Replacement Fluids in Continuous Renal Replacement Therapy: A Contemporary Review

Dr Neeraj Manikath , claude.ai

Abstract

Continuous renal replacement therapy (CRRT) has become the cornerstone of renal support in critically ill patients. The selection and dosing of replacement fluids represent crucial determinants of therapeutic efficacy and patient outcomes. This review synthesizes current evidence on replacement fluid composition, prescription strategies, and emerging concepts to guide clinicians in optimizing CRRT delivery.

Introduction

The prescription of CRRT extends beyond simply choosing a modality; it encompasses critical decisions about replacement fluid characteristics and dosing that directly impact solute clearance, acid-base balance, electrolyte homeostasis, and ultimately, patient survival. With over 13% of ICU patients requiring renal replacement therapy and mortality rates remaining elevated at 40-60%, optimizing every aspect of CRRT prescription is paramount.[1,2]

Types of Replacement Fluids

Commercially Available Solutions

The landscape of replacement fluids has evolved significantly from early improvised solutions to sophisticated, buffered preparations. Modern commercially available solutions typically contain physiological concentrations of sodium (140 mmol/L), chloride (109-110 mmol/L), and varying buffer compositions.[3]

Buffer Systems:

1. Bicarbonate-based solutions: These have emerged as the preferred option in contemporary practice. The KDIGO guidelines recommend bicarbonate-buffered solutions over lactate-based alternatives due to superior hemodynamic stability and metabolic control.[4] Standard bicarbonate concentrations range from 32-35 mmol/L, though formulations with 22-25 mmol/L exist for patients with metabolic alkalosis.

2. Lactate-based solutions: While historically popular due to stability and shelf-life advantages, lactate metabolism requires hepatic function and can be impaired in shock states. Each molecule of lactate generates one bicarbonate molecule upon metabolism, but in patients with severe liver dysfunction or tissue hypoperfusion (lactate >5 mmol/L), accumulation may occur.[5]

3. Citrate-containing solutions: Regional anticoagulation protocols employ citrate, which provides both anticoagulation and buffering capacity. Each citrate molecule generates three bicarbonate equivalents upon metabolism, necessitating careful monitoring to avoid metabolic alkalosis.[6]

Pearl #1: In patients with severe lactic acidosis (lactate >10 mmol/L) or liver failure (INR >3), avoid lactate-buffered solutions entirely. Switch to bicarbonate-based replacement fluids to prevent lactate accumulation.

Customized Solutions

Some centers prepare customized replacement fluids using multi-chamber bags, allowing tailored electrolyte compositions for specific clinical scenarios:

• Hyperkalemia: Potassium-free solutions
• Hypophosphatemia: Phosphate-supplemented fluids (0.5-1.2 mmol/L)
• Dysnatremia: Adjusted sodium concentrations (120-160 mmol/L)

Oyster #1: Customized solutions increase complexity, cost, and risk of preparation errors. Reserve for patients with refractory electrolyte disturbances unmanageable with standard fluids and supplementation strategies.

Dosing Strategies

The Effluent Dose Concept

CRRT dose is prescribed as effluent flow rate normalized to body weight, typically expressed as mL/kg/h. Effluent encompasses both ultrafiltrate and dialysate, representing the total volume of blood "cleared" per unit time.[7]

Landmark Trials:

The ATN Study (2008) compared intensive (35 mL/kg/h) versus conventional (20 mL/kg/h) dosing in 1,124 critically ill patients, finding no mortality benefit with higher doses.[8] Similarly, the RENAL Study (2009) randomized 1,508 patients to 25 versus 40 mL/kg/h, again demonstrating no survival advantage.[9]

The IVOIRE Study (2013) specifically examined septic patients, comparing 70 mL/kg/h versus 35 mL/kg/h for the first 96 hours. Despite theoretical benefits of enhanced cytokine clearance, no mortality difference emerged.[10]

Current Recommendation: Based on this robust evidence, delivered dose of 20-25 mL/kg/h represents the evidence-based target.[4,11]

Hack #1: Prescribe 25-30 mL/kg/h to account for downtime. Studies show delivered dose averages 80-85% of prescribed dose due to circuit interruptions, clotting, and procedures. To achieve a delivered dose of 25 mL/kg/h, prescribe approximately 30 mL/kg/h.

Pre-dilution versus Post-dilution

The timing of replacement fluid administration profoundly affects efficiency:

Post-dilution: Replacement fluid is administered after the hemofilter. This maximizes solute clearance efficiency as blood concentration entering the filter remains undiluted. However, hemoconcentration increases filtration fraction (FF), elevating clotting risk when FF exceeds 25-30%.[12]

Pre-dilution: Fluid administration before the filter dilutes plasma, reducing clearance efficiency by approximately 15-20% but dramatically improving filter longevity by reducing FF to 15-20%. Pre-dilution is essential when using vascular access with high recirculation or when anticoagulation is contraindicated.[13]

Post-dilution clearance formula: Clearance ≈ Replacement fluid rate + Dialysate rate

Pre-dilution clearance formula: Clearance = (Replacement fluid rate × Blood flow rate) / (Blood flow rate + Replacement fluid rate) + Dialysate rate

Pearl #2: Use pre-dilution mode when filtration fraction exceeds 25% or when circuit lifespan is <24 hours. Increase the prescription by 20-30% to maintain equivalent solute clearance.

Weight Considerations

Dosing controversies persist regarding the appropriate weight denominator:

• Actual body weight: May overdose obese patients
• Ideal body weight (IBW): May underdose obese patients
• Adjusted body weight: IBW + 0.4 × (Actual - IBW)

The DO-RE-MI Study (2016) suggested using actual body weight up to 100 kg, then capping the dose, as clearance requirements plateau in extreme obesity.[14]

Hack #2: For patients >120 kg, use adjusted body weight or cap the prescribed dose at 3,000 mL/h to avoid excessive ultrafiltration and electrolyte depletion while maintaining adequate clearance.

Special Populations and Scenarios

Hypercatabolic States

Rhabdomyolysis, tumor lysis syndrome, and severe sepsis generate massive solute loads requiring enhanced clearance. Some experts advocate for higher doses (35-40 mL/kg/h) in these contexts, though RCT evidence is lacking.[15]

Pearl #3: In rhabdomyolysis with rapidly rising creatinine kinase (>50,000 U/L) or tumor lysis with refractory hyperkalemia/hyperphosphatemia, consider increasing CRRT dose to 35-40 mL/kg/h for the first 48-72 hours, then de-escalate as biochemical control is achieved.

Drug Dosing Considerations

CRRT significantly impacts pharmacokinetics of renally eliminated and highly water-soluble drugs. The effluent dose directly correlates with drug clearance.[16]

Critical drugs requiring adjustment:

• Beta-lactams: Dose for CrCl 30-50 mL/min with standard CRRT
• Vancomycin: Loading dose 25-30 mg/kg, maintenance based on levels (target trough 15-20 mg/L)
• Antifungals: Caspofungin unchanged; fluconazole requires doubling; voriconazole unchanged

Oyster #2: Drug dosing nomograms are based on prescribed, not delivered doses. Document actual delivered dose for pharmacists. Therapeutic drug monitoring is essential for aminoglycosides, vancomycin, and antiepileptics.

Fluid Balance Management

CRRT enables precise fluid management through net ultrafiltration rates. However, aggressive deresuscitation may harm:

The REVERSE Study (2020) suggested that negative fluid balance >50 mL/kg in the first week associated with increased mortality in CRRT patients.[17]

Hack #3: Target neutral to modestly negative fluid balance (-500 to -1,000 mL/24h) after initial resuscitation rather than aggressive deresuscitation. Monitor inferior vena cava collapsibility and dynamic fluid responsiveness parameters.

Electrolyte Management

Potassium

Standard replacement fluids contain 2-4 mmol/L potassium. Potassium-free solutions are essential for severe hyperkalemia (>6.5 mmol/L), but prolonged use causes rebound hypokalemia.

Pearl #4: Switch to potassium-containing (2-4 mmol/L) replacement fluid once serum potassium falls below 5.0 mmol/L to prevent rebound hypokalemia. Monitor potassium every 4-6 hours during the transition period.

Phosphate

Hypophosphatemia occurs in 50-80% of CRRT patients, as standard solutions are phosphate-free. Severe hypophosphatemia (<0.3 mmol/L) impairs respiratory weaning and increases mortality risk.[18]

Hack #4: Implement a protocolized phosphate supplementation strategy: Add 10-20 mmol sodium phosphate to each 5-liter replacement fluid bag when serum phosphate <0.6 mmol/L, aiming for targets of 0.8-1.2 mmol/L.

Calcium

Citrate anticoagulation necessitates calcium-free replacement fluids with separate systemic calcium replacement. Standard bicarbonate-buffered solutions contain 1.5-1.75 mmol/L calcium.

Pearl #5: In patients with severe hypocalcemia (ionized calcium <0.9 mmol/L) unrelated to citrate use, consider increasing replacement fluid calcium concentration or providing supplemental calcium chloride infusions, targeting ionized calcium 1.1-1.3 mmol/L.

Quality Indicators and Monitoring

Delivered Dose Verification

The prescribed dose often differs substantially from delivered dose due to:

• Circuit clotting and changes
• Interruptions for procedures/imaging
• Access flow limitations
• Downtime during nursing handovers

Hack #5: Calculate delivered dose daily using the formula: Delivered dose = (Total effluent volume in 24h / body weight in kg) / 24 hours

Document this in the medical record to ensure adequacy and guide prescription adjustments.

Circuit Lifespan

Optimal filter longevity (>48-72 hours) indicates effective anticoagulation, appropriate access, and proper fluid prescription. Frequent clotting (<24 hours) mandates evaluation of:

• Filtration fraction (should be <25%)
• Access flow adequacy (blood flow >150 mL/min)
• Anticoagulation efficacy
• Patient prothrombotic state

Emerging Concepts

High-Volume Hemofiltration (HVHF)

HVHF (>50 mL/kg/h) for septic shock has shown promise in small studies for cytokine removal and hemodynamic improvement, but the IVOIRE and EUPHRATES trials failed to demonstrate mortality benefits.[10,19]

Oyster #3: HVHF is resource-intensive, expensive, and unsupported by high-quality evidence for routine sepsis management. Reserve for exceptional circumstances in research protocols.

Hemoadsorption

Cytokine adsorption cartridges (CytoSorb) represent novel adjuncts, though evidence remains limited. The CYTRIS Trial showed no mortality benefit despite reducing IL-6 levels.[20]

Regional Citrate Anticoagulation Considerations

Regional citrate increases the buffering load. With standard citrate (4% trisodium citrate at 3-4 mmol/L blood flow), metabolic alkalosis develops in 20-30% of patients. This necessitates lower bicarbonate replacement fluids (18-22 mmol/L) or calcium-containing fluids with reduced buffer content.[6]

Practical Prescription Framework

Step 1: Choose replacement fluid based on:

• Liver function: Bicarbonate if impaired
• Acid-base status: Standard (32-35 mmol/L) for acidosis, low-bicarbonate (22-25 mmol/L) for alkalosis
• Anticoagulation: Citrate protocols require specific citrate-compatible solutions

Step 2: Calculate dose prescription:

• Standard: 25-30 mL/kg/h (accounting for 15-20% downtime)
• Obese patients: Use adjusted body weight or cap at 3,000 mL/h
• Hypercatabolic: Consider 35-40 mL/kg/h initially

Step 3: Select modality:

• CVVHDF (combined hemodialysis-filtration): Most efficient
• CVVH (hemofiltration): When dialysate unavailable
• Pre- vs post-dilution based on filtration fraction

Step 4: Customize electrolytes:

• Potassium: 0 mmol/L for K+ >6.5, then 2-4 mmol/L
• Phosphate: Supplement to maintain >0.6 mmol/L
• Calcium: Per citrate protocol or 1.5-1.75 mmol/L

Step 5: Monitor and adjust:

• Delivered dose calculation daily
• Electrolytes every 4-6 hours initially, then every 12 hours
• Acid-base status every 12-24 hours
• Circuit lifespan tracking

Conclusion

Replacement fluid selection and dosing represent fundamental yet complex aspects of CRRT prescription. Evidence firmly supports a delivered dose of 20-25 mL/kg/h, achieved through prescriptions of 25-30 mL/kg/h to account for downtime. Bicarbonate-buffered solutions offer advantages over lactate-based alternatives in most patients. Individualization based on body habitus, metabolic status, and specific clinical scenarios optimizes outcomes. Meticulous attention to delivered dose verification, electrolyte management, and acid-base balance distinguishes excellent from adequate CRRT provision. As technology evolves and evidence accumulates, continuous refinement of replacement fluid strategies will further improve outcomes in this vulnerable population.

References

1. Hoste EA, et al. Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med. 2015;41(8):1411-1423.

2. Bagshaw SM, et al. Prognosis for long-term survival and renal recovery in critically ill patients with severe acute renal failure: a population-based study. Crit Care. 2005;9(6):R700-709.

3. Gaudry S, et al. Optimisation of renal replacement therapy in intensive care. Ann Intensive Care. 2019;9(1):82.

4. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl. 2012;2:1-138.

5. Bellomo R, et al. Lactate and the kidney. Curr Opin Crit Care. 2002;8(6):517-523.

6. Oudemans-van Straaten HM, et al. Citrate anticoagulation for continuous venovenous hemofiltration. Crit Care Med. 2009;37(2):545-552.

7. Ronco C, et al. Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial. Lancet. 2000;356(9223):26-30.

8. VA/NIH Acute Renal Failure Trial Network. Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med. 2008;359(7):7-20.

9. RENAL Replacement Therapy Study Investigators. Intensity of continuous renal-replacement therapy in critically ill patients. N Engl J Med. 2009;361(17):1627-1638.

10. Joannes-Boyau O, et al. High-volume versus standard-volume haemofiltration for septic shock patients with acute kidney injury (IVOIRE study): a multicentre randomized controlled trial. Intensive Care Med. 2013;39(9):1535-1546.

11. Bellomo R, et al. Acute kidney injury in the ICU: from injury to recovery. Intensive Care Med. 2017;43(6):856-866.

12. Uchino S, et al. Pre-dilution vs. post-dilution during continuous veno-venous hemofiltration: impact on filter life and azotemic control. Nephron Clin Pract. 2003;94(4):c94-98.

13. Brunet S, et al. Diffusive and convective solute clearances during continuous renal replacement therapy at various dialysate and ultrafiltration flow rates. Am J Kidney Dis. 1999;34(3):486-492.

14. Honore PM, et al. Optimizing CRRT dosing in obese patients: the DO-RE-MI study insights. Crit Care. 2016;20:52.

15. Clark WR, et al. Quantification of hemodialysis: analysis of methods and the relevance to patient outcome. Blood Purif. 2018;45(1-3):129-136.

16. Roberts DM, et al. Therapeutic drug monitoring in critically ill patients on continuous renal replacement therapy. Crit Care. 2011;15(5):R134.

17. Murugan R, et al. Association of net ultrafiltration rate with mortality among critically ill adults with acute kidney injury receiving continuous venovenous hemodiafiltration. JAMA Netw Open. 2019;2(6):e195418.

18. Fiaccadori E, et al. Hypophosphatemia and phosphorus requirement in critically ill patients receiving CRRT. Curr Opin Crit Care. 2015;21(6):560-567.

19. Rimmelé T, Kellum JA. High-volume hemofiltration in the intensive care unit: a blood purification therapy. Anesthesiology. 2012;116(6):1377-1387.

20. Hawchar F, et al. Extracorporeal cytokine adsorption in septic shock: a proof of concept randomized controlled trial. JACC. 2019;73(6):654-665.