Continuous Renal Replacement Therapy

Acute kidney injury (AKI) is common and serious. The incidence of AKI in hospitalized patients ranges from 5% to 7% and is rising rapidly.1–4 In a multinational study of critically ill patients, the prevalence of AKI requiring dialysis was 5.7% with a mortality rate of 60.3%.⁵ In addition, patients with AKI have a higher risk for developing other nonrenal comorbid conditions,⁶ and when present in conjunction with other conditions, AKI is associated with higher mortality rate.^7–9 The use of renal replacement therapy (RRT) for treatment of AKI has been ongoing over the last 60 years.¹⁰ According to Hoste and Schurgers, 200 to 300 patients per 1 million population per year develop AKI and are treated with RRT.¹¹ Despite this, these patients still have a mortality rate of 50% to 60%.¹¹Advances and optimization of RRT could benefit the high mortality rate associated with AKI.

The establishment of continuous renal replacement therapy (cRRT) evolved as a treatment for the hemodynamically unstable patient unable to undergo standard intermittent hemodialysis (IHD). Although world trends for cRRT use show an increase in utilization, the majority of the world continues to treat AKI with IHD.¹² Although cRRT offers many theoretical advantages such as better fluid balance, hemodynamic management, and renal recovery, the superiority of cRRT over IHD for RRT in the intensive care unit (ICU) remains controversial.¹³

This chapter first reviews the physiologic principles behind the multifaceted aspect of cRRT before moving onto the technical aspects and clinical issues. We also discuss possible technical complications and ethical considerations in the use of cRRT.

Physiologic Principles

Dialysis uses a semipermeable membrane to alter the molecular composition and concentration of blood to restore the body back toward homeostatic balance. Blood flows along one side of the semipermeable membrane and a wash solution, dialysate, flows on the opposite side of the membrane (Fig. 18.1). Dialysis relies upon two physical forces—diffusion and convection—either in isolation or in combination (Fig. 18.2). In diffusion, the net movement of solute is directly dependent on the diffusivity of the solute and solvent, permeability of the membrane, surface area across the membrane, and concentration gradient. Other membrane characteristics also play a role: thickness, pore size, and electrostatic charge. In order to maximize the concentration gradient between the blood and dialysate, the dialysate runs countercurrent to the flow of blood. Any substance that is in higher concentration in the blood than the dialysate flows “down” its concentration gradient and leaves the blood and flows into the dialysate. Conversely, any solute that is in higher concentration in the dialysate (e.g., bicarbonate) will leave the dialysate, cross the semipermeable membrane, and enter the blood. The movement of molecules down their concentration gradient from one solution to another continues until equilibrium is achieved in both the blood and dialysate. Diffusion is more efficient in the clearance of small-molecular-weight substances (less than 500 daltons [D]). This is particularly useful in correcting the imbalance in small molecule electrolytes (e.g., K, Ca, Mg, PO₄) (see Fig. 18.1). Thus, thoughtful manipulation of dialysate allows the clinician to decide what will be removed from the blood and what will be added to the blood during a dialysis session.

Figure 18.2 Diffusion and convection are schematically represented. During diffusion, the solute flux (Jx) is a function of the solute concentration gradient (dc) between the two sides of the semipermeable membrane, the temperature (T), the diffusivity coefficient (D), the membrane thickness (dx), and the surface area (A), according to the following equation: Jx = DTA (dx/dx). Convective flux of solute (Jf) requires instead a pressure gradient between the two sides of the membrane (transmembrane pressure, or TMP), which moves a fluid (plasma water) with its crystalloid content in a process called ultrafiltration (which is also dependent on the membrane permeability coefficient, or Kf). Colloids and cells will not cross the semipermeable membrane, depending on the pores’ size. Jf = Kf × TMP and TMP = Pb − Pd − π where Pb is the blood hydrostatic pressure, Pd is the hydrostatic pressure on the ultrafiltrate side of the membrane, and p is the oncotic pressure. From Ronco, C. In Critical Care Nephrology, 2/E. Phila., WB Saunders, 2008. (Fig. 210-001).

In convection, solutes move across a membrane in response to or following solvent flux or drag: solutes are moving along with the solvent containing them (Fig. 18.3). This is similar to a wave pushing seashells onto the shore. Solvent drag is limited only by the pore size or electrostatic charge of any semipermeable membrane that is applied across the passage of the solution. In convection, the concentration of a solute is similar on either side of the membrane. Convection is more efficient at the clearance of large-molecular-weight substances (500-5000 D). Convective removal of plasma water from blood across a large-pore, semipermeable membrane results in an ultrafiltrate with a solute composition equivalent to plasma water.

Figure 18.3 Diffusion is the result of microscopic molecular movements. A, Convection without diffusion moves all molecules equally and does not result in separation. B, Unhindered ordinary diffusion causes initially separated molecules to move together. C, Forced diffusion, provided by an external force, separates molecules when the force acts differently on different molecular types. From Ronco, C. In Critical Care Nephrology, 2/E. Phila., WB Saunders, 2008. (Fig. 209-001).

Fluid removal is termed ultrafiltration (UF). UF utilizes hydrostatic pressure, which is applied across a semipermeable membrane. This is a form of convective removal of solute. The clearance of molecules in UF is dependent on the volume of fluid removed. It may be applied in isolation (in volumes usually <5 L/day) or in combination with other blood clearance techniques, such as dialysis. Table 18.1 reviews the commonly used terms in cRRT.

Table 18.1

Modalities of Continuous Renal Replacement Therapy (cRRT)

CVVH, continuous venovenous hemofiltration; CVVHD, continuous venovenous hemodialysis; CVVHDF, continuous venovenous hemodiafiltration; SCUF, slow continuous ultrafiltration.

One other form of clearance of the blood is through a process called adsorption. This refers to molecules in the blood sticking or adhering to the semipermeable membrane. This process is dependent on the molecules contained in the blood and the composition of the semipermeable membrane. Adsorption is usually time dependent (i.e., as the semipermeable membrane is used over time, it will become saturated with a given molecule). The process begins anew when the membrane is changed (approximately every 72 hours). Some inflammatory cytokine clearance occurs through this process.¹⁴

Modalities

The various modalities of cRRT are depicted in Table 18.1 and Figure 18.4.

Figure 18.4 Schematic representation of the most common continuous renal replacement therapy (RRT) setups. A, Slow continuous ultrafiltration (SCUF). B, Continuous venovenous hemofiltration (CVVH). C, Continuous venovenous hemodialysis (CVVHD). D, Continuous venovenous hemodiafiltration (CVVHDF). See text for specifications. Dark triangles represent blood flow direction; light triangles indicate the flow of dialysate/replacement solutions. Di, dialysate in; Do, dialysate out; P, pump; Qb, blood flow; Qd, dialysate solution flow; Qf, replacement solution flow; Quf, ultrafiltration flow; Rpost, replacement solution postfilter; Rpre, replacement solution prefilter; Uf, ultrafiltration; V, vein. From Ronco, C. In Critical Care Nephrology, 2/E. Phila., WB Saunders, 2008. (Fig. 210-002).

When UF only is employed on a continuous basis, this is termed slow continuous ultrafiltration (SCUF). This modality would be considered in patients with volume overload, for example, in congestive heart failure (CHF) or anasarca from nephrotic syndrome or liver disease.

Dialysis may also be performed on an intermittent basis (IHD or sustained low-efficiency dialysis [SLED]) (see Fig. 18.1) or a continuous basis (Figs. 18.4 and 18.5). When performed continuously, this is known as continuous venovenous hemodialysis (CVVHD). The “venovenous” refers to the access employed and will be discussed in a later section. As described earlier, this is a diffusion-based process that primarily provides small molecule clearance.

Figure 18.5 Schematic representation of different renal replacement modalities: hemodialysis, hemofiltration, and hemodiafiltration. From Ronco, C. In Critical Care Nephrology, 2/E. Phila., WB Saunders, 2008. (Fig. 215-001).

Hemofiltration (HF) relies on convective removal of plasma solute, in high fluid volumes, across a semipermeable membrane (see Fig. 18.5). Hydrostatic pressure is applied across the semipermeable membrane as a positive pressure on the blood side of the membrane or a negative pressure on the fluid collection side, or both. Fluid lost through this process is restored with replacement fluid in either a predilutional mode (before the filter containing the semipermeable membrane) or in a postdilutional mode (after the filter). The composition of the effluent fluid created by this system of plasma water exchange (hemofiltrate) depends on the membrane sieving coefficient for that particular solute and that particular semipermeable membrane. The sieving coefficient is expressed in terms of the ratio of the solute concentrations of the hemofiltrate to the plasma and is a function of membrane thickness, pore size, and electrostatic charge (Fig. 18.6). Hemofiltration is more efficient in middle-molecular-weight compound clearance, but less so for smaller solutes. When performed on a continuous basis, this is known as continuous venovenous hemofiltration (CVVH).

Figure 18.6 In vivo measured sieving coefficients for various serum contents during hemofiltration with a noncuprophane membrane. From Ronco, C. In Critical Care Nephrology, 2/E. Phila., WB Saunders, 2008. (Fig. 019-001).

Finally, hemodiafiltration (HDF) combines both diffusive and convective solute removal (see Fig. 18.5). When performed continuously, this is known as continuous venovenous hemodiafiltration (CVVHDF). Dialysate is used in this configuration and runs countercurrent to the blood. Concurrently, replacement solution is infused either prefilter or postfilter. This allows for both efficient low-molecular-weight and enhanced middle-molecular-weight clearances. This modality has been employed for sepsis and multiorgan failure, in which removal of cytokine mediator substances is thought to be important.¹⁵

Figure 18.4 illustrates the mechanics of each of these modalities. Any modality may be described according to its frequency (I [intermittent] versus C [continuous]) and technique (H or HF [hemofiltration], HD, HDF, or UF) as shown in Table 18.2. To date, no one modality has been shown to be superior to the others. Continuous techniques are additionally described according to their vascular access: arteriovenous (AV) or venovenous (VV) (see later discussion under “Access”). Much debate has occurred regarding the superiority of intermittent therapies versus the continuous therapies. To date, the continuous therapies have not been shown to be superior in clinical outcomes to the intermittent therapies. Although the intermittent therapies (IHD and SLED) may be less costly, the continuous modalities allow for hemodynamic stability, enhanced fluid removal, and delivered dose of dialysis.¹⁶

Table 18.2

Commonly Used Forms of Extracorporeal Renal Replacement Therapy

AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; ARF, acute renal failure; CHF, congestive heart failure; CRF, chronic renal failure; CVVH, continuous venovenous hemofiltration; CVVHDF, continuous venovenous hemodiafiltration; CVVUF, continuous venovenous ultrafiltration; IH, intermittent hemofiltration; IHD, intermittent hemodialysis; IHDF, intermittent hemodiafiltration; IUF, intermittent ultrafiltration; MOF, multiple organ failure; SCUF, slow continuous ultrafiltration; SLED, sustained low-efficiency dialysis.

Principles of Ultrafiltration

Achieving fluid balance by removal is the most frequently requested application for dialytic intervention and is considered the simplest form of continuous therapy. Fluid is drawn from the blood space across a semipermeable membrane. The fluid removed, or ultrafiltrate, has the characteristics of plasma water. With knowledge of the sieving coefficients of a particular membrane for various solutes, the ultrafiltrate can be used to determine the composition of serum and can help avoid an excessive number of blood draws.

In prescribing UF, a specific volume of fluid loss should be determined, with the UF rate (Q_F) set to achieve that loss over a set time frame. It cannot be overemphasized that this form of therapy is by nature slow. The steady, constant loss of fluid at a rate that does not exceed the plasma-refilling rate gives this form of therapy its hemodynamic stability. If extremely rapid UF in a short time frame is the therapeutic intent, intermittent forms of pump-driven UF are more efficient and therefore the treatment of choice.

The artificial membranes usually employed have a high UF coefficient (K_Uf), allowing water to pass quite freely. Any pressure difference between the blood side and the ultrafiltrate side of the filter results in fluid passage. Higher pressures in the blood compartment of the filter result in net fluid flow from the blood to the ultrafiltrate compartment. This flow is enhanced by applying negative pressures to the ultrafiltrate compartment through gravity or by pumped mechanical suction. This pressure should be held constant and not be subject to rapid variations. If transmembrane pressures are too high, membrane rupture and blood loss may result.

Common UF rates range from 100 to 400 mL/hour. Larger amounts may be obtained if there is a need for rapid fluid removal. Automated continuous machines control UF through a volume-driven system, establishing a fixed loss of a determined amount of fluid from the system over a given time period (usually on an hourly basis).

The blood flow rate (Q_B) has a significant effect on any UF system. During UF, plasma water is removed from the blood as it moves through the dialysis filter, thereby increasing the viscosity of blood in the filter. If the viscosity increases excessively, the system will clot. Therefore, whenever UF is being prescribed, an appropriate Q_B must be prescribed in order to accommodate the prescribed UF.

Careful attention should be given to the amount of access recirculation. Rates greater than 15% are associated with a greater incidence of clotting. This tendency is more evident at higher UF rates (>300 mL/hour), at which the returning blood tends to have a higher hematocrit, creating a more viscous, afferent blood flow.

Principles of Hemofiltration

As more fluid removal is performed, additional fluid may be needed to replace that which is lost. This is termed hemofiltration or plasma water exchange. Fluid replacement can be delivered into the blood circuit either prefilter, before UF has occurred (predilutional hemofiltration), or after fluid has been removed by the filter (postdilutional hemofiltration).

In predilutional hemofiltration, ultrafiltrated fluid reflects the mixture of blood and replacement solution. To use ultrafiltrate as a surrogate for blood sampling (see previous discussion) would be problematic because correction has to be made for the degree of dilution and for the electrolytic composition of the replacement fluid. Because the oncotic pressure of blood is reduced within the filter, a greater rate of fluid removal is possible at the same transmembrane hydrostatic pressure. This increased rate of fluid removal is offset by dilution of plasma solute. In other words, the overall mass transfer of uremic toxins is reduced, and higher rates of fluid exchange are required to compensate. It is common to have exchange rates of 30 to 40 L/day. Predilutional hemofiltration may also be used for patients with high hematocrit levels in an effort to reduce clotting episodes.

Postdilutional fluid replacement has the advantage of being easier to perform, with lower rates of fluid exchange compared with the predilutional system. One problem with this form of replacement is the increased oncotic pressures at the venous end of the filter. With high rates of exchange or high degrees of access recirculation, blood viscosity may be increased to the extent that clotting may occur. Therefore, fluid exchange rates may be dictated by such factors as hematocrit, blood flow, and access recirculation. Table 18.3 compares predilutional and postdilutional CVVH.

Table 18.3

Comparison of Pre- and Postdilution Techniques for Continuous Venovenous Hemodiafiltration/Hemofiltration

Feature	Predilution	Postdilution
Clearance	Less clearance per milliliter	High small solute clearance per milliliter
Efficiency	Reduced efficiency by 10-15% and reduced filtration fraction
Ultrafiltration rate limitations	Ultrafiltration rate not limited	Ultrafiltration rate limited by blood pressure and hemoconcentration
Blood viscosity	Low viscosity of the blood	High viscosity of the blood and increased risk of clotting

The end point of hemofiltrative therapy is determined by the balance between solutes removed with the ultrafiltrate and those replaced with the substitution fluid. A blood pump is used to increase blood flow and allow higher filtration rates. Infusion pumps are used for the delivery of replacement solution.

The system should be kept below a filtration fraction of 15% in postdilution and 30% in predilution hemofiltration for efficient operation and a lower risk of clotting.

Principles of Hemodialysis

In hemodialysis (HD), the flow of dialysate is countercurrent to that of blood to maximize transmembrane concentration differences across all blood concentrations and at all levels of the filter. Blood flow (100 to 300 mL per minute) is maintained well above the usual dialysate flow rates (15 to 30 mL per minute). By contrast, in IHD, blood, rather than dialysate flow, is the limiting factor in diffusive clearance. Clearance of low-molecular-weight substances (e.g., urea, creatinine) is “flow-dependent” because there is little resistance to transmembrane movement posed by the porous membrane. Substances of larger molecular weight (e.g., β₂-microglobulin, vitamin B₁₂) are relatively slow in crossing the dialyzer membrane and are “membrane-dependent” molecules. Using the high-flux membrane characteristics generally employed with continuous therapies, substances with molecular weights (masses) of 20,000 to 30,000 D are transferred at rates that have an inverse relationship to their molecular weights.

Electrolytes, urea, and creatinine easily cross membranes at a rate that is directly proportional to membrane surface area, temperature, and concentration difference, and inversely proportional to viscosity, distance from the membrane, and molecular size. Changing the concentration of various elements in the dialysate alters solute balance. Balance is achieved, however, only between transferable particles. Protein-bound solutes are not subject to the concentration gradients that drive the molecular transport across the membrane. This concept is the basis for altered drug kinetics when patients are subjected to continuous supportive therapy.

In CVVHD, dialysate flow rates remain the most influential factor in determining urea clearance.¹⁷ Dialysate usually is delivered via pumps at rates of 15 to 40 mL per minute. Given adequate blood flow through the circuit, one can see why the limiting factor for flow-dependent transfer is the relatively low dialysate flow rate. Blood flow and filter membrane have limited effects on the diffusion of molecules compared with the potential of dialysate flow changes.

In addition to the diaysate inflow, the dialysate outflow also must be controlled. By setting the outflow rate higher than dialysate inflow rates, one can create a negative transmembrane pressure promoting UF across the dialysis membrane. This difference in flow is used to establish the rate of UF. An increase or decrease in this flow difference would increase or decrease the rate of fluid loss. Dialysate flow is external to and independent of blood flow, and therefore, one may see continued dialysate flow in a system with virtually no blood flow. Although decreases in hemofiltration flow rates may indicate system clotting, dialysate flow rate changes have no predictive value for clotting and may continue despite blood-side occlusion.

Continuous Renal Replacement Therapy Versus Intermittent Therapy

The clinical presentation and circumstances may favor either intermittent or continuous therapies (Table 18.4). There are many theoretical benefits that may favor the use of cRRT over intermittent forms of therapy, such as improved hemodynamic stability, faster resolution of fluid overload, and increased dialysis dose delivery (Table 18.5). Box 18.1 lists some nonrenal indications for using cRRT. However, clinical trials demonstrating an evidence-based assessment of these potential advantages are still lacking.

Box 18.1 Nonrenal Indications for Continuous Renal Replacement Therapy (cRRT)

Lactic acidosis – with ongoing production

Crush injury – Myoglobin removal

Tumor lysis syndrome

Temperature control

Massive volume overload

High ammonia

Removal of toxins with high intracellular concentrations (e.g., Li+)

Maintenance of cerebral perfusion pressure (CPP) (suggested by some evidence)

Table 18.4

Clinical Considerations in Continuous versus Intermittent Renal Support in the Intensive Care Unit

APACHE II, Acute Physiology and Chronic Health Evaluation II [disease severity classification system].

Table 18.5

Intermittent and Continuous Forms of Renal Replacement Therapy

cRRT, continuous renal replacement therapy; IHD, intermittent hemodialysis; SLED, sustained low-efficiency hemodialysis.

Hemodynamic stability is one of the most important advantages for the use of cRRT over intermittent modalities. Slower removal of solute and fluid from the intravascular space by continuous techniques should allow adequate time for refilling from the interstitium and intracellular space, theoretically minimizing therapy-induced hypotension. There are longer term implications for renal recovery, with IHD-related hemodynamic instability potentially predisposing to recurrent renal injury. The data from rigorous, comparative studies seem to lead to varying conclusions, however.

Continuous therapies are able to deliver a higher dose of clearance compared to intermittent therapies. The concept of dose will be covered later in this chapter. Intermittent therapy may have to be provided at a high frequency to produce equivalent levels of solute removal.

Definitive data to support many of the suspected advantages of cRRT are still lacking. In fact, Box 18.2 lists some of the disadvantages of cRRT. Interpretation of much of the published data has been hampered by retrospective analysis, the use of historical control groups, incomplete randomization, incomplete descriptions of patient populations and dialysis dose delivery, and study group–control group heterogeneity.

Box 18.2 Disadvantages of Continuous Renal Replacement Therapy (cRRT)