Continuous Renal Replacement Therapy
Ashita J. Tolwani
Phuong-Chi T. Pham
Continuous renal replacement therapy (CRRT) is beneficial for hemodynamically unstable patients and generally provides better volume control than intermittent hemodialysis (IHD) in critically ill unstable patients with acute kidney injury (AKI).
CRRT provides better hemodynamic stability due to slower volume removal and solute removal per unit time as compared to IHD.
Observational studies demonstrate a trend for improved renal recovery with CRRT compared to IHD, but randomized controlled trials (RCTs) have not shown this.
Randomized studies have not shown a survival benefit with CRRT as compared to IHD.
CRRT is preferred in patients with acute liver failure, cardiogenic shock, septic shock, and multiorgan failure.
Indications for CRRT in patients with kidney failure include the following
Need for continuous solute control (e.g., tumor lysis syndrome, rhabdomyolysis)
Need for continuous volume control (e.g., heart failure, acute respiratory distress syndrome)
Increased intracranial pressure (ICP)
Slow correction of severe dysnatremias
High risk of osmotic disequilibrium with IHD
Disadvantages of CRRT compared with IHD
Intensive care unit (ICU) level care
Slower removal of toxins (which means that CRRT is not the RRT of choice for drug intoxications or severe hyperkalemia)
Anticoagulation is often needed.
Increased drug clearance with difficulty in dosing medications
TIMING: EARLY VERSUS LATE RRT
The optimal timing of RRT initiation remains undefined.
A 2019 meta-analysis on the timing of initiation of RRT in AKI involving 18 RCTs from 1997 to 2018, n = 2,856, showed no significant difference in mortality between early initiation and delayed initiation of RRT in both critically ill and community-acquired AKI patients, as well as in a subgroup of patients with sepsis and in cardiac surgery recipients. An early RRT strategy was associated with a significantly higher incidence of the need for RRT for AKI patients (relative risk [RR] 1.24, 95% confidence interval [CI]: 1.13 to 1.36, p < 0.01). That is, delayed start avoided RRT altogether in some patients because they were allowed the time to recover adequate kidney function (Yi L et al. Med (Baltimore)).
The international STARRT-AKI (Standard vs. Accelerated Initiation of RRT in Acute Kidney Injury) trial designed to determine whether accelerated initiation of RRT (aRRT, initiation of RRT within 12 hours after meeting eligibility criteria) reduces mortality compared to a standard strategy of RRT (sRRT, initiation based on conventional indications for AKI lasting >72h) revealed that aRRT was not associated with lower risk of death at 90 days compared with sRRT. Lower rates of adverse events and dependence on RRT were noted in the sRRT group.
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Determinants of the CRRT prescription include modality, dose, hemofilter selection, blood flow, anticoagulation, and fluid removal goals.
CRRT modality (Fig. 12.1)
Convective solute clearance
Continuous venovenous hemofiltration (CVVH)
Solutes removed: both small and middle molecular weight (MW) molecules up to potential size of 15 to 20,000 Da (e.g., myoglobin, β-2 microglobulin, inulin, B12, interleukin-8 [IL-8], tumor necrosis factor [TNF], IL-10, IL-6)
Operative fluid: replacement fluid (RF)
Diffusive solute clearance
Continuous venovenous hemodialysis (CVVHD)
Solutes removed: electrolytes, uric acid, urea, creatinine (up to molecular size of 500 to 1,000 Da)
Operative fluid: dialysate
Both convective and diffusive solute clearance
Continuous venovenous hemodiafiltration (CVVHDF)
Operative fluids: dialysate and RF
Placement of the RF for CVVH or CVVHDF can be prefilter or postfilter or both:
RF is infused into the arterial line (prefilter) prior to filtration at the hemofilter.
Disadvantages: Dilution of solute concentration reduces clearance.
Advantage: less ultrafiltration (UF) rate limitation and prolonged circuit life
RF is infused into venous line (postfilter) prior to returning blood into patient.
Disadvantage: UF rate is limited to a certain percentage of blood flow rate to prevent hemoconcentration and minimize the risk of hemofilter clotting.
Advantage: Clearance is directly related to UF rate.
All modalities are equally acceptable forms of CRRT.
No study has demonstrated a benefit from any specific modality of CRRT.
No study has demonstrated a benefit of convective over diffusive therapy.
Convective therapy may increase clearance of middle weight molecules but may also shorten filter life.
Slow continuous ultrafiltration (SCUF)
Modality used for plasma water removal with minimal solute clearance, blood flow is typically 100 to 250 mL/min.
High-volume hemofiltration (HVHF)
Using total UF rates >50 mL/kg/h has been suggested to be better in sepsis in observational studies due to removal of cytokines, but data from randomized trials have not shown any change in mortality.
Concerns with HVHF: loss of nutrients, protective molecules, and antibiotics
Current guidelines state an effluent flow rate of 20 to 25 mL/kg/h is sufficient, with care to ensure that the target dose of therapy is actually delivered. Target dose may not be achieved due to intermittent discontinuation of CRRT for procedures, clotting of filter, or any other reason.
In order to ensure delivery of the target dose, a prescription of a higher dose at 25 to 30 mL/kg/h may be needed.
All modalities of CRRT use high-permeability, high-flux biocompatible membranes.
Typical membrane materials used are polyacrylonitrile (AN69), polyarylethersulfone (PAES), and polyethersulfone (PES). There are no data suggesting that one type of membrane is better.
Because of their negative charge, polyacrylonitrile membranes may allow more adsorption and removal of middle MW solutes, such as cytokines. However, no difference in outcomes has been demonstrated.
The polyacrylonitrile membranes can cause bradykinin release. An untreated AN69 membrane should not be used in patients with recent or ongoing angiotensin-converting enzyme (ACE) inhibitor use, as this has been reported to cause anaphylaxis.
Low blood flow rates (<100 to 150 mL/min in adults) can increase hemofilter clotting due to stasis of blood and an increased filtration fraction (FF) (especially in convective modalities) because the FF is inversely proportional to the blood flow.
A higher blood flow rate (200 to 350 mL/min) may be required if anticoagulation is not used in order to maintain filter patency.
If citrate anticoagulation is used, blood flow rates < 150 mL/min are preferred to allow for lower citrate rates and to prevent high systemic citrate levels and associated adverse effects (see Complications of citrate below).
When using CVVHD or CVVHDF, the blood flow rate should be ≥ 2.5 times the dialysate flow rate. This allows for complete saturation of dialysate and preserves the linear relationship of dialysate rate and small solute clearance.
When using postfilter RF, the blood flow rate should be ≥5 times the RF rate to optimize the FF.
When using prefilter RF, the blood flow rate should be ≥6 times the RF rate to optimize solute clearance efficiency.
The blood flow rate does not affect hemodynamic stability because the volume of blood in the circuit at any one time does not change as blood flow rate changes.
Heparin (unfractionated heparin, low MW) or regional heparinization with protamine
Citrate (see sample of citrate anticoagulation protocol used at the University of Alabama in Appendix A)
Citrate versus heparin
Citrate binds ionized calcium (iCa2+) from the blood and inhibits the coagulation cascade. Infusion of citrate into the CRRT circuit (arterial blood) to achieve levels between 2 and 4 mmol/L reduces iCa2+ to <0.35 mmol/L and prolongs bleeding time to infinity. Normal plasma citrate level is ˜0.05 mmol/L. The blood returning
to the patient from the hemofilter combines with the mixed venous blood in the body and prevents systemic anticoagulation. A separate continuous systemic calcium infusion is required to replace the calcium lost in the effluent and to normalize the systemic ionized calcium (Fig. 12.2).
Citrate has been shown to confer higher filter life and lower need for blood transfusions (presumably due to lower bleeding complications) compared to heparin in multiple RCTs.
Citrate is cleared easily because of its small MW.
Citrate is not recommended with SCUF because minimal total UF rates limit citrate removal, resulting in a large load of citrate directly entering the patient’s blood.
Current Kidney Disease: Improving Global Outcomes Organization (KDIGO) suggests the use of regional anticoagulation with citrate.
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