Continuous Renal Replacement Therapy in Pediatric Patients

Introduction

Continuous renal replacement therapy (CRRT) is the preferred modality for the optimal management of fluid and electrolytes as well as nutritional support for children developing acute kidney injury (AKI) in the pediatric intensive care unit (PICU).

Recent awareness about the association between fluid overload (FO) and adverse outcomes in patients with AKI has led to a practice change resulting in the earlier use of CRRT even with mild to moderate FO. Despite the fundamentals of CRRT between adults and children being the same, there are some differences that exist in the utility of pediatric CRRT that relate to the size of the circuit, flow parameters, extracorporeal blood volume or blood priming, and vascular access. Inborn errors of metabolism as an indication for CRRT are exclusive to the pediatric population.

CRRTs, either as continuous venovenous hemofiltration (CVVH) or hemodiafiltration (CVVHD), are used frequently in critically ill children. Improving recognition of AKI in younger patients and increasing comfort with providing CRRT for neonatal patients have led to a shift toward offering this therapy to this population. Newly developed miniaturized machines like the Cardio-Renal Pediatric Dialysis Emergency Machine (Carpediem), the Newcastle Infant Dialysis and Ultrafiltration System (NIDUS), and Aquadex have shown success in the use of CRRT in critically ill neonates with extremely low birth weight (ELBW) as small as 800 g.

With the ever-increasing use of extracorporeal membrane oxygenation (ECMO) in children, the role of CRRT in combination and the potential complications that occur with its use need an understanding of the flow characteristics, the importance of circuit connections, and strategies to minimize complications.

Alternatives to CRRT like hemodialysis (HD) and peritoneal dialysis (PD) are not favorable for critically ill patients with hemodynamic instability. HD has the potential to also lead to disequilibrium, and PD can compromise the respiratory dynamics and is less effective in treating patients with exogenous intoxications and inborn errors of metabolism.

Indications and Options

The Prospective Pediatric Continuous Renal Replacement Therapy (ppCRRT) Registry is a multicenter collaborative registry that prospectively collected and analyzed data from children who received CRRT between 2001 and 2005 at 13 centers in the United States. They reported that 294/344 (86%) CRRTs were performed for FO, AKI, electrolyte abnormalities, or a combination of these. The other 50 (15%) CRRT procedures were for nonrenal indications, of which 21 (42%) were for inborn errors of metabolism, 18 (36%) were for drug toxicity, and 11 (22%) were for tumor lysis syndrome. Within these indications are use with patients on ECMO and liver failure molecular absorbent recirculating system (MARS).

CRRT is composed of and refers to a variety of modalities, continuous arteriovenous hemofiltration (CAVH), continuous arteriovenous hemodialysis (CAVHD), continuous arteriovenous hemodiafiltration (CAVHDF), CVVH, continuous venovenous hemodialysis (CVVHD), and continuous venovenous hemodiafiltration (CVVHDF). Historically, continuous arteriovenous therapies were employed, but with the advent of newer machinery and techniques, their use has declined appropriately. We will, therefore, not address the continuous arteriovenous therapies further. Defining and understanding the terminology employed with these technologies require an appreciation for some of the basic concepts underlying their utility.

Diffusion and/or convection may accomplish transport of solutes across semipermeable membranes. Both methods of solute transfer occur in the normal mammalian kidneys, with diffusion occurring in the tubules and convection primarily occurring in the glomerulus.

Diffusion, which is the predominant method utilized in HD, CVVHD, and partly in CVVHDF, refers to solute movement across a membrane (down a concentration gradient), resulting in the same concentration on either side of the membrane.

Dialysis is, in fact, solute removal by diffusion of the solute across a membrane (however, in clinical settings, dialysis usually means a combination of diffusion and convection). During dialysis, the electrolyte solution (dialysate) runs in the opposite direction (countercurrent) to blood flow, separated by a semipermeable membrane.

The rate of mass transfer/diffusion is determined by the characteristics of the solute (size, charge, protein binding), the dialysis membrane (type, porosity, thickness, surface area), the rate of solute delivery (blood flow rate and dialysate rate, which in turn helps generate concentration gradient), and the gradient of substance in the dialysate to blood.

Diffusion removes substances < 20 kDa (urea, creatinine, uric acid, ions, interleukin-6 [IL-6], endotoxin, heparin, pesticides, ammonia, most protein-bound drugs) and causes less damage to platelets and leukocytes but poorly removes larger molecules.

Convection is the movement of molecules through a semipermeable membrane associated with the fluid being removed during ultrafiltration (UF). The solute molecule is swept through a membrane by a moving stream of ultrafiltrate. Convective transport is independent of solute concentration gradients across the membrane. The porosity of the membrane determines which solutes are removed. Positive pressure is generated in the blood compartment by increasing the hydrostatic pressure in the blood compartment and increasing the rate of blood flow to the membrane, or the negative pressure in the dialysate compartment facilitates UF, created by decreasing the oncotic pressure of plasma by predilution.

Convection is a more effective method for fluid removal for middle-sized molecules (< 60 kDa) removed (i.e., mediators in sepsis), for example, IL-8, tumor necrosis factor (TNF), IL-10, IL-6, complement, eicosanoids, platelet-activating factor, and myocardial depressants.

Convection, CVVH and partly by CVVHDF, refers to the movement of solute together with solvent by means of filtration across a semipermeable membrane. This occurs in response to a transmembrane (TMP) pressure gradient.

1)Convection:

• Filtration is governed by Qf = Km TMP, where:

• Qf = filtration rate (mL/h), Km = membrane permeability coefficient, and TMP = transmembrane pressure (mm Hg) {TMP = Pb-Puf-p, where Pb = hydrostatic pressure of blood, Puf = hydraulic pressure of the dialysate/ultrafiltrate compartments and p = protein oncotic pressure}

• Solute transport is governed by Jc = UF(x) _uf , where:

• UF = ultrafiltrate volume and (x) _uf = solute x concentration in the ultrafiltrate

• Convective treatment clearance is represented by Kc = Qf(x) _uf /(x) _Pw , where:

• Qf = UF rate and (x) _uf /(x) _Pw = ratio of ultrafiltrate and plasma water solute concentrations (or the sieving coefficient [SC])

2)Diffusion:

• Solute transport is governed by Jd = DTA (dc/dx), where:

• Jd = solute flux, D = diffusion coefficient, T = solution temperature, A = membrane surface area, dc = concentration gradient between compartments and dx = membrane thickness

The generation of crystalloids and plasma water from whole blood across a semipermeable membrane in response to a TMP gradient is referred to as UF. During UF, passage of solutes across the membrane is based on their membrane SC.

SC is the ratio of the concentration of solutes in the ultrafiltrate to that of plasma. A high SC is desirable for middle molecules but undesirable for albumin sized molecules.

• SC = 1—describes complete permeability (for urea and creatinine)

• SC = 0—reflects complete impermeability

• SC > 1—requires an external energy source

During UF, the driving pressure forces solutes (such as urea and creatinine) against the membrane, and the solutes penetrate the pores of the membrane to an extent determined by the membrane SC for that molecule. Major factors determining SC include solute molecular size, protein binding, and filter porosity.

CVVH utilizes convection almost exclusively along with high UF rates. The ultrafiltrate produced is replaced completely or in part by sterile filter replacement fluid (Qf), also referred to as FRF. Patient weight loss results from the difference between UF and reinfusion rates. Replacement fluid can be administered either pre-membrane filter (predilutional) or post-membrane filter (postdilutional) ( Fig. 82.1 A ). Predilutional replacement is preferred for venous-venous circuits as it decreases the blood viscosity and may improve filter longevity as well as decrease anticoagulant requirements. Postdilution replacement is preferred for arteriovenous circuits and may result in improved solute clearance. Solute clearance is dependent on membrane surface area and blood flow rate. Accordingly, any factors that influence these parameters ultimately affect the efficiency of the prescription.

CVVHD offers primarily diffusive solute clearance through the use of dialysis fluid (Qd). The variables in solute clearance are blood flow, membrane surface area, and dialysate rate, but some convective clearance occurs with low-volume UF. The low-volume UF is directly related to fluid removal titrated to the desired patient weight loss plus removal of obligate fluids (medication drips, total parenteral nutrition [TPN], etc.) being provided to the patient. The general principles governing CRRT clearance are based on the same properties as intermittent HD (IHD). The dialysis fluid may be commercially made or custom made. In many cases, the components of the dialysate are identical to the filter replacement fluid utilized in CVVH ( Fig. 82.1 B).

CVVHDF offers both convective and diffusive solute clearance through the combination of dialysis fluid (Qd) and filter replacement fluid (Qf). This combination technique may offer an improved clearance rate of some intoxicants and middle molecules. Once again, fluid balance can be maintained or titrated to the desired rate by the administration of a sterile solution. Replacement fluid can be administered either pre-or postfilter. In this case, the UF rate would tend to be intermediate between the high volume seen in CVVH and the low (minimal) UF rate seen in CVVHD ( Fig. 82.1 C).

Prescription

Unlike chronic dialysis, there are no standard recommendations for targeted clearance (i.e., Kt/V). Intuitively, improved dialysis clearance would be associated with improved patient outcomes, although the data supporting this belief is limited. CVVH or CVVHD(F) offers excellent modes of continuous dialysis and are generally equally effective, with CVVH having some potential advantages for middle molecule clearance. The choice of modality is dependent, in part, on the method of anticoagulation and solutions used (Laliberte-Murphy, Palsson, and Niles 2001), as well as institutional pharmacy policies.

The rate of dialysis (Qd) with or without filter replacement fluid (Qf) can be referred to as the dialysis dose. The optimal dialysis dose is not known and likely varies depending on the clinical situation. There has been a trend toward increased dialysis dose rates in adult patients at the initiation of CRRT. Historically dialysis dose rates in adult centers were 1 L/h, but now typical prescriptions have flow rates between 1.5–2.0 l/h (Clark and Ronco 2000). Ronco et al. demonstrated that in adult patients with AKI, a Qf of at least 35 mL/h/kg was associated with improved patient survival. A subset of these patients was reevaluated, and in the setting of sepsis, a Qf of 45 mL/kg/h was associated with improved patient survival. Subsequently, two larger randomized trails, the RENAL and the ATN studies did not support an improved outcome with higher Qf rates. The inflammatory cascade in sepsis has become the target of recent treatment goals. Human studies have demonstrated that using high-volume hemofiltration (HVHF), targeting removal of either inflammatory or inciting molecules, decreased vasopressor requirements with trends toward improved survival in adult septic patients. Ratanarat et al. provided more support that pulse HVHF is effective in improving hemodynamic stability and improved survival in the septic patient. The Qf was 85 mL/kg/h for 6–8 hours daily until clinically stable. Pulse therapy appears to provide a similar outcome to 24-hour continued HVHF, with much less financial burden and workload on the support staff. The maximum Qf may be limited by the total UF rate allowed by the dialysis filter. In most children, achieving dialysis dose rates comparable to 35–45 mL/kg/h is readily obtainable. The author’s prescription in the setting of sepsis often consists of CVVHDF for the first 48–72 hours, with Qf 75% and Qd 25% of the total dialysis dose of 4 L/h/1.73 m ² . After this time period, therapy is transitioned to either CVVHD or CVVH, with a dialysis dose of 2 L/h/1.73 m ² .

While published guidelines for the implementation of pediatric CRRT do exist, most centers providing CRRT to children base it on their own experience and needs. The authors’ standard prescription for CVVHD has a blood flow rate of 3–5 mL/kg/min, with higher blood flow rates (6–10 mL/kg/min) being used in patients for whom anticoagulation is contraindicated or for whom high clearance rates are desirable. Filter replacement fluid (Qf), either pre- or postfilter or countercurrent dialysate (Qd), is delivered at 2 L/h/1.73 m ² . Indications for adjustments in dosing are addressed in the prior paragraph. Even though CVVHD is primarily a diffusion-based therapy, the prescriber must remember that some degree of convection therapy is present because of prescribed net fluid removal and removal of ongoing intravenous fluids being provided to the patient. Goldstein et al. described a mean contribution of 17% convection clearance to the total dose of dialysis in patients on CVVHD. Fluid removal is usually between 0.5 and 2.0 mL/kg/h, depending on patient volume status and hemodynamics. This rate is a direct extrapolation of work on HD by Donckerwolcke and Bunchman, who demonstrated this to be a safe and effective UF rate in pediatric HD. We have found that in some severely edematous patients, increasing pressor support to permit safe UF can be helpful in the initial 24–48 hours of CRRT, resulting in improved cardiac and pulmonary function as the patient’s degree of volume overload is reduced.

As in HD, the extracorporeal volume of the CRRT circuit should be < 10% of the patient’s blood volume. Patients less than 10 kg have blood volumes of about 80 mL/kg, while larger children have blood volumes closer to 70 mL/kg. Under circumstances where the patient's circuit volume is in excess of 10% of the patient's total blood volume, blood priming often becomes necessary. The packed red cells obtained from most blood banks possess a high hematocrit (HCT) level (around 50%–60%) and need to be reconstituted to around 30% with 0.9% saline in order to avoid clotting the circuit. Anticipation of the potential for the development of hypothermia in youngsters with a significant portion of their blood volume in the extracorporeal space is imperative. Under these circumstances, the use of patient warmers, heating pads applied to the circuit tubing, or manufactured blood warmers should be utilized.