2.4 Continuous Renal Replacement Therapy

Continuous Renal Replacement Therapy (CRRT) provides slow, continuous removal of fluid and solutes over 24 hours a day. Unlike traditional intermittent hemodialysis (IHD), which shifts massive fluid volumes over 3-4 hours, CRRT is hemodynamically tolerated by critically ill patients in shock on vasopressor support.

Mechanisms of Solute Clearance

Understanding how CRRT removes waste dictates the choice of modality and impacts drug dosing.

1. Diffusion: The movement of solutes across a semi-permeable membrane down a concentration gradient (from high to low concentration). Dialysate fluid is pumped counter-current to blood flow to maintain this gradient. Diffusion is highly efficient at removing small molecules (e.g., urea, creatinine, potassium, lithium).
2. Convection: Solute is dragged across the membrane along with plasma water in response to a hydrostatic pressure gradient. This bulk flow of fluid is called ultrafiltration. Convection is excellent at removing middle-to-large molecules (e.g., inflammatory cytokines, myoglobin, vancomycin). Because massive amounts of fluid are removed, a sterile "replacement fluid" must be infused back into the patient to prevent severe hypovolemia.
3. Adsorption: Solutes adhere to the membrane itself. This is a secondary mechanism that can clear certain inflammatory mediators and drugs, but the filter quickly becomes saturated.

CRRT Modalities

The specific CRRT modality dictates whether diffusion, convection, or both are utilized.

• SCUF (Slow Continuous Ultrafiltration): Uses only hydrostatic pressure to pull off fluid. No dialysate or replacement fluid is used. Primary goal: Volume removal only. Minimal solute clearance.
• CVVHD (Continuous Veno-Venous Hemodialysis): Uses dialysate fluid flowing counter-current to the blood. Primary mechanism: Diffusion. Excellent for small molecule clearance (e.g., severe hyperkalemia, uremia).
• CVVH (Continuous Veno-Venous Hemofiltration): Uses high rates of ultrafiltration to drag solutes across the membrane, coupled with the infusion of replacement fluid. Primary mechanism: Convection. Better for clearing larger molecules.
• CVVHDF (Continuous Veno-Venous Hemodiafiltration): Combines dialysate fluid and replacement fluid. Mechanisms: Diffusion and Convection. Provides maximum solute clearance across a wide range of molecular sizes.

Anticoagulation Strategies in CRRT

Blood clotting within the extracorporeal circuit (filter clotting) is the primary complication of CRRT. Maintaining circuit patency is crucial for effective therapy and minimizing blood loss.

Regional Citrate Anticoagulation (RCA)

RCA is the KDIGO guideline-preferred method for CRRT anticoagulation due to a lower risk of systemic bleeding compared to heparin.

• Mechanism: Calcium is a vital cofactor in the coagulation cascade. Citrate is infused into the blood as it enters the CRRT circuit (pre-filter), where it chelates (binds) ionized calcium, effectively paralyzing the clotting cascade within the filter.
• Systemic Reversal: Before the blood returns to the patient, a calcium infusion (calcium chloride or gluconate) is administered (post-filter) to restore systemic ionized calcium levels and systemic coagulability.
• Metabolism: The citrate-calcium complex enters the patient's systemic circulation, where the liver, skeletal muscle, and renal cortex metabolize the citrate into bicarbonate.
• Complications:
  • Hypocalcemia: If post-filter calcium replacement is inadequate.
  • Citrate Toxicity: Occurs in severe liver failure or shock when the body cannot metabolize citrate. Characterized by rising total calcium, dropping ionized calcium (Total Ca to iCa ratio > 2.5), and worsening metabolic acidosis.
  • Metabolic Alkalosis: If citrate is metabolized too rapidly into excessive bicarbonate.

Unfractionated Heparin

Heparin is infused continuously into the circuit. It is easy to use and monitor (via aPTT), but it provides systemic anticoagulation, significantly increasing the bleeding risk in critically ill patients. It also carries the risk of Heparin-Induced Thrombocytopenia (HIT).

Pharmacokinetic Considerations in CRRT

CRRT drastically alters the pharmacokinetics of many drugs, particularly antimicrobials. Pharmacists must adjust doses based on specific CRRT parameters.

Drugs that are heavily cleared by CRRT possess the following characteristics:

• Low Protein Binding: Only unbound, free drug can cross the filter membrane. Highly protein-bound drugs (e.g., ceftriaxone, phenytoin) are not effectively cleared by CRRT.
• Small Volume of Distribution (Vd): Drugs contained mostly within the plasma (low Vd) are easily accessible to the filter. Drugs distributed deep into tissues (e.g., amiodarone, azithromycin) have a high Vd and are poorly cleared.
• Low Molecular Weight: Smaller drugs are cleared more rapidly, particularly via diffusion (CVVHD). Convection (CVVH) expands the range to larger molecules.

The most important CRRT setting for determining drug clearance is the Effluent Flow Rate (the total volume of dialysate + replacement fluid + net fluid removal). Higher effluent rates result in higher drug clearance, necessitating higher or more frequent dosing.