Formulating Initial CRRT Prescription and Anticoagulation Strategy

1. Introduction

Continuous renal replacement therapy (CRRT) is a cornerstone treatment for hemodynamically unstable patients with acute kidney injury. Critical care pharmacists drive safe, individualized prescriptions—optimizing solute clearance, fluid balance, circuit life, and bleeding risk.

Role of the Pharmacist and Key Outcomes

• Pharmacist’s Role: Design CRRT orders, select modality, adjust drug dosing based on CRRT parameters, and develop institutional protocols for CRRT management.
• Key Therapeutic Outcomes:
  • Adequate solute and fluid removal.
  • Maintenance of acid-base and electrolyte homeostasis.
  • Maximization of CRRT filter lifespan.
  • Minimization of bleeding complications associated with anticoagulation.

2. Effluent Dose Calculation

Effluent dose (mL/kg/hr) quantifies solute clearance in CRRT. Landmark trials (ATN, RENAL) and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend a target effluent dose of 20–25 mL/kg/hr. Higher dosing regimens have not demonstrated a mortality benefit and may increase risks.

• Definition: The effluent dose represents the total volume of fluid removed from the blood per unit of time, normalized to patient weight. It includes dialysate flow and replacement fluid flow.
• Formula: Effluent Dose (mL/kg/hr) = (Dialysate Rate [mL/hr] + Pre-filter Replacement Fluid Rate [mL/hr] + Post-filter Replacement Fluid Rate [mL/hr]) ÷ Patient Weight (kg).
• Target Range: Aim for a prescribed effluent dose of 20–25 mL/kg/hr. Routine escalation above 25 mL/kg/hr to compensate for anticipated filter downtime is generally not recommended.
• Delivered vs. Prescribed Dose: Monitor actual delivered dose, accounting for filter downtime. Adjust flow rates as needed to achieve the target delivered dose, rather than empirically overshooting the prescribed dose.

3. Replacement and Dialysate Fluid Selection

The choice of replacement fluid and/or dialysate is critical. Buffer type and electrolyte composition must be carefully selected to match the patient’s acid-base status, specific electrolyte derangements, and institutional product availability.

Buffer Options

• Bicarbonate-based fluids: Generally preferred due to their physiological nature and effectiveness in rapidly correcting metabolic acidosis.
• Lactate-based fluids: Can be used, but caution is advised in patients with severe liver dysfunction or profound shock, as lactate metabolism to bicarbonate may be impaired, potentially worsening lactic acidosis.
• Acetate-based fluids: Less commonly used; high concentrations can lead to vasodilation and hemodynamic instability.

Electrolyte Profiles

• Sodium: Typically 135–145 mmol/L, adjusted based on serum sodium.
• Potassium: Ranges from 0–4 mmol/L. Select a potassium concentration based on the patient’s serum potassium level and anticipated needs (e.g., potassium-free for hyperkalemia, 2-4 mmol/L for normokalemia or mild hypokalemia).
• Calcium and Magnesium: Concentrations should be tailored to the patient’s levels and the chosen anticoagulation strategy (especially important with regional citrate anticoagulation).
• Phosphate: Many commercial CRRT solutions are phosphate-free. Proactive supplementation, either via premixed phosphate-containing solutions or separate intravenous infusion, is often necessary to prevent hypophosphatemia.

Logistics and Monitoring

• Commercial Premixes: Utilize commercially available, standardized premixed solutions whenever possible to enhance safety and reduce compounding errors.
• Custom Compounding: If custom fluids are compounded, ensure clear labeling, adherence to sterile compounding practices, and verification of stability.
• Monitoring: Regularly monitor serum pH, electrolytes (sodium, potassium, calcium, magnesium, phosphate), and acid-base status (e.g., every 4–6 hours initially, then less frequently once stable) to guide adjustments in fluid composition.

4. Anticoagulation Strategies

Maintaining circuit patency while minimizing systemic bleeding risk is a crucial balancing act in CRRT. The choice of anticoagulation—regional citrate anticoagulation (RCA), systemic unfractionated heparin (UFH), or no anticoagulation—depends on patient-specific factors.

A. Regional Citrate Anticoagulation (RCA)

• Mechanism: Citrate is infused pre-filter, chelating ionized calcium (iCa) within the CRRT circuit, thereby inhibiting the calcium-dependent steps of the coagulation cascade. The citrated blood then passes through the filter. Most of the citrate-calcium complexes are removed by the effluent. The remaining citrate entering the patient is metabolized (primarily in the liver, muscle, and kidney) to bicarbonate. Systemic ionized calcium levels are maintained by a separate calcium infusion.
• Dosing: Citrate infusion rate is typically adjusted to achieve a pre-filter (circuit) iCa target of 0.25–0.35 mmol/L. Systemic iCa is maintained at 1.12–1.32 mmol/L via a continuous calcium chloride or calcium gluconate infusion. Initial citrate dose is often around 3-4 mmol/L of blood flow.
• Monitoring:
  • Pre-filter (circuit) and systemic ionized calcium levels (e.g., every 2-6 hours initially).
  • Total calcium to ionized calcium ratio (Total Ca/iCa ratio): A ratio >2.5 suggests citrate accumulation.
  • Serum pH, bicarbonate, anion gap, and sodium (risk of metabolic alkalosis, hypernatremia).
• Contraindications (Relative or Absolute): Severe liver failure (impaired citrate metabolism), pre-existing severe lactic acidosis, refractory hypotension (as large citrate loads can transiently decrease SVR).
• Advantages: Generally provides the longest filter lifespan and is associated with a lower risk of systemic bleeding compared to heparin. Often considered the first-line anticoagulation method by KDIGO.
• Disadvantages: Can cause metabolic complications (citrate toxicity/accumulation leading to metabolic alkalosis or, paradoxically, acidosis if severe; hypernatremia; hypocalcemia or hypercalcemia if not managed properly). Requires meticulous monitoring and a well-defined protocol.

B. Systemic Unfractionated Heparin (UFH)

• Mechanism: UFH potentiates the activity of antithrombin III, which then inactivates thrombin (Factor IIa) and Factor Xa, among other coagulation proteases, thus preventing clot formation systemically and within the circuit.
• Dosing: An optional initial bolus (e.g., 20–50 units/kg, though often omitted to reduce bleeding risk) followed by a continuous infusion (e.g., 5–15 units/kg/hr). Dose adjustments are based on coagulation monitoring.
• Monitoring:
  • Activated partial thromboplastin time (aPTT), with a target typically between 45–60 seconds.
  • Alternatively, anti-Factor Xa levels, with a target typically between 0.3–0.7 units/mL (may be preferred in settings of inflammation or lupus anticoagulant).
  • Platelet count monitoring (e.g., every 2–3 days) for surveillance of heparin-induced thrombocytopenia (HIT).
• Contraindications: Active bleeding, severe thrombocytopenia (e.g., platelets <50 ×10⁹/L, though thresholds vary), history of HIT, recent major surgery or trauma with high bleeding risk.
• Advantages: Simple to administer, widely available, relatively inexpensive, and has a rapid onset and offset of action. Reversible with protamine sulfate.
• Disadvantages: Increased risk of systemic bleeding, variable anticoagulant response requiring frequent monitoring and dose adjustments, and the potential for developing HIT.

C. No Anticoagulation

• Indications: Patients with severe underlying coagulopathy (e.g., liver failure with elevated INR), profound thrombocytopenia (e.g., platelets <30 ×10⁹/L), active major hemorrhage, or very high risk of bleeding where any anticoagulation is deemed unsafe.
• Strategies to Prolong Filter Life (if feasible):
  • Maintain high blood flow rates (e.g., ≥200 mL/min, if tolerated).
  • Utilize pre-filter replacement fluid (pre-dilution) to reduce hemoconcentration within the filter.
  • Perform regular saline flushes (though evidence for benefit is limited and may increase fluid load).
  • Schedule frequent filter inspections and consider elective filter changes.
• Risks: High likelihood of rapid filter clotting, leading to reduced delivered CRRT dose, increased blood loss with discarded circuits, and increased nursing workload due to frequent filter changes.

5. Algorithmic Approach to CRRT Prescription and Anticoagulation

A systematic, protocol-driven approach to initiating CRRT can help standardize care, minimize errors, and ensure all critical prescription components are addressed. This typically involves a stepwise process from indication assessment to ongoing monitoring and adjustment.

1. Assess Indication and Choose Modality: Confirm the indication for CRRT (e.g., severe AKI with uremia, refractory fluid overload, life-threatening electrolyte abnormalities, certain intoxications). Select the CRRT modality (e.g., CVVH, CVVHD, CVVHDF) based on primary therapeutic goals (solute clearance vs. fluid removal) and local expertise/protocols.
2. Calculate Effluent Dose: Target an effluent dose of 20–25 mL/kg/hr. Use actual body weight for most patients; consider ideal or adjusted body weight in patients with extreme obesity or significant edema, per institutional policy.
3. Select Replacement/Dialysate Fluid: Choose fluids with appropriate buffer (bicarbonate preferred) and electrolyte concentrations (sodium, potassium, calcium, magnesium, phosphate) tailored to the patient’s current laboratory values and metabolic status.
4. Determine Anticoagulation Strategy:
   • Regional Citrate Anticoagulation (RCA) is generally preferred if no contraindications (e.g., severe liver failure).
   • If RCA is contraindicated or not feasible, consider Systemic Unfractionated Heparin (UFH) if bleeding risk is acceptable.
   • If both RCA and UFH are contraindicated (e.g., high bleeding risk, HIT), opt for No Anticoagulation, employing strategies to maximize filter life.
5. Initiate Therapy and Implement Protocolized Monitoring: Start CRRT according to the prescribed settings. Implement a rigorous monitoring plan including:
   • Circuit pressures (access, return, transmembrane, effluent).
   • For RCA: Pre-filter iCa, systemic iCa, total Ca/iCa ratio, pH, anion gap.
   • For UFH: aPTT or anti-Xa levels, platelet counts.
   • General: Serum electrolytes, acid-base status, fluid balance, delivered effluent dose.
6. Adjust Settings Based on Delivered Dose and Laboratory Results: Continuously evaluate the effectiveness and safety of the CRRT prescription. Make adjustments to flow rates, fluid composition, and anticoagulation as needed based on delivered dose calculations, laboratory parameters, and patient’s clinical response.

6. Key Pearls and Pitfalls

Effective CRRT management requires vigilance to avoid common pitfalls related to prescription calculations, metabolic complications, and anticoagulation management. Proactive troubleshooting and a strong understanding of CRRT principles are essential for optimizing therapy and patient outcomes.

• Calculation Errors:
  • Pitfall: Incorrect patient weight (using outdated or estimated weights), errors in unit conversions (e.g., L/hr vs. mL/min), or miscalculation of effluent dose components.
  • Pearl: Always verify patient weight at CRRT initiation. Use standardized calculators or double-check manual calculations. Ensure clarity on whether actual, ideal, or adjusted body weight is being used per institutional protocol.
• Regional Citrate Anticoagulation (RCA) Pitfalls:
  • Pitfall: Development of metabolic alkalosis (from citrate metabolism to bicarbonate), hypernatremia (if citrate solution has high sodium content), hypocalcemia (if calcium replacement is inadequate), or citrate accumulation/toxicity (especially in liver failure, leading to a widened anion gap metabolic acidosis despite high systemic bicarbonate).
  • Pearl: Monitor acid-base status, electrolytes, and Total Ca/iCa ratio closely. Adjust citrate and calcium infusion rates proactively based on protocol and lab results. Recognize early signs of citrate accumulation (Total Ca/iCa >2.5).
• Systemic Unfractionated Heparin (UFH) Pitfalls:
  • Pitfall: Increased risk of systemic bleeding, development of Heparin-Induced Thrombocytopenia (HIT), or sub-therapeutic/supra-therapeutic anticoagulation due to variable patient response or drug interactions.
  • Pearl: Regularly assess for signs of bleeding. Monitor platelet counts for HIT surveillance. Use appropriate coagulation monitoring (aPTT or anti-Xa) with established target ranges and adjust heparin dose promptly. Be aware of altered heparin pharmacokinetics in critical illness.
• No Anticoagulation Pitfalls:
  • Pitfall: Frequent filter clotting leading to significant CRRT downtime, reduced delivered dose, increased blood loss, and higher nursing workload.
  • Pearl: Anticipate shorter filter lifespans. Maximize blood flow rates (if tolerated), consider pre-dilution if using CVVH/CVVHDF. Have a low threshold for filter changes to maintain effective therapy. Plan nursing resources accordingly.
• Communication and Collaboration:
  • Pitfall: Lack of clear communication between disciplines (nephrology, critical care, pharmacy, nursing) regarding CRRT goals, settings, adjustments, and monitoring, leading to errors or suboptimal management.
  • Pearl: Implement daily interdisciplinary rounds to discuss CRRT patients. Ensure meticulous documentation of all prescription parameters, adjustments, monitoring results, and rationale for changes. Foster a collaborative environment where all team members feel empowered to voice concerns.