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THE PHYSIOLOGY OF RENAL REPLACEMENT THERAPY
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Renal replacement therapy (RRT), or “dialysis,” uses the basic concept of molecular movement across a semipermeable membrane to provide particle and water removal from the blood.1
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This requires two types of movements:
Diffusion: Solute exchange across a membrane between two solutions based on concentration gradient (from high to low concentration), permeability of the membrane, and surface area of the membrane
Used in HEMODIALYSIS or whenever a dialysate is used
Favors small particle movement
Faster movement with a large concentration gradient
Convection: Solute movement or “drag” with filtration across a membrane driven either by hydrostatic or osmotic pressures independent of concentration gradient
ULTRAFILTRATION: Water removal across a membrane using a pressure gradient
Particles AND water move together; if removing large amounts, will have to provide replacement fluid with electrolytes to compensate for filtration losses
Removes small and medium-sized particles; amount depends on amount of filtered water and the sieving coefficient of the membrane
Large particles will not be removed if they are larger than the pores of the membrane
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RENAL REPLACEMENT THERAPY MODALITIES
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PERITONEAL DIALYSIS (PD)
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Description: Uses the peritoneum as the membrane for both convection- and diffusion-based solute clearance. Need a healthy, intact peritoneum (no diaphragmatic hernias, adhesions, or active peritonitis).
Advantages: Can be run emergently and continuously without vascular access; PD catheters can be placed at the bedside percutaneously by the intensivist or interventional radiologist if pediatric surgeons are unavailable.
Indications: Efficacious in fluid overload and is less invasive and has little hemodynamic impact, making it safe in neonates and infants.
Complications: Hernias, peritonitis, hyperglycemia, respiratory compromise if giving dwells of more than 60 mL/kg, dialysate leakage, pleural effusions.
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INTERMITTENT HEMODIALYSIS (IHD)
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Description: Removes venous blood from the patient into an extracorporeal circuit past a membrane to provide mainly diffusion in a rapid manner via a 3- or 4-hour session
Advantages: Effective for small molecule clearance
Indications: Good for hyperkalemia, toxic exposures, tumor lysis syndrome
Considerations: Solute clearance depends on molecular weight, dialysate flow, membrane properties, and blood flow
Complications: Discussed in detail later
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CONTINUOUS RENAL REPLACEMENT THERAPY (CRRT)
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Description: Removes venous blood from the patient into an extracorporeal circuit past a membrane to provide diffusion and/or convention, intended to run 24 hours a day
Advantages: Provides slow, gentle adjustable removal of fluid and waste over time, more precise in reaching solute clearance and ultrafiltration goals than PD
Indications: Hemodynamically unstable patients, effective in all indications for RRT
Complications: Discussed in detail later
Types of CRRT
SCUF (slow continuous ultra-filtration): Free water and some small molecule clearance, no replacement fluid or dialysate is typically used
CVVH (continuous veno-venous hemofiltration): Convective-based solute clearance that requires replacement fluids
CVVHD (continuous veno-venous hemodialysis): Diffusion-based solute clearance, removes small particles down a concentration gradient; minimal convection
CVVHDF (continuous veno-venous hemodiafiltration): Both high-grade convection (replacement fluids) and diffusion (dialysate)
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INDICATIONS FOR RENAL REPLACEMENT THERAPY
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RRT is indicated emergently for any life-threatening changes in fluid, electrolyte, or acid–base balance.
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RECOMMENDED INDICATIONS FOR RRT IN CRITICALLY ILL CHILDREN
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Acute kidney injury with or without oliguria
Toxic ingestion
RRT modality: IHD is the preferred modality, may need to augment with CRRT to avoid rebound peak plasma levels in specific situations.
Considerations: The clearance of a drug depends on a sieving coefficient that is determined by molecular weight, charge, volume of distribution, and stoichiometry. Drugs that have a large volume of distribution, such as vancomycin, will take a long time to clear from the body.
The more protein-bound the drug, the harder it is to remove from the blood because of the molecular size of albumin, a large molecule. Using albumin 2 to 4 mg/dL in the dialysate can improve the efficiency of clearing protein-bound drugs.
Inborn errors of metabolism with hyperammonemia
Severe electrolyte imbalance refractory to medical therapy (hyperkalemia, hypercalcemia, hyperphosphatemia)
Symptomatic uremia: No longer using a strict numeric threshold to determine need for RRT for uremia
Fluid overload >10% to 15%: Equates to a positive fluid balance of >100 to 150 mL/kg; or fluid overload resistant to medical management and leading to systemic hypertension, edema, multiorgan failure, and/or cardiovascular instability
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CONTROVERSIAL USES OF RRT
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RRT has been used for immunomodulation in multiorgan failure due to septic shock. Studies have shown CRRT can remove some inflammatory mediators nonselectively; however, under closer investigation only a small percentage of cytokines is actually removed from plasma due to molecular size and structure. Despite adjusting modalities and filters, there have not been any reports of sustained or significant decreases in plasma cytokine levels using CRRT alone.2 There are neither supporting data nor current recommendations to use CRRT in children with septic shock without signs of AKI.
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WRITING A PRESCRIPTION FOR CONTINUOUS RENAL REPLACEMENT THERAPY
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The subspecialty in charge of ordering CRRT fluids, flow rates, and electrolyte composition is institution dependent. Pediatric intensivists are more commonly taking ownership in place of pediatric nephrologists, especially in hospitals where pediatric nephrologists are not available.
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Small-solute prescription is written in terms of volume of either dialysis fluid (diffusion) and/or replacement fluid (convection) as mL/kg/hr in adults or mL/1.73m2/hr in children. Typical CRRT flow rate is 2 to 2. 5 L/1.73 m2/hr divided between dialysate and replacement. This requires a blood flow rate of approximately 3 to 5 mL/kg/min.3 If using CRRT for hyperammonemia, the recommended flow rate is much higher at 8 L/1.73 m2/hr. Flow rates used in CRRT are slower than IHD but can achieve the same daily clearance over 24 hours with less metabolic variation from a single IHD session.
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If ordering CRRT, it is important to determine the daily fluid balance goal for your patient. When ordering this, divide the daily goal by 24 to obtain the hourly fluid removal goal. The bedside nurse will use this goal to adjust the amount of fluid removed every hour to adjust for large volume medications or blood products. Current recommendations in hemodynamically unstable children are to set the first 24-hour fluid goal at euvolemia and then begin gentle fluid removal over 48 to 72 hours.
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DIALYSATE OR REPLACEMENT FLUID COMPOSITION
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The primary electrolytes in standard solutions used for RRT are sodium, potassium, calcium, magnesium, chloride, glucose, and bicarbonate or lactate. There are commercially available solutions that differ in terms of electrolyte composition and the inclusion or exclusion of calcium. Electrolytes can be added to these base solutions to tailor the effects of CRRT to custom patient goals (Table 52-1).
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Heparin versus citrate: Heparin- and citrate-based protocols exist for anticoagulation to avoid circuit and filter clotting. Heparin requires systemic anticoagulation and can infer bleeding and drug-related risks. The current recommendation is to use citrate regional circuit anticoagulation in CRRT unless a contraindication exists, such as severe liver failure or previous citrate toxicity.
Citrate anticoagulation: When using citrate, calcium levels in the circuit and patient must be carefully monitored. The calcium bound by citrate in the circuit has to be returned to the patient via a continuous infusion of calcium chloride via an additional access point in the circuit after filtration or, if need be, via an additional central line.
Typical citrate rates are 1.5 times the blood flow rate.
Calcium infusion should run at approximately 0.4 times the citrate rate.
Flow rates of citrate should start at approximately 50% lower in neonates because hepatic metabolism of citrate is immature in this age group.
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TECHNICAL CONSIDERATIONS
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Obtaining venous access: Both intermittent hemodialysis and CRRT require temporary or permanent venous access (Table 52-2). The right internal jugular vein is the preferred site for placement, followed by the femoral veins. The subclavian should be used in emergency settings only. The catheter should be at least 10 to 14 French to allow adequate blood flow rates3; children under 30 kg will require smaller catheters based on weight.
Priming the circuit: The circuit must be filled with a fluid prior to initiation of CRRT. A typical CRRT circuit can hold approximately 120 to 200 mL of fluid. Normal saline is the fluid of choice if the volume in the circuit is a small percentage of the patient's blood volume. If circuit volume represents more than 10% of the patient's blood volume (which is 60–80 mL/kg), packed red blood cells (RBCs) are a more appropriate priming fluid to prevent hypotension and anemia. Depending on the modality of RRT and the type of circuit used, this could affect any patient less than 15 kg.
Temperature of fluids: Ensure all dialysate and replacement fluids are warmed up to 34.5°C to 37.5°C to avoid hemodynamic instability and hypothermia; higher temperature fluids also provide more efficient solute clearance.
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CHOOSING THE TIMING, DOSAGE, AND TYPE OF RENAL REPLACEMENT THERAPY
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“EARLY” VERSUS “LATE”
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Theoretically, initiating RRT prior to the onset of the damaging effects of metabolic derangements like uremia or fluid overload should provide a survival benefit for children requiring RRT. Retrospective adult data supported the use of early RRT and higher filtration rates in septic shock patients and were validated in two prospective randomized controlled trials (RCTs). However, starting RRT before AKI occurs is not recommended, as prophylactic RRT in adults at risk for AKI without evidence of azotemia provided no survival benefit.2
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Pediatric data have not been as conclusive about when to start RRT, except in cases of fluid overload (FO). The only consistent independent risk factor for mortality in children requiring RRT remains percent fluid overload at the time of RRT initiation.5 Estimated glomerular filtration rate (GFR), age, weight, urine output, diuretic use, and severity of illness are all not consistently significantly associated with mortality in pediatric patients with AKI on RRT. Data do agree that having FO greater than 10% to 20% from ICU admission to RRT initiation is an independent risk factor for mortality in several disease states, with an adjusted odds ratio of mortality as high as 8.5.6 Using CRRT to remove fluid after this threshold is passed does not lessen the mortality risk; only starting RRT before it is met does.1 Being 20% fluid overloaded equates to having a net fluid balance of 200 mL/kg.
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“HIGH DOSE” VERSUS “LOW DOSE”
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Two large randomized, multicenter adult studies—the Randomized Evaluation of Normal versus Augmented Level Renal Replacement Therapy (RENAL) Study and the Veterans Administration/ National Institutes of Health Acute Renal Failure Trial Network (ATN) Study—showed no survival or renal recovery benefit from increasing RRT above 20 to 25 mL/kg/hr of effluent flow.7 Although no prospective pediatric data exist, retrospective data show no outcome improvement associated with CRRT dose.8 The most recent Kidney Disease: Improving Global Outcomes (KDIGO) international consensus guidelines recommend delivering an effluent volume of 25 mL/kg/hr, which equates to the standard pediatric CRRT flow rate of 2 to 2.5 L/1.73m2/hr.4
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In theory, CRRT should provide more gradual solute and fluid removal leading to fewer episodes of renal and gastrointestinal (GI) ischemia to allow for faster recovery and improved survival than IHD. There are consistent data and strong recommendations for CRRT over IHD in cases of hemodynamic instability and cerebral edema because of avoidance of blood pressure variability and osmotic cellular shifts.9 Other indications are less clear.
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Prospective randomized adult studies suggest that use of IHD is associated with higher mortality than CRRT in critically ill patients. The RENAL and ATN studies also found that renal recovery and mortality were worse in patients receiving IHD versus CRRT even after adjusting for severity and organ-failure scoring.7 The conclusion of the adult data is that CRRT is the only appropriate strategy in critically ill patients at risk for hemodynamic instability if renal recovery is to be optimized.
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Recent advances in technology have changed the choice of RRT modality by pediatric nephrologists from predominantly PD to now most often CRRT. The Prospective Pediatric CRRT Registry provided data that shows that CRRT is safe and feasible in infants less than 10 kg irrespective of disease severity, contrary to initial beliefs. No prospective randomized pediatric studies exist that compare IHD to CRRT; however, in the critical care unit, CRRT is a safe and feasible option with less hemodynamic and metabolic impact and should be considered first in most circumstances.1 Choice of modality should also include consideration of the comfort of each institution's staff to administer the therapy. CRRT requires extensive resource utilization, knowledge, and comfort, which could overcome its potential benefit in certain clinical situations.
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PICU COMPLICATIONS FROM BLOOD-BASED RENAL REPLACEMENT THERAPY
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PEDIATRIC RRT OUTCOMES
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Renal Recovery: Use of RRT does not affect potential for recovery of renal function.
Mortality: Survival rates for critically ill children with AKI receiving RRT have not changed over the last few decades, persisting around 52%. Survival is lower in those receiving PD (49%–64%) and CRRT (34%–58%) than those receiving IHD (73%–89%).1
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TIMING OF COMPLICATIONS
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The risk of complications is greatest at the initiation of CRRT. It is essential for intensive care physicians to be at the bedside when starting CRRT to provide close monitoring of all vital signs, especially blood pressure, heart rate, oxygen saturation, and neurologic status. Rescue doses of calcium and vasopressors may be necessary depending on the stability of the patient.
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LIST OF COMPLICATIONS FROM CRRT OR IHD
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Related to catheter placement or maintenance: Infection, bleeding, thrombosis, pneumothorax, and the other complications associated with placement and maintenance of a large-bore central venous catheter
Hemodynamic instability: Especially upon initiation of CRRT from fluid shifts and inflammatory response
Disequilibrium syndrome: Only seen in IHD
Hypothermia
Air embolism
Anaphylaxis
Hemorrhage
Leukopenia
Electrolyte derangements: Most often sodium, phosphorous, and magnesium
Metabolic alkalosis: Caused by the normal hepatic metabolism of each citrate molecule into three bicarbonate molecules
Bradykinin release syndrome: Life-threatening allergic-type reaction causing rapid hypotension, rash, wheezing, and bradycardia
Mechanism: When acidic whole blood (used to prime a circuit or from the patient) comes in contact with a specific type of dialysis circuit, the AN-69, it can cause a massive bradykinin release. This leads to profound hypotension and an anaphylactic reaction.
Timing: Immediate, <5 minutes
Management: Treat like anaphylaxis. May be avoided by rinsing the membrane with bicarbonate, increasing the pH of the blood in circuit or patient, or avoiding use of the AN-69 membrane. The AN-69 membrane is specifically used in small patients and in septic shock as it supposedly provides optimal cytokine removal.
Citrate toxicity (previously “citrate lock”)
Mechanism: Occurs in patients on CRRT when the citrate infusion is not cleared by normal hepatic metabolism. Citrate then binds to free calcium and forms circulating complexes within the blood, raising the total calcium to very high levels. Ionized calcium should stay the same until more citrate accumulates; then is able to bind and it will start to fall. Tetany can result.
Management: Once total calcium exceeds 11.5 mg/dL, stop or decrease the citrate infusion and increase circuit clearance by higher dialysate or replacement flow rates.
Rapid clearance of medications
To assess if medication doses should be adjusted when on CRRT, go to the Dialysis of Drugs Handbook: http://www.seanmeskill.com/DialysisDrugs2010.pdf
REFERENCES
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Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120(4):179–184.