Blood Flow (ml/min)

Replacement Fluid Composition (mmol/l)

CAV-HD

52–125

Normal saline

Hoffmann et al.34 CVV-HD (1995)

125

Prefilter: normal saline + KCl 4, alternate with 0.45% saline + KCl 4 Postfilter: 0.45% saline +MgSO4+ CaCl2

Palsson and Niles35 (1999)

CVV-HD

180

Tolwani et al.36 (2001)

CVV-HD

125–150

Tobe et al.37 (2003)

CVV-HDF

100

Mitchell et al.38 (2003)

CVV-HD

75

Swartz et al.39 (2004)

CVV-HD

200

Gupta et al.40 (2004)

CVV-HDF

150

33

Mehta et al. (1990)

Citrate 13.3, Na 140, Cl 101.5, Mg 0.75, dextrose 0.2% —

Dialysis Fluid Composition (mmol/l) Na 117, CI 122.5, Mg 0.75, K 4, dextrose 2.5%

Citrate Source 4% Trisodium citrate 4% Trisodium citrate

—

—

Customized citrate solution

Normal saline + MgSO4 1.0, KCI 3

4% Trisodium citrate

Normocarb

ACD-A

—

Variable Ca 1.75–1.78

ACD-A

—

Na 135, HCO3 28, Cl 105, MgSO4 1.3, glucose 1g/l

ACD-A

PD fluid: Na 132, Ca 1.25, Cl 95, Mg 0.5, lactate 360 mg/dl, 1.5% dextrose

ACD-A

Normal saline

Normal saline ± MgSO4 and KCI

Figure 70.9  Comparison of regional citrate anticoagulation protocols. ACD-A, anticoagulant citrate dextrose form A; CAV-HD, continuous arteriovenous hemodialysis; CVV-HD, continuous venovenous hemodialysis; CVV-HDF, continuous venovenous hemodiafiltration; PD, peritoneal dialysis.

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appropriate for a patient unable to achieve ultrafiltration goals with iHD because of hemodynamic instability, and HVHF may be more appropriate than iHD for a highly catabolic septic patient. Ultimately, the skill and experience of the staff providing renal replacement therapy probably influence patient outcomes as much as the choice of modality does.

DRUG DOSING IN ACUTE RENAL REPLACEMENT THERAPY For patients undergoing CRRT, 20 liters of daily filtrate correspond to a glomerular filtration rate of ∼14 ml/min, and the dose of drugs should be calculated accordingly. Any drug with a low therapeutic index that can be readily measured should be measured frequently early in the course of ARRT, until a stable pattern appears. One day of CRRT is in general comparable to one iHD treatment with regard to drug removal.

REFERENCES 1. Bagshaw SM, George C, Bellomo R. Changes in the incidence and outcome for early acute kidney injury in a cohort of Australian intensive care units. Crit Care. 2007;11:R68. 2. De Vriese AS, Colardyn FA, Philippé JJ, et al. Cytokine removal during continuous hemofiltration in septic patients. J Am Soc Nephrol. 1999; 10:846-853. 3. Joannes-Boyau O, Honore PM, Boer W, Collin V. Are the synergistic effects of high-volume haemofiltration and enhanced adsorption the missing key in sepsis modulation? Nephrol Dial Transplant. 2009;24: 354-357. 4. Bagshaw SM, Uchino S, Bellomo R, et al. Timing of renal replacement therapy and clinical outcomes in critically ill patients with severe acute kidney injury. J Crit Care. 2009;24:129-140. 5. Bouman C, Oudemans-Van Straaten HM, Tijssen JG, et al. Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: A prospective, randomized trial. Crit Care Med. 2002;30: 2205-2211. 6. Kellum JA, Mehta RL, Levin A, et al. Development of a clinical research agenda for acute kidney injury using an international, interdisciplinary, three-step modified Delphi process. Clin J Am Soc Nephrol. 2008;3: 887-894. 7. Ponikvar JB, Rus RR, Kenda RB, et al. Low-flux versus high-flux synthetic dialysis membrane in acute renal failure: Prospective randomized study. Artif Organs. 2001;25:946-950. 8. Paganini E, Sandy D, Moreno L, et al. The effect of sodium and ultrafiltration modelling on plasma volume and haemodynamic stability in intensive care patients receiving haemodialysis for acute renal failure: A prospective, stratified, randomized, cross-over study. Nephrol Dial Transplant. 1996;11(Suppl):32-37. 9. Tonelli M, Astephen P, Andreou P, et al. Blood volume monitoring in intermittent hemodialysis for acute renal failure. Kidney Int. 2002;62: 1075-1080. 10. Marshall M, Golper T. Intermittent hemodialysis. In: Murray P, Brady H, Hall J, eds. Intensive Care In Nephrology. Oxon, UK: Taylor & Francis; 2006:181-198. 11. Paganini EP, Tapolyai M, Goormastic M, et al. Establishing a dialysis therapy/patient outcome link in intensive care unit acute dialysis for patients with acute renal failure. Am J Kidney Dis. 1996; 28(Suppl):S81-S89. 12. Schiffl H, Lang S, Fischer R. Daily hemodialysis and the outcomes of acute renal failure. N Eng J Med. 2002;346:305-310. 13. Palevsky PM, Zhang JH, O’Connor TZ, et al. Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med. 2008; 359:7-20. 14. Casino F, Lopez T. The equivalent renal urea clearance: A new parameter to assess dialysis. Nephrol Dial Transplant. 1996;11:1574-1581.

15. Frankenfield D, Reynolds HN, Wiles CE 3rd, et al. Urea removal during continuous hemodiafiltration. Crit Care Med. 1993;22:407-412. 16. Kudoh Y, Iimura O. Slow continuous hemodialysis—new therapy for acute renal failure in critically ill patients—Part 1. Theoretical considerations and new technique. Jpn Circ J. 1988;52:1171-1182. 17. Brunet S, Leblanc M, Geadah D, et al. Diffusive and convective solute clearances during continuous renal replacement therapy at various dialysate and ultrafiltration flow rates. Am J Kidney Dis. 1999;34:486-492. 18. Troyanov S, Cardinal J, Geadah D, et al. Solute clearances during continuous venovenous haemofiltration at various ultrafiltration flow rates using Multiflow-100 and HF1000 filters. Nephrol Dial Transplant. 2003;18:961-966. 19. Ronco C, Bellomo R. Complications with renal replacement therapy. Am J Kidney Dis. 1996;28(Suppl 3):S100-S104. 20. Manns M, Sigler MH, Teehan BP. Continuous renal replacement therapies: An update. Am J Kidney Dis. 1998;32:185-207. 21. Ronco C. Continuous renal replacement therapies for the treatment of acute renal failure in intensive care patients. Clin Nephrol. 1993;40:187-198. 22. Ronco C, Bellomo R, Homel P, et al. Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: A prospective randomised trial. Lancet. 2000;356:26-30. 23. Saudan P, Niederberger M, De Seigneux S, et al. Adding a dialysis dose to continuous hemofiltration increases survival in patients with acute renal failure. Kidney Int. 2006;70:1312-1317. 24. Tolwani AJ, Campbell RC, Stofan BS, et al. Standard versus high-dose CVVHDF for ICU-related acute renal failure. J Am Soc Nephrol. 2008;19:1233-1238. 25. Bellomo R, Cass A, Cole L, et al. Intensity of continuous renalreplacement therapy in critically ill patients. N Engl J Med. 2009;361: 1627-1638. 26. Leblanc M, Moreno L, Robinson OP, et al. Bicarbonate dialysate for continuous renal replacement therapy in intensive care unit patients with acute renal failure. Am J Kidney Dis. 1995;26:910-917. 27. Marshall MR, Golper TA, Shaver MJ, et al. Sustained low-efficiency dialysis for critically ill patients requiring renal replacement therapy. Kidney Int. 2001;60:777-785. 28. Oliver M. Acute dialysis catheters. Semin Dial. 2001;14:432-435. 29. Leblanc M, Fedak S, Mokris G, Paganini E. Blood recirculation in temporary central catheters for acute hemodialysis. Clin Nephrol. 1996;45:315-319. 30. Centers for Disease Control and Prevention. Guidelines for the prevention of intravascular catheter-related infections. MMWR. 2002; 51(RR-10). 31. National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Vascular Access, 2000. Am J Kidney Dis. 2001;37(Suppl 1): S137-S181. 32. Pannu N, Klarenbach S, Wiebe N, et al. Renal replacement therapy in patients with acute renal failure: A systematic review. JAMA. 2008; 299:793-805. 33. Mehta RL, McDonald BR, Aguilar MM, Ward DM. Regional citrate anticoagulation for continuous arteriovenous hemodialysis in critically ill patients. Kidney Int. 1990;38:976-981. 34. Hoffmann JN, Hartl WH, Deppisch R, et al. Hemofiltration in human sepsis: Evidence for elimination of immunomodulatory substances. Kidney Int. 1995;48:1563-1570. 35. Palsson R, Niles JL. Regional citrate anticoagulation in continuous venovenous hemofiltration in critically ill patients with a high risk of bleeding. Kidney Int. 1999;55:1991-1997. 36. Tolwani AJ, Campbell RC, Schenk MB, et al. Simplified citrate anticoagulation for continuous renal replacement therapy. Kidney Int. 2001;60:370-374. 37. Tobe SW, Aujla P, Walele AA, et al. A novel regional citrate anticoagulation protocol for CRRT using only commercially available solutions. J Crit Care. 2003;18:121-129. 38. Mitchell A, Daul AE, Beiderlinden M, et al. A new system for regional citrate anticoagulation in continuous venovenous hemodialysis (CVVHD). Clin Nephrol. 2003;59:106-114. 39. Swartz R, Pasko D, O’Toole J, Starmann B. Improving the delivery of continuous renal replacement therapy using regional citrate anticoagulation. Clin Nephrol. 2004;61:134-143. 40. Gupta M, Wadhwa NK, Bukovsky R. Regional citrate anticoagulation for continuous venovenous hemodiafiltration using calcium-containing dialysate. Am J Kidney Dis. 2004;43:67-73.