CRRT Pharmacology

Clinical Overview

Continuous Renal Replacement Therapy (CRRT) profoundly alters drug pharmacokinetics through three primary mechanisms: convection (ultrafiltration/solute drag), diffusion (dialysis across concentration gradients), and adsorption (binding to filter membranes). The sieving coefficient (Sc) quantifies the fraction of unbound drug crossing the membrane, while the extraction ratio (ER) measures total drug removal from blood passing through the circuit. [1-3]

Drug removal varies significantly with CRRT modality (CVVH vs CVVHD vs CVVHDF), effluent dose (20-25 mL/kg/h standard in Australia/NZ per RENAL trial), membrane type (polysulfone, AN69, PMMA), protein binding, molecular weight, and volume of distribution. [4-6] Regional citrate anticoagulation further complicates pharmacology by altering hepatic drug metabolism and calcium-dependent processes. [7,8]

Key Clinical Challenge: Standard renal dosing nomograms designed for intermittent hemodialysis (IRRT) or estimated GFR substantially underdose antibiotics in CRRT, particularly beta-lactams and aminoglycosides, leading to treatment failure in critically ill septic patients. [9-11] Conversely, drugs with narrow therapeutic indices (aminoglycosides, vancomycin, levetiracetam) require therapeutic drug monitoring (TDM) to prevent toxicity. [12,13]

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Mechanisms of Drug Removal in CRRT

1. Convection (Ultrafiltration)

Convection is the primary clearance mechanism in CVVH and the dominant contributor in CVVHDF. Hydrostatic pressure drives plasma water across the semipermeable membrane, creating ultrafiltrate. Dissolved solutes are "dragged" along with the solvent (solute drag) regardless of concentration gradients. [14,15]

Efficiency: Convection is particularly effective for middle-molecular-weight solutes (500-5,000 Da) such as vancomycin (MW 1,449 Da), inflammatory cytokines, and β2-microglobulin. Small molecules (below 500 Da) and large molecules are cleared equally well by convection if the membrane pore size permits. [16,17]

Pre-dilution vs Post-dilution:

• Pre-dilution: Replacement fluid infused before the filter dilutes blood, reducing filter clotting but decreasing solute clearance by 15-20%. Requires higher effluent rates (typically 30-35 mL/kg/h) to achieve equivalent clearance.
• Post-dilution: Replacement fluid infused after the filter maximizes solute clearance but increases hemoconcentration, predisposing to filter clotting. [18,19]

Clinical Application: Vancomycin clearance by CVVH approximates 20-30 mL/min at standard effluent rates (20-25 mL/kg/h), necessitating higher doses than traditional "renal dosing" guidelines suggest. [20,21]

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2. Diffusion (Dialysis)

Diffusion is the primary clearance mechanism in CVVHD and a secondary contributor in CVVHDF. Solutes move across the membrane from high concentration (blood) to low concentration (dialysate) according to Fick's law. [22,23]

Efficiency: Diffusion excels at clearing small molecules (below 500 Da) such as urea (MW 60 Da), creatinine (MW 113 Da), electrolytes, and most antibiotics. Clearance decreases exponentially as molecular weight increases beyond 1,000 Da. [24,25]

Dialysate Flow Rate: Higher dialysate flow rates (1,500-2,500 mL/h) increase the concentration gradient and enhance diffusive clearance. However, above 2,000 mL/h, incremental gains diminish (saturation effect). [26,27]

Clinical Application: Beta-lactams (penicillins, cephalosporins, carbapenems) are efficiently removed by diffusion due to low protein binding and small molecular size. Meropenem clearance by CVVHD is 15-25 mL/min, requiring doses of 1g q8h or continuous infusion. [28,29]

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3. Adsorption

Adsorption is the binding of drugs (and inflammatory mediators) to the surface of the filter membrane. This is a saturable, time-dependent process most prominent in the first 6-12 hours of filter use, declining as binding sites become occupied. [30,31]

Membrane-Specific Effects:

• AN69 (polyacrylonitrile): High negative surface charge; strongly adsorbs positively charged molecules (aminoglycosides, vancomycin, cytokines). [32,33]
• Polysulfone: Hydrophobic; adsorbs lipophilic drugs (propofol, fentanyl, midazolam). [34,35]
• PMMA (polymethylmethacrylate): Moderate adsorption; β2-microglobulin removal. [36]

Clinical Impact: Adsorption contributes 10-30% of total drug clearance in the first 6-12 hours, then becomes negligible. TDM should be performed after 24 hours of stable CRRT to avoid overestimating clearance. [37,38]

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Sieving Coefficient (Sc) and Extraction Ratio (ER)

Sieving Coefficient (Sc)

The sieving coefficient quantifies the fraction of unbound drug that passes through the membrane into ultrafiltrate/dialysate. [39,40]

Sc = \frac{C_{ultrafiltrate}}{C_{plasma, unbound}}

Interpretation:

• Sc = 1.0: Drug crosses membrane freely (e.g., urea, creatinine, small unbound antibiotics).
• Sc = 0.8-0.9: Moderate restriction (e.g., vancomycin, aminoglycosides).
• Sc < 0.5: Significant restriction due to molecular size, protein binding, or membrane characteristics.
• Sc ≈ 0: Minimal clearance (e.g., highly protein-bound drugs like ceftriaxone, phenytoin). [41,42]

Key Determinants:

1. Protein Binding: Only the free (unbound) fraction is available for filtration. Drugs with greater than 90% protein binding (e.g., ceftriaxone 95%, ertapenem 95%) have minimal CRRT clearance despite small molecular size. [43,44]
2. Molecular Weight: Most CRRT membranes have a molecular weight cutoff (MWCO) of 20,000-40,000 Da, but clearance efficiency decreases above 1,000 Da due to membrane tortuosity. [45]
3. Membrane Pore Size: High-flux membranes (larger pores) permit greater clearance of middle-molecular-weight solutes. [46]

Clinical Example: Vancomycin (MW 1,449 Da, 30-55% protein-bound) has an Sc of 0.7-0.9 in CVVH, meaning 70-90% of unbound vancomycin in plasma appears in ultrafiltrate. [47,48]

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Extraction Ratio (ER)

The extraction ratio measures the fraction of drug removed from blood passing through the CRRT circuit, accounting for blood flow rate and filter efficiency. [49,50]

ER = \frac{C_{arterial} - C_{venous}}{C_{arterial}}

Typical Values:

• High ER (0.3-0.6): Small, unbound molecules (e.g., beta-lactams, aminoglycosides).
• Moderate ER (0.1-0.3): Middle-molecular-weight or moderately protein-bound drugs (e.g., vancomycin).
• Low ER (below 0.1): Highly protein-bound or large-volume-of-distribution drugs (e.g., digoxin, amiodarone). [51,52]

Relationship to Clearance:

CL_{CRRT} = ER \times Q_B

Where Q_B is blood flow rate (typically 150-250 mL/min in CRRT). [53]

Clinical Application: If vancomycin has an ER of 0.25 and Q_B = 200 mL/min, then CL_CRRT = 0.25 × 200 = 50 mL/min, equivalent to a GFR of 50 mL/min. This clearance is added to residual renal clearance and non-renal clearance to calculate total clearance. [54,55]

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CRRT Modality Comparison: CVVH vs CVVHD vs CVVHDF

Continuous Venovenous Hemofiltration (CVVH)

Mechanism: Pure convection. Ultrafiltrate is generated by hydrostatic pressure; replacement fluid is infused to maintain fluid balance. [56]

Drug Clearance: Optimal for middle-molecular-weight solutes (500-5,000 Da). Clearance is proportional to ultrafiltration rate (effluent dose). [57,58]

Effluent Dose:

• Standard: 20-25 mL/kg/h (RENAL trial, ATN trial: no benefit from higher doses). [4,59]
• High-volume CVVH (HVHF): 35-50 mL/kg/h; increases drug clearance by 40-100% but no mortality benefit and higher complications (hypophosphatemia, hypokalemia, nutrient losses). [60,61]

Antibiotic Clearance (at 25 mL/kg/h in 70 kg patient):

• Vancomycin: 1.5-2.0 L/h (25-33 mL/min)
• Gentamicin: 1.2-1.8 L/h (20-30 mL/min)
• Meropenem: 1.5-2.5 L/h (25-42 mL/min) [62,63]

Clinical Pearl: CVVH is preferred in hemodynamically unstable patients due to gradual fluid removal, but requires higher antibiotic doses than CVVHD due to efficient convective clearance. [64]

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Continuous Venovenous Hemodialysis (CVVHD)

Mechanism: Pure diffusion. Dialysate flows countercurrent to blood flow; no ultrafiltrate is generated (or minimal for fluid balance). [65]

Drug Clearance: Optimal for small molecules (below 500 Da). Clearance is proportional to dialysate flow rate (typically 1,500-2,500 mL/h). [66,67]

Antibiotic Clearance (at 2,000 mL/h dialysate):

• Vancomycin: 0.8-1.2 L/h (13-20 mL/min) — lower than CVVH due to reduced diffusion of MW 1,449 Da.
• Gentamicin: 1.5-2.0 L/h (25-33 mL/min) — similar to CVVH.
• Meropenem: 1.8-2.5 L/h (30-42 mL/min) — similar to CVVH. [68,69]

Clinical Pearl: CVVHD is less commonly used in Australia/NZ compared to CVVHDF. It may result in slightly lower vancomycin clearance than CVVH but similar beta-lactam clearance. [70]

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Continuous Venovenous Hemodiafiltration (CVVHDF)

Mechanism: Combined convection and diffusion. Dialysate flows countercurrent to blood; ultrafiltrate is also generated; replacement fluid is infused. [71,72]

Drug Clearance: Most efficient modality for both small and middle-molecular-weight solutes. Total clearance = diffusive clearance + convective clearance. [73,74]

Effluent Dose Calculation:

\text{Total Effluent} = \text{Dialysate Flow} + \text{Ultrafiltration Rate}

Example: Dialysate 1,500 mL/h + Ultrafiltration 500 mL/h = 2,000 mL/h total effluent (28 mL/kg/h in 70 kg patient). [75]

Antibiotic Clearance (at 25 mL/kg/h total effluent):

• Vancomycin: 2.0-2.5 L/h (33-42 mL/min) — highest clearance due to combined mechanisms.
• Gentamicin: 1.8-2.5 L/h (30-42 mL/min).
• Meropenem: 2.5-3.5 L/h (42-58 mL/min) — requires continuous infusion or q6h dosing. [76,77]

Clinical Standard: CVVHDF is the default modality in most Australian/NZ ICUs due to superior small and middle solute clearance. [78,79]

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High-Volume Hemofiltration (HVHF)

Definition: Ultrafiltration rates greater than 35 mL/kg/h, typically 50-70 mL/kg/h. [80,81]

Rationale: Early hypothesis suggested HVHF might remove inflammatory mediators (cytokines, DAMPs) and improve septic shock outcomes. [82,83]

Evidence:

• IVOIRE trial (2013): 70 mL/kg/h vs 35 mL/kg/h in septic shock; no mortality difference (32% vs 40%, p=0.12). [84]
• Meta-analyses: No survival benefit; increased complications (hypophosphatemia 80-90%, hypokalemia, hypothermia, filter clotting). [85,86]

Pharmacological Impact: HVHF doubles drug clearance compared to standard CRRT (20-25 mL/kg/h). [87,88]

Antibiotic Dosing in HVHF (50 mL/kg/h):

• Vancomycin: Loading 25-30 mg/kg, then 20 mg/kg q12h (vs q24h in standard CRRT). TDM essential.
• Meropenem: 2g q8h continuous infusion or 1g q6h.
• Piperacillin-Tazobactam: 4.5g q6h or continuous infusion 18g/day.
• Gentamicin: 7 mg/kg q24h with TDM (trough below 1 mg/L). [89,90]

Australian Context: HVHF is rarely used in routine practice post-IVOIRE trial. Standard effluent dose remains 20-25 mL/kg/h per ANZICS-CORE CRRT protocols. [91]

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Antibiotic Dosing in CRRT

Vancomycin

Pharmacokinetics:

• MW: 1,449 Da
• Protein binding: 30-55% (increases in critical illness due to hypoalbuminemia → higher free fraction → greater CRRT clearance). [92,93]
• Vd: 0.4-1.0 L/kg (increased in sepsis due to capillary leak).
• Normal t½: 4-6 hours; prolonged in AKI without CRRT to 48-72 hours. [94]

CRRT Clearance: 20-40 mL/min (varies with modality, effluent dose, membrane). CVVHDF clears vancomycin 30-50% more efficiently than CVVHD. [95,96]

Dosing Strategy (2020 ATS/IDSA Guidelines): [97]

1. Loading Dose: 25-30 mg/kg actual body weight (maximum 3,000 mg) to rapidly achieve target AUC. Do NOT reduce loading dose for CRRT.
2. Maintenance Dose: 15-20 mg/kg q12-24h based on:
   • Effluent dose (higher dose → q12h)
   • Residual renal function (CrCl greater than 20 mL/min → q12h)
   • TDM targets (AUC/MIC 400-600)
3. Therapeutic Drug Monitoring: Measure trough after 3rd-4th dose (steady state). Target trough 15-20 mg/L for serious infections. AUC-guided dosing preferred over trough-only (Bayesian software). [98,99]

Obesity: Use actual body weight for loading and maintenance dosing (vancomycin distributes into adipose tissue). [100]

Augmented Renal Clearance (ARC): If patient has residual GFR + CRRT, total clearance may approach 50-80 mL/min → higher doses required (20 mg/kg q12h). [101,102]

Toxicity: Target AUC below 600 to minimize vancomycin-associated acute kidney injury (V-AKI), especially in combination with piperacillin-tazobactam. [103,104]

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Beta-Lactams (Penicillins, Cephalosporins, Carbapenems)

Pharmacodynamics: Time-dependent killing. Efficacy correlates with fT>MIC (free time above MIC). Target 100% fT>MIC for bacteriostatic effect; 100% fTgreater than 4×MIC for bacterial eradication and resistance suppression. [105,106]

Common Issue: Standard renal dosing achieves below 40% fTgreater than 4×MIC in CRRT patients due to:

1. Increased Vd (capillary leak, fluid resuscitation).
2. Augmented clearance (residual renal function + CRRT clearance).
3. Hypoalbuminemia (increased free fraction → increased CRRT removal). [107,108]

Solution: Extended infusion (over 3-4 hours) or continuous infusion (over 24 hours) to maximize fT>MIC. [109,110]

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Meropenem

Pharmacokinetics:

• MW: 383 Da
• Protein binding: 2% (almost entirely free → highly cleared by CRRT).
• Vd: 0.2-0.4 L/kg (increased to 0.5-0.8 L/kg in sepsis).
• Sieving coefficient: 0.9-1.0 (freely crosses membrane). [111,112]

CRRT Clearance: 25-50 mL/min (equivalent to GFR 25-50 mL/min). [113]

Dosing:

• Standard CRRT (20-25 mL/kg/h): 1g q8h infused over 3 hours OR 0.5-1g loading, then 3g/day continuous infusion.
• High-effluent CRRT (greater than 30 mL/kg/h): 2g q8h extended infusion OR 6g/day continuous infusion.
• CNS infections: 2g q8h (meropenem has excellent CSF penetration). [114,115]

Stability: Stable for 6-8 hours at room temperature in 0.9% NaCl. For 24-hour continuous infusion, prepare fresh bag q8h or refrigerate. [116]

TDM: Recommended in severe sepsis/CNS infections. Target trough 8-16 mg/L (4× MIC for Pseudomonas MIC 2-4 mg/L). [117,118]

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Piperacillin-Tazobactam

Pharmacokinetics:

• MW: Piperacillin 517 Da, Tazobactam 322 Da.
• Protein binding: Piperacillin 30%, Tazobactam 30%.
• Sieving coefficient: 0.8-1.0 (both components freely cleared). [119,120]

CRRT Clearance: 30-60 mL/min (higher than meropenem due to larger Vd and faster elimination). [121]

Dosing:

• Standard CRRT: 4.5g q6h infused over 4 hours OR 4.5g loading, then 18g/day continuous infusion.
• High-effluent CRRT: 4.5g q4-6h OR continuous infusion 24g/day.
• Obesity: Use actual body weight for dosing (distributes into adipose tissue). [122,123]

Stability: Stable for 24 hours at room temperature in 0.9% NaCl (suitable for continuous infusion). [124]

Toxicity: Monitor for hypokalemia (distal tubular potassium wasting), bleeding (platelet dysfunction), drug fever, and hypersensitivity (5-8% cross-reactivity with penicillin allergy). [125,126]

Combination with Vancomycin: Increases risk of V-AKI by 2-3 fold. Avoid combination if possible; if necessary, optimize vancomycin AUC below 600. [127,128]

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Cefepime

Pharmacokinetics:

• MW: 481 Da
• Protein binding: 20%
• Sieving coefficient: 0.85-1.0 [129]

CRRT Clearance: 20-40 mL/min. [130]

Dosing:

• Standard CRRT: 2g q12h OR 1g loading, then 4g/day continuous infusion.
• High-effluent CRRT: 2g q8h. [131,132]

Neurotoxicity: Cefepime accumulation causes non-convulsive status epilepticus, encephalopathy, myoclonus, and seizures, especially in renal impairment. Risk factors: age greater than 65, pre-existing brain injury, hypoalbuminemia. [133,134]

TDM: Recommended in encephalopathy. Target trough below 20-30 mg/L to minimize neurotoxicity while maintaining efficacy (MIC for Pseudomonas typically 2-8 mg/L). [135,136]

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Aminoglycosides (Gentamicin, Tobramycin, Amikacin)

Pharmacodynamics: Concentration-dependent killing. Efficacy correlates with Cmax/MIC ratio. Target Cmax/MIC ≥8-10 for Gram-negative bacteria. [137,138]

Pharmacokinetics:

• MW: Gentamicin 478 Da, Amikacin 585 Da.
• Protein binding: below 10% (almost entirely free).
• Vd: 0.2-0.3 L/kg (extracellular fluid; increased 2-fold in sepsis).
• Sieving coefficient: 0.8-1.0 (freely cleared by CRRT). [139,140]

CRRT Clearance: 15-30 mL/min (approximately 50% of normal renal clearance). [141]

Dosing:

• Gentamicin/Tobramycin:
  • "Loading: 5-7 mg/kg ideal body weight (use adjusted body weight in obesity: IBW + 0.4 × (TBW - IBW))."
  • "Maintenance: 5-7 mg/kg q24-48h based on TDM."
• Amikacin:
  • "Loading: 25-30 mg/kg IBW/AdjBW."
  • "Maintenance: 15-20 mg/kg q24-48h based on TDM. [142,143]"

Therapeutic Drug Monitoring (ESSENTIAL): [144]

• Peak (1 hour post-infusion): Gentamicin 20-30 mg/L, Amikacin 60-80 mg/L.
• Trough (pre-dose): Gentamicin below 1 mg/L, Amikacin below 5 mg/L to minimize nephrotoxicity and ototoxicity.
• Extended-interval dosing: Measure mid-interval level (12-14 hours post-dose) and use Hartford nomogram to adjust interval.

Augmented Renal Clearance: Patients with residual GFR greater than 50 mL/min + CRRT may require q24h dosing with higher doses (7-8 mg/kg gentamicin). [145,146]

Toxicity: Nephrotoxicity (proximal tubular necrosis, often irreversible AKI), ototoxicity (vestibular > cochlear, irreversible), neuromuscular blockade (especially in myasthenia gravis, high doses, or concurrent neuromuscular blockers). [147,148]

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Fluoroquinolones (Ciprofloxacin, Moxifloxacin)

Pharmacodynamics: Concentration-dependent killing. Target AUC/MIC greater than 125 or Cmax/MIC greater than 10. [149,150]

Ciprofloxacin:

• MW: 331 Da
• Protein binding: 20-40%
• Vd: 2-3 L/kg (large Vd → minimal CRRT removal)
• Sieving coefficient: 0.6-0.8
• CRRT Clearance: 10-20 mL/min (minor contribution to total clearance). [151,152]
• Dosing: 400 mg IV q12h (no adjustment needed for CRRT). For severe Pseudomonas infections, consider 400 mg q8h. [153]

Moxifloxacin:

• MW: 401 Da
• Protein binding: 40-50%
• Vd: 1.7-2.5 L/kg
• CRRT Clearance: below 5 mL/min (negligible; primarily hepatic metabolism). [154,155]
• Dosing: 400 mg IV q24h (no adjustment for CRRT). [156]

Toxicity: QTc prolongation (moxifloxacin > ciprofloxacin), tendon rupture (Achilles), photosensitivity, C. difficile infection. Avoid in myasthenia gravis (worsens weakness). [157,158]

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Antifungals

Fluconazole

Pharmacokinetics:

• MW: 306 Da
• Protein binding: 11%
• Vd: 0.6-0.8 L/kg
• Sieving coefficient: 0.8-1.0 (freely cleared). [159,160]

CRRT Clearance: 15-25 mL/min (significant; fluconazole is primarily renally eliminated). [161]

Dosing:

• Loading: 800 mg (12 mg/kg) on Day 1.
• Maintenance CRRT: 400-800 mg q24h (6-12 mg/kg) depending on:
  • Effluent dose (higher dose → 800 mg q24h).
  • Site of infection (CNS, endocarditis → 800 mg q24h).
  • Candida species (MIC susceptibility). [162,163]

TDM: Target trough greater than 10-20 mg/L for invasive candidiasis. [164]

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Echinocandins (Caspofungin, Micafungin, Anidulafungin)

Pharmacokinetics:

• MW: 1,093-1,213 Da (large molecules)
• Protein binding: greater than 97% (highly protein-bound)
• Vd: 0.3-0.5 L/kg
• Sieving coefficient: below 0.1 (minimal CRRT clearance due to high protein binding and large MW). [165,166]

CRRT Clearance: below 5 mL/min (negligible). [167]

Dosing: No adjustment required.

• Caspofungin: 70 mg loading, then 50 mg q24h.
• Micafungin: 100 mg q24h (invasive candidiasis), 150 mg q24h (esophageal candidiasis).
• Anidulafungin: 200 mg loading, then 100 mg q24h. [168,169]

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Other Drugs in CRRT

Anticoagulants

Unfractionated Heparin (UFH)

Pharmacokinetics:

• MW: 3,000-30,000 Da (heterogeneous mixture)
• Protein binding: High (binds AT-III, endothelium, platelets)
• CRRT Clearance: Negligible (large MW, protein-bound). [170]

Dosing for Systemic Anticoagulation: Standard ICU protocols (no adjustment for CRRT).

Dosing for Circuit Anticoagulation:

• Pre-filter bolus: 2,000-5,000 units.
• Pre-filter infusion: 500-1,500 units/h titrated to circuit ACT 180-220 seconds or aPTT 45-60 seconds. [171,172]

Monitoring: Circuit aPTT (from pre-filter line) vs patient aPTT (from arterial line). Aim for therapeutic circuit aPTT with minimal systemic anticoagulation. [173]

Complications: Heparin-induced thrombocytopenia (HIT), bleeding (40-60% of CRRT patients experience bleeding events), filter clotting (filter life 24-36 hours with heparin vs 48-72 hours with citrate). [174,175]

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Enoxaparin

Pharmacokinetics:

• MW: 4,500 Da (average)
• CRRT Clearance: Minimal but measurable (anti-Xa activity reduced by 10-20% in CRRT). [176,177]

Dosing:

• VTE Prophylaxis: 40 mg SC q24h (no adjustment for CRRT).
• Therapeutic Anticoagulation: 1 mg/kg SC q12h (standard dosing; monitor anti-Xa levels if available). [178,179]

Monitoring: Target anti-Xa 0.6-1.0 units/mL (4 hours post-dose) for therapeutic anticoagulation. Anti-Xa levels may be lower than expected in CRRT due to increased clearance and increased Vd. [180]

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Regional Citrate Anticoagulation (RCA)

Mechanism: Citrate chelates ionized calcium in the circuit, preventing coagulation cascade activation. Citrate is metabolized to bicarbonate in the liver (Krebs cycle), releasing calcium. [181,182]

Pharmacological Impact:

1. Calcium-Dependent Enzymes: Reduced ionized calcium in the circuit may theoretically reduce activity of calcium-dependent drugs (e.g., calcium channel blockers), but systemic ionized calcium is maintained through calcium chloride infusion → minimal clinical impact. [183]
2. Hepatic Drug Metabolism: Citrate metabolism generates acetyl-CoA, which may upregulate CYP450 enzymes and increase hepatic clearance of certain drugs (theoretical; limited clinical evidence). [184]
3. Metabolic Alkalosis: Citrate metabolism generates 3 molecules of bicarbonate per citrate molecule → compensatory metabolic alkalosis (corrected by reducing dialysate/replacement fluid bicarbonate concentration). [185,186]
4. Citrate Accumulation: In liver failure (Child-Pugh C) or severe shock with hepatic hypoperfusion, citrate accumulates → hypocalcemia (total calcium elevated, ionized calcium low), metabolic acidosis, wide anion gap. [187,188]

Drug Dosing Adjustments: None required. Citrate does not significantly alter antibiotic or other drug clearance compared to heparin anticoagulation. [189,190]

Monitoring:

• Calcium ratio (total Ca : ionized Ca). Normal below 2.5. Ratio greater than 2.5 indicates citrate accumulation → stop citrate, switch to heparin or no anticoagulation. [191]
• Ionized calcium (systemic): Maintain 1.0-1.2 mmol/L via calcium chloride infusion.

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Antiepileptics

Levetiracetam

Pharmacokinetics:

• MW: 170 Da
• Protein binding: below 10%
• Vd: 0.5-0.7 L/kg
• Sieving coefficient: 0.9-1.0 (freely cleared). [192,193]

CRRT Clearance: 15-30 mL/min (significant — levetiracetam is 60% renally eliminated unchanged). [194]

Dosing:

• Loading: 1,000-1,500 mg IV (no adjustment).
• Maintenance CRRT: 500-1,000 mg q12h (vs 500 mg q12h in normal renal function). Higher doses required in CRRT than in ESRD without RRT. [195,196]

Neurotoxicity: Accumulation causes somnolence, behavioral changes, psychosis, myoclonus. Risk is lower in CRRT than in ESRD without RRT, but still occurs if dosing is excessive. [197,198]

TDM: Measure trough. Target 12-46 mg/L (therapeutic range). [199]

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Valproate

Pharmacokinetics:

• MW: 144 Da
• Protein binding: 90-95% (highly protein-bound; decreased to 80-85% in hypoalbuminemia → increased free fraction → increased CRRT clearance). [200,201]
• Vd: 0.1-0.5 L/kg

CRRT Clearance: 5-15 mL/min (low due to high protein binding, but increased in hypoalbuminemia). [202]

Dosing: 500-1,000 mg q8-12h IV (standard dosing; monitor levels). [203]

TDM: Measure total and free valproate levels. Total level 50-100 mg/L may correspond to free level 5-10 mg/L in normal albumin, but free level 10-20 mg/L in hypoalbuminemia → toxicity. Target free level 5-15 mg/L. [204,205]

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Sedatives and Analgesics

Propofol

Pharmacokinetics:

• MW: 178 Da
• Protein binding: 98%
• Vd: 2-10 L/kg (very large; lipophilic)
• CRRT Clearance: below 5 mL/min (negligible; primarily hepatic metabolism). [206,207]

Dosing: Standard ICU dosing (25-75 mcg/kg/min). No adjustment for CRRT. [208]

Propofol Infusion Syndrome (PRIS): Limit to below 4 mg/kg/h for below 48 hours. Monitor triglycerides, lactate, CK, ECG. CRRT does not remove propofol, so PRIS risk is unchanged. [209,210]

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Fentanyl

Pharmacokinetics:

• MW: 337 Da
• Protein binding: 80-85%
• Vd: 3-6 L/kg (very large; lipophilic)
• CRRT Clearance: below 5 mL/min (negligible). [211,212]

Dosing: Standard ICU dosing (25-200 mcg/h infusion). No adjustment for CRRT. [213]

Clinical Pearl: Fentanyl accumulates in adipose tissue and muscle during prolonged infusions → prolonged awakening after discontinuation (unrelated to CRRT). [214]

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Midazolam

Pharmacokinetics:

• MW: 326 Da
• Protein binding: 95-97%
• Vd: 1-3 L/kg
• CRRT Clearance: below 5 mL/min (negligible; hepatic metabolism to active metabolites). [215,216]

Dosing: Standard ICU dosing (1-5 mg/h). No adjustment for CRRT. [217]

Active Metabolites: α-hydroxymidazolam (50% activity of parent drug) accumulates in renal failure → prolonged sedation. CRRT removes metabolites slowly (MW 342 Da, protein-bound). [218,219]

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Vasopressors and Inotropes

General Principle: Vasopressors and inotropes have large volumes of distribution, extensive tissue binding, or rapid metabolism → negligible CRRT clearance. [220,221]

Milrinone Exception: Renally eliminated (80% unchanged in urine). [222,223]

Dosing in CRRT:

• Loading: 25 mcg/kg over 10 minutes (consider omitting loading dose to avoid hypotension).
• Maintenance: 0.25-0.375 mcg/kg/min (vs 0.5 mcg/kg/min in normal renal function). [224,225]

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Therapeutic Drug Monitoring (TDM) in CRRT

Indications for TDM: [226,227]

1. Narrow therapeutic index: Aminoglycosides, vancomycin, digoxin, phenytoin, valproate, theophylline.
2. High inter-patient variability: Beta-lactams in sepsis, levetiracetam.
3. Treatment failure: Subtherapeutic levels suspected.
4. Toxicity: Symptoms of drug toxicity (neurotoxicity, nephrotoxicity).
5. Altered pharmacokinetics: Obesity, ARC, hypoalbuminemia, high-effluent CRRT.

Timing of Sampling: [228,229]

• Trough levels (pre-dose): Vancomycin, aminoglycosides, beta-lactams.
• Peak levels (1 hour post-infusion): Aminoglycosides (concentration-dependent killing).
• Steady-state: After 3-5 half-lives (e.g., vancomycin steady state ~24-48 hours in CRRT).
• Post-filter stabilization: Delay TDM for 24 hours after CRRT initiation (adsorption effect wanes). [230]

Interpretation:

• Subtherapeutic levels: Increase dose or shorten interval. Consider continuous infusion for beta-lactams.
• Supratherapeutic levels: Decrease dose or prolong interval. For aminoglycosides, extend interval to q48-72h if trough greater than 1 mg/L.

Bayesian Dosing Software: Preferred over empiric dosing for vancomycin, aminoglycosides. Uses patient-specific covariates (age, weight, CRRT settings) and measured levels to predict optimal dosing. [231,232]

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Dosing Nomograms and Calculators

Limitations of Fixed Nomograms: [233,234]

• Assume standard CRRT settings (e.g., 20-25 mL/kg/h effluent), but actual settings vary (15-40 mL/kg/h).
• Do not account for:
  • Residual renal function (may add 20-50 mL/min clearance).
  • Augmented renal clearance (CrCl greater than 130 mL/min in 20-65% of ICU patients).
  • Hypoalbuminemia (increased free fraction → increased CRRT clearance).
  • Obesity (altered Vd).
  • Downtime (filter clotting, procedures → intermittent CRRT → lower average clearance). [235,236]

Recommended Resources:

1. Kidney Disease: Improving Global Outcomes (KDIGO): AKI guidelines with drug dosing appendix. [237]
2. UpToDate Drug Dosing in RRT: Regularly updated, includes CRRT-specific recommendations.
3. Renal Drug Database (University of Ghent): Subscription-based; comprehensive CRRT dosing.
4. ANZICS CORE CRRT Protocols: Australian/NZ-specific protocols (20-25 mL/kg/h standard). [238]

Manual Calculation (when nomograms unavailable): [239,240]

CL_{total} = CL_{CRRT} + CL_{residual renal} + CL_{non-renal}

CL_{CRRT} = Sc \times Q_{effluent}

Example (Gentamicin in CVVHDF):

• Sc = 0.9
• Effluent dose = 25 mL/kg/h × 70 kg = 1,750 mL/h = 29 mL/min
• CL_CRRT = 0.9 × 29 = 26 mL/min
• Residual renal CL = 0 (anuric)
• Non-renal CL = 2-3 mL/min
• Total CL = 26 + 0 + 3 = 29 mL/min

Dosing interval:

\tau = \frac{Vd \times \ln(C_{max}/C_{min})}{CL_{total}}

Assume Vd = 0.3 L/kg × 70 kg = 21 L, Cmax = 20 mg/L, Cmin = 1 mg/L:

\tau = \frac{21 \times \ln(20/1)}{29 \times 60 \times 10^{-3}} = \frac{21 \times 3.0}{1.74} = 36 \text{ hours}

Dose = 5 mg/kg q36h (round to q24-48h based on TDM).

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Australian and New Zealand Context

ANZICS-CORE CRRT Protocols [241,242]

Standard Effluent Dose: 20-25 mL/kg/h based on RENAL trial (2009, PMID 19812446). [4]

• RENAL trial: 1,508 patients randomized to 25 mL/kg/h vs 40 mL/kg/h. No difference in 90-day mortality (44.7% vs 44.7%, p=0.99), renal recovery, or ICU length of stay. Higher dose increased hypophosphatemia. [243]

Modality: CVVHDF preferred (85% of Australian ICUs). [244]

Anticoagulation: Regional citrate first-line (60% of centers); heparin second-line (30%); no anticoagulation third-line (10% — if bleeding risk). [245,246]

Indigenous Health Considerations: [247,248]

• Aboriginal and Torres Strait Islander Australians: 3-5× higher incidence of ESRD (diabetic nephropathy, hypertensive nephropathy, glomerulonephritis). AKI requiring CRRT is also more common (1.5-2× incidence).
• Cultural Communication: Involve Aboriginal Health Workers (AHWs) in discussions about RRT initiation, goals of care, and transition to maintenance dialysis.
• Remote/Rural CRRT: Limited availability in remote Northern Territory, Western Australia, Queensland. Royal Flying Doctor Service (RFDS) retrieval to tertiary centers required. Drug dosing during transport: use portable CRRT machines (CARPEDIEM, Prismaflex portable) or hold antibiotics for below 6 hours (beta-lactams), give loading dose before transfer (vancomycin).

Māori Health Considerations (New Zealand): [249,250]

• Higher ESRD incidence: 2-3× higher than non-Māori due to diabetic nephropathy, hypertensive nephropathy.
• Whānau (family) involvement: Include whānau in CRRT initiation discussions, TDM result interpretation, transition to chronic dialysis.
• Tikanga (cultural protocols): Respect karakia (prayer) before procedures, acknowledge kaumātua (elders), involve Māori health navigators.

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Exam Practice: Short Answer Questions (SAQs)

SAQ 1: Antibiotic Dosing in CRRT (15 marks)

Scenario: A 75 kg male with septic shock and AKI is on CVVHDF (effluent dose 25 mL/kg/h, regional citrate anticoagulation). Blood cultures grow Pseudomonas aeruginosa (meropenem MIC 2 mg/L). Serum albumin 20 g/L, residual urine output 0 mL/day.

Questions:

1. What are the three mechanisms of drug removal in CRRT? (3 marks)
2. Calculate the expected CRRT clearance of meropenem. Explain your reasoning. (4 marks)
3. What is your meropenem dosing regimen? Justify your choice. (5 marks)
4. Would you recommend TDM for meropenem? Why or why not? (3 marks)

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Model Answer:

1. Mechanisms of drug removal (3 marks):

• Convection (ultrafiltration): Solute drag across membrane with plasma water driven by hydrostatic pressure. Effective for small and middle-molecular-weight solutes. [1 mark]
• Diffusion (dialysis): Solute movement down concentration gradient from blood to dialysate. Most effective for small molecules (below 500 Da). [1 mark]
• Adsorption: Drug binding to filter membrane surface. Saturable process, most prominent in first 6-12 hours. Membrane-dependent (AN69 > polysulfone). [1 mark]

2. Expected CRRT clearance of meropenem (4 marks):

Meropenem pharmacokinetics: [0.5 marks]

• MW 383 Da (small molecule)
• Protein binding 2% (almost entirely free)
• Sieving coefficient 0.9-1.0 (freely crosses membrane)

Calculation: [1.5 marks]

• Effluent dose = 25 mL/kg/h × 75 kg = 1,875 mL/h = 31.25 mL/min
• CL_CRRT calculation = 0.95 × 31.25 = 30 mL/min

Total clearance: [1.5 marks]

• Residual renal clearance = 0 (anuric)
• Non-renal clearance = 10-15 mL/min (hepatic metabolism, biliary excretion)
• Total clearance = 30 + 0 + 12 = 42 mL/min (approximately 50% higher than standard "severe renal impairment" assumptions)

Interpretation: [0.5 marks] CRRT contributes 70% of total meropenem clearance in this patient.

3. Meropenem dosing regimen (5 marks):

Target: 100% fTgreater than 4×MIC (4 × 2 mg/L = 8 mg/L continuous trough). [1 mark]

Rationale for extended/continuous infusion: [1.5 marks]

• Meropenem exhibits time-dependent killing (efficacy correlates with fT>MIC).
• Standard intermittent boluses (1g q8h over 30 min) achieve trough below 4 mg/L in CRRT due to increased clearance and hypoalbuminemia (increased free fraction).
• Extended/continuous infusion maintains stable concentrations above target.

Recommended regimen: [1.5 marks]

• Option 1: 1g loading dose (infused over 30 min), then 1g q8h infused over 3 hours (prolongs time above MIC).
• Option 2 (preferred): 1g loading dose, then 3-4g/day continuous infusion (100% fT>MIC guaranteed).

Stability consideration: [0.5 marks] Meropenem is stable for 6-8 hours in 0.9% NaCl at room temperature. For continuous infusion, prepare fresh bag q8h or refrigerate syringe.

Adjust for obesity/ARC: [0.5 marks] If patient had residual renal function (CrCl greater than 50 mL/min) or obesity, consider higher dose (2g q8h or 6g/day continuous infusion).

4. TDM for meropenem (3 marks):

Recommend TDM: YES (in certain circumstances). [1 mark]

Rationale: [1.5 marks]

• High-MIC pathogen (MIC 2 mg/L is at susceptibility breakpoint for Pseudomonas; EUCAST breakpoint ≤2 mg/L). Target 4× MIC requires trough 8 mg/L.
• Hypoalbuminemia increases free fraction → increased CRRT clearance → risk of subtherapeutic levels.
• High inter-patient variability in critically ill patients (Vd 0.2-0.8 L/kg, clearance 20-60 mL/min).

TDM target: [0.5 marks]

• Measure trough (steady state after 24 hours of continuous infusion).
• Target trough 8-16 mg/L (4-8× MIC for Pseudomonas MIC 2 mg/L).

When TDM is NOT necessary:

• Susceptible organism (MIC below 0.5 mg/L).
• Empiric therapy only (de-escalation planned once cultures finalize).
• Resource-limited settings without access to beta-lactam assays.

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SAQ 2: Citrate Anticoagulation and Drug Metabolism (15 marks)

Scenario: A 68-year-old woman with septic shock and AKI is commenced on CVVHDF with regional citrate anticoagulation (effluent dose 25 mL/kg/h, citrate infusion 3 mmol/L). On Day 3 of CRRT, she develops confusion and myoclonus. Vancomycin was dosed as 1g loading, then 1g q24h (no levels measured).

Laboratory results:

• Total calcium 3.0 mmol/L (↑)
• Ionized calcium 0.8 mmol/L (↓)
• Albumin 25 g/L
• pH 7.28, lactate 4.5 mmol/L, anion gap 24 mmol/L

Questions:

1. What is the most likely diagnosis? Explain the pathophysiology. (4 marks)
2. Does citrate anticoagulation significantly affect drug clearance in CRRT? (3 marks)
3. What is the differential diagnosis for confusion and myoclonus in this patient? (4 marks)
4. Outline your management plan. (4 marks)

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Model Answer:

1. Most likely diagnosis: Citrate accumulation (4 marks)

Diagnosis: [1 mark] Citrate toxicity/accumulation secondary to impaired hepatic citrate metabolism.

Pathophysiology: [3 marks]

• Citrate (trisodium citrate) is infused into the pre-filter circuit to chelate ionized calcium → prevents coagulation cascade activation in the circuit. [0.5 marks]
• Citrate-calcium complexes are removed by CRRT into effluent. [0.5 marks]
• Citrate that enters the systemic circulation is normally metabolized by the liver (Krebs cycle) to 3 molecules of bicarbonate + release of calcium. [0.5 marks]
• In hepatic dysfunction (cirrhosis, acute liver failure) or hepatic hypoperfusion (shock, high lactate 4.5 mmol/L), citrate metabolism is impaired → citrate accumulates. [0.5 marks]
• Accumulated citrate continues to chelate systemic ionized calcium → hypocalcemia (ionized Ca 0.8 mmol/L). [0.5 marks]
• Citrate itself is an organic anion → contributes to high anion gap metabolic acidosis (AG 24). [0.5 marks]

Diagnostic Criteria: [included in pathophysiology marks]

• Total calcium : ionized calcium ratio greater than 2.5 (3.0 / 0.8 = 3.75 — highly suggestive).
• Metabolic acidosis + high anion gap + hyperlactatemia (citrate metabolism produces lactate as intermediate).

2. Effect of citrate on drug clearance (3 marks):

Short answer: Citrate anticoagulation does NOT significantly alter drug clearance in CRRT. [1 mark]

Evidence: [1.5 marks]

• Multiple pharmacokinetic studies comparing citrate vs heparin anticoagulation show no significant difference in antibiotic clearance (vancomycin, beta-lactams, aminoglycosides) when CRRT settings (modality, effluent dose, blood flow) are controlled. [0.5 marks]
• Sieving coefficients for most drugs are unchanged by citrate vs heparin. [0.5 marks]
• Filter lifespan is longer with citrate (48-72 hours vs 24-36 hours with heparin), which may result in more consistent drug clearance over time (less downtime). [0.5 marks]

Theoretical concerns (limited clinical evidence): [0.5 marks]

• Citrate metabolism generates acetyl-CoA, which may upregulate hepatic CYP450 enzymes → theoretical increase in hepatic drug metabolism. However, this has not been demonstrated clinically for antibiotics or common ICU drugs.
• Calcium-dependent enzyme activity (e.g., calcium channel blockers) is unaffected because systemic ionized calcium is maintained via calcium chloride infusion.

Clinical recommendation: Use standard CRRT-based drug dosing regardless of anticoagulation method (citrate vs heparin).

3. Differential diagnosis for confusion and myoclonus (4 marks):

Differential diagnosis (any 4 of the following, 1 mark each):

1. Citrate toxicity: Hypocalcemia (ionized Ca 0.8 mmol/L) causes neuromuscular irritability, confusion, tetany, seizures, myoclonus. Supported by Ca:iCa ratio 3.75. [1 mark]

2. Uremic encephalopathy: AKI with inadequate CRRT clearance → accumulation of uremic toxins (urea, guanidinosuccinic acid, β2-microglobulin). Myoclonus, asterixis, confusion, seizures. Check urea level. [1 mark]

3. Drug accumulation:

   • Vancomycin: Dosed 1g q24h without TDM. If levels are supratherapeutic (greater than 30-40 mg/L), can cause ototoxicity and mild neurotoxicity (rare). [0.5 marks]
   • Other drugs: Levetiracetam (if prescribed), opioids (fentanyl metabolites), benzodiazepines (midazolam metabolites accumulate in renal failure). [0.5 marks]

4. Septic encephalopathy: Septic shock with multiorgan failure → systemic inflammation, blood-brain barrier disruption, cytokine-mediated neuronal dysfunction. Fluctuating consciousness, confusion, no focal signs. [1 mark]

5. Metabolic disturbances:

   • Hypomagnesemia (common in CRRT; removed by dialysis) → myoclonus, seizures. [0.5 marks]
   • Hypoglycemia or hyperglycemia. [0.5 marks]

6. Hypoperfusion/ischemia: Hypotension (septic shock) → watershed infarcts, hypoxic-ischemic encephalopathy.

7. Cerebral edema (if severe AKI → uremia → osmotic shifts).

Investigations to differentiate:

• Magnesium, glucose, phosphate.
• Vancomycin trough level (if greater than 40 mg/L, consider vancomycin toxicity; if 10-20 mg/L, less likely).
• Urea (if greater than 30-40 mmol/L despite CRRT, suggests inadequate clearance).
• Arterial blood gas (worsening acidosis suggests citrate toxicity or sepsis).
• EEG (if non-convulsive status epilepticus suspected).

4. Management plan (4 marks):

Immediate management (within 1 hour):

1. Stop citrate anticoagulation [1 mark]

   • Switch to heparin anticoagulation (if no contraindication) or no anticoagulation (if high bleeding risk).
   • Expect filter life to decrease (24-36 hours vs 48-72 hours), but patient safety is priority.

2. Correct hypocalcemia [0.5 marks]

   • Calcium chloride 10%: 10-20 mL IV over 10 minutes (monitor for arrhythmias, especially if on digoxin).
   • Recheck ionized calcium q1-2h. Target ionized Ca 1.0-1.2 mmol/L.

3. Optimize CRRT clearance [0.5 marks]

   • Ensure effluent dose 25 mL/kg/h (adequate urea/toxin clearance).
   • Check circuit pressures, blood flow (ensure no recirculation/clotting).

4. Review drug levels [0.5 marks]

   • Vancomycin trough (urgent if available): If greater than 30-40 mg/L, hold next dose.
   • Magnesium, phosphate (replace if low).

5. Supportive care for myoclonus [0.5 marks]

   • Benzodiazepines (midazolam 2-5 mg IV PRN) for severe myoclonus/seizure prophylaxis.
   • Avoid levetiracetam or valproate until drug-related causes excluded.

Subsequent management (6-24 hours):

6. Monitor for citrate clearance [0.5 marks]

   • Citrate has t½ 30-60 minutes (if hepatic function normal). Symptoms should improve within 2-4 hours of stopping citrate.
   • If symptoms persist greater than 6 hours, consider alternative diagnoses (uremic encephalopathy, septic encephalopathy, non-convulsive status).

7. Re-dose vancomycin [0.5 marks]

   • If trough is subtherapeutic (below 10 mg/L), resume dosing.
   • If trough is 10-20 mg/L (therapeutic), continue q24-48h dosing.
   • If trough is greater than 30 mg/L, hold dose until trough below 20 mg/L, then resume at lower dose/longer interval.

8. Assess suitability for ongoing CRRT [0.5 marks]

   • If citrate toxicity recurs despite stopping citrate → investigate for hepatic dysfunction (INR, bilirubin, transaminases).
   • If liver failure (Child-Pugh C, INR greater than 2.5, lactate persistently greater than 4 mmol/L), citrate is contraindicated → use heparin or no anticoagulation.

Prevention (future patients):

• Screen for citrate contraindications: liver failure (Child-Pugh C), severe shock with lactate greater than 5 mmol/L, hepatic ischemia.
• Monitor Ca:iCa ratio q4-6h during citrate CRRT. Stop citrate if ratio greater than 2.5.

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Exam Practice: Viva Scenarios

Viva Scenario 1: CRRT Drug Dosing Principles (20 marks)

Examiner Opening: "I'd like to discuss the pharmacological principles of drug dosing in patients receiving continuous renal replacement therapy. Let's start with the basics."

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Examiner: What are the three primary mechanisms by which drugs are removed during CRRT?

Expected Answer (3 marks): The three mechanisms are:

1. Convection (ultrafiltration): Solute drag across the membrane with plasma water driven by hydrostatic pressure. Most effective for small and middle-molecular-weight solutes. Predominant in CVVH and CVVHDF. [1 mark]
2. Diffusion (dialysis): Solute movement down a concentration gradient from blood to dialysate. Most effective for small molecules (below 500 Da). Predominant in CVVHD and CVVHDF. [1 mark]
3. Adsorption: Drug binding to the filter membrane surface. Saturable and time-dependent, most significant in the first 6-12 hours. Membrane-specific (AN69 adsorbs aminoglycosides; polysulfone adsorbs lipophilic drugs). [1 mark]

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Examiner: What is the sieving coefficient? How is it calculated?

Expected Answer (2 marks): The sieving coefficient (Sc) quantifies the fraction of unbound drug that passes through the CRRT membrane into ultrafiltrate or dialysate. [1 mark]

Sc = \frac{C_{ultrafiltrate}}{C_{plasma, unbound}}

• Sc = 1.0: Drug crosses freely (e.g., urea, small unbound antibiotics).
• Sc = 0: Minimal clearance (highly protein-bound drugs).
• Sc depends on molecular weight, protein binding, and membrane pore size. [1 mark]

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Examiner: A patient is on CVVHDF with an effluent dose of 25 mL/kg/h (body weight 80 kg). You're dosing piperacillin-tazobactam. The sieving coefficient is 0.9. What is the CRRT clearance of piperacillin?

Expected Answer (3 marks):

Step 1: Calculate effluent rate. [0.5 marks]

• Effluent dose = 25 mL/kg/h × 80 kg = 2,000 mL/h = 33.3 mL/min.

Step 2: Calculate CRRT clearance. [1 mark]

CL_{CRRT} = Sc \times Q_{effluent} = 0.9 \times 33.3 = 30 \text{ mL/min}

Step 3: Interpret. [1.5 marks]

• Piperacillin CRRT clearance is 30 mL/min, equivalent to a GFR of 30 mL/min.
• Piperacillin is primarily renally eliminated (68% unchanged in urine), so this represents a significant contribution to total clearance.
• Total clearance = CRRT clearance + residual renal clearance + non-renal clearance (hepatic/biliary ~10-15 mL/min).
• If the patient is anuric, total clearance ≈ 30 + 0 + 12 = 42 mL/min.

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Examiner: How does CVVHDF differ from CVVH in terms of drug clearance?

Expected Answer (2 marks):

CVVHDF (Continuous Venovenous Hemodiafiltration): [1 mark]

• Combines diffusion and convection.
• Most efficient for both small molecules (diffusion) and middle-molecular-weight solutes (convection).
• Total clearance = diffusive clearance + convective clearance.
• Higher drug clearance than CVVH or CVVHD alone for most drugs (especially middle MW like vancomycin).

CVVH (Continuous Venovenous Hemofiltration): [0.5 marks]

• Pure convection.
• Effective for middle-molecular-weight solutes (500-5,000 Da).
• Less efficient for small molecules unless effluent rate is very high.

Clinical Implication: [0.5 marks] CVVHDF generally requires higher antibiotic doses than CVVH for drugs like vancomycin (which benefit from both diffusion and convection).

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Examiner: Let's discuss vancomycin specifically. What factors affect vancomycin clearance in CRRT?

Expected Answer (3 marks):

Vancomycin characteristics: [0.5 marks]

• MW 1,449 Da (middle molecule)
• Protein binding 30-55% (only unbound fraction cleared)
• Vd 0.4-1.0 L/kg (increased in sepsis/capillary leak)

Factors affecting CRRT clearance: [2.5 marks, 0.5 marks each]

1. CRRT modality: CVVHDF > CVVH > CVVHD (diffusion + convection most efficient).
2. Effluent dose: Higher effluent rates (30-40 mL/kg/h) increase clearance proportionally.
3. Protein binding: Hypoalbuminemia (common in critical illness) → increased free fraction → increased CRRT clearance.
4. Membrane type: High-flux membranes (larger pore size) increase middle-molecule clearance. AN69 membranes adsorb vancomycin in first 6-12 hours.
5. Pre-dilution vs post-dilution: Pre-dilution dilutes blood → reduces clearance by 15-20% compared to post-dilution.

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Examiner: What is your vancomycin dosing regimen for a 75 kg patient on CVVHDF (25 mL/kg/h) with septic shock and no residual renal function?

Expected Answer (4 marks):

Loading Dose: [1 mark]

• 25-30 mg/kg actual body weight (2020 ATS/IDSA guidelines).
• 25 mg/kg × 75 kg = 1,875 mg (round to 2,000 mg or two 1,000 mg vials).
• Infuse over 1-2 hours (avoid Red Man Syndrome from rapid infusion).
• Do NOT reduce loading dose for CRRT (loading dose targets Vd, not clearance).

Maintenance Dose: [1.5 marks]

• 15-20 mg/kg q12-24h.
• Initial dose: 15 mg/kg × 75 kg = 1,125 mg (round to 1,000-1,250 mg) q12h.
• Choose q12h (vs q24h) because:
  • Standard effluent dose (25 mL/kg/h) → vancomycin clearance ~20-30 mL/min.
  • No residual renal function → CRRT is sole route of clearance.
  • Septic shock → increased Vd → faster distribution.

Therapeutic Drug Monitoring: [1 mark]

• Measure trough (pre-dose) after 3rd-4th dose (steady state ~24-48 hours).
• Target trough 15-20 mg/L for serious infections (bacteremia, pneumonia, endocarditis).
• Preferably use AUC-guided dosing (Bayesian software): Target AUC/MIC 400-600.
• Recheck levels q3-5 days or if CRRT settings change (effluent dose, modality).

Adjust for toxicity: [0.5 marks]

• If trough greater than 20 mg/L or AUC greater than 600, reduce dose or prolong interval (vancomycin-associated AKI risk).

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Examiner: Moving on to beta-lactams. Why is continuous infusion preferred over intermittent boluses for meropenem in CRRT?

Expected Answer (3 marks):

Pharmacodynamics: [1 mark]

• Meropenem (and all beta-lactams) exhibit time-dependent killing.
• Efficacy correlates with fT>MIC (percentage of time free drug concentration exceeds MIC).
• Target: 100% fT>MIC for bacteriostatic effect; 100% fTgreater than 4×MIC for bacterial eradication and resistance suppression.

Problem with intermittent boluses in CRRT: [1 mark]

• Meropenem has low protein binding (2%) → highly cleared by CRRT (clearance 25-50 mL/min).
• Intermittent boluses (e.g., 1g q8h over 30 min) produce high peak concentrations but low trough concentrations (below 4 mg/L at 8 hours).
• If MIC is 2-4 mg/L (common for Pseudomonas, Acinetobacter), trough may fall below MIC for 30-50% of the dosing interval → treatment failure.

Advantage of continuous infusion: [1 mark]

• Maintains stable concentration above MIC for 100% of the time (100% fT>MIC).
• Allows use of same total daily dose as intermittent (e.g., 3g/day continuous vs 1g q8h intermittent).
• Reduces peak concentrations → potentially lower risk of dose-related toxicity (seizures, though rare).

Practical considerations:

• Stability: Meropenem stable for 6-8 hours in 0.9% NaCl at room temperature → prepare fresh bag q8h or refrigerate for 24-hour infusion.
• Compatibility: Compatible with most IV fluids; avoid mixing with calcium-containing solutions.

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Closing Prompt: "Thank you, that's excellent. Let's move on to discuss a clinical case involving therapeutic drug monitoring..."

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Viva Scenario 2: Therapeutic Drug Monitoring and Complex Dosing (20 marks)

Examiner Opening: "I'd like to present a case and discuss therapeutic drug monitoring in CRRT. A 65-year-old man (weight 90 kg, height 175 cm) with diabetic ketoacidosis complicated by septic shock and AKI is on CVVHDF (effluent dose 30 mL/kg/h, regional citrate anticoagulation). He has no residual urine output. Blood cultures grow E. coli ESBL-producer (meropenem MIC 0.5 mg/L). You start meropenem 1g q8h (intermittent infusion). On Day 3, the patient is not improving clinically."

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Examiner: What are your concerns about the current meropenem dosing?

Expected Answer (3 marks):

Concerns: [3 marks, 1 mark each]

1. High effluent dose (30 mL/kg/h) increases meropenem clearance:

   • Standard dosing assumes effluent 20-25 mL/kg/h.
   • 30 mL/kg/h × 90 kg = 2,700 mL/h = 45 mL/min effluent.
   • Meropenem Sc ~0.95 → CRRT clearance = 0.95 × 45 = 43 mL/min.
   • Total clearance = 43 (CRRT) + 0 (anuric) + 10-15 (hepatic) = 53-58 mL/min (much higher than anticipated).

2. Intermittent infusion may produce subtherapeutic trough levels:

   • Target 100% fTgreater than 4×MIC = 4 × 0.5 = 2 mg/L.
   • With clearance 55 mL/min and intermittent q8h dosing, trough at 8 hours may be below 2 mg/L → subtherapeutic.

3. Increased volume of distribution in DKA and sepsis:

   • DKA: osmotic diuresis (before AKI) → total body water depletion → but septic shock + resuscitation → capillary leak → increased Vd for hydrophilic drugs (meropenem).
   • Vd may be 0.5-0.8 L/kg (vs normal 0.2-0.4 L/kg) → loading dose may have been insufficient.

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Examiner: You decide to perform therapeutic drug monitoring. When would you measure the level, and what is your target concentration?

Expected Answer (3 marks):

Timing of TDM: [1.5 marks]

• Measure trough (pre-dose, just before 4th or 5th dose) to ensure steady-state achieved.
• Steady state is reached after 3-5 half-lives. Meropenem t½ in CRRT ≈ 3-4 hours → steady state by 12-20 hours.
• Practical: Measure trough at 24-48 hours after initiation.

Target concentration: [1.5 marks]

• Trough target: 2-8 mg/L (1-4× MIC for MIC 0.5 mg/L; ideally 4× MIC = 2 mg/L).
• For severe sepsis or resistant organisms, target 8-16 mg/L (higher multiples of MIC).
• If continuous infusion is used, measure mid-infusion level (any time at steady state): Target 8-16 mg/L.

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Examiner: The trough level comes back at 1.2 mg/L. What do you do?

Expected Answer (3 marks):

Interpretation: [0.5 marks] Trough 1.2 mg/L is subtherapeutic (below target 2 mg/L for 4× MIC).

Management options: [2.5 marks]

Option 1: Increase dose (intermittent): [1 mark]

• Increase to 2g q8h (infused over 30 min - 1 hour).
• This doubles the dose, which should approximately double the trough (predict trough ~2.4 mg/L).
• Recheck trough after 2-3 doses.

Option 2: Shorten interval: [0.5 marks]

• Change to 1g q6h (increases frequency by 33%).
• Less practical (more nursing workload), but may achieve steadier levels.

Option 3: Switch to continuous infusion (PREFERRED): [1 mark]

• Give 1g loading dose (if last dose was greater than 4 hours ago), then start 4-6g/day continuous infusion.
• 4g/day continuous = 167 mg/h infusion.
• Predicted steady-state concentration:

C_{ss} = \frac{\text{Infusion rate}}{CL_{total}} = \frac{167 \text{ mg/h}}{55 \text{ mL/min} \times 60 \text{ min/h} \times 10^{-3} \text{ L/mL}} = \frac{167}{3.3} = 50 \text{ mg/L}

Wait, that's too high. Let me recalculate assuming clearance 55 mL/min = 3.3 L/h:

C_{ss} = \frac{167 \text{ mg/h}}{3.3 \text{ L/h}} = 50 \text{ mg/L}

That seems high. Let me reconsider: If we target Css = 8 mg/L and clearance = 3.3 L/h:

\text{Infusion rate} = C_{ss} \times CL = 8 \times 3.3 = 26.4 \text{ mg/h} = 634 \text{ mg/day}

That's far too low. The issue is I need to verify the math.

Actually, let's use a simpler approach:

• At steady state, infusion rate = elimination rate.
• Elimination rate = CL × Css.
• If we want Css = 8 mg/L and CL = 3.3 L/h:
  • Infusion rate = 8 mg/L × 3.3 L/h = 26.4 mg/h = 634 mg/day.

This is too low for a serious infection. The issue is that continuous infusion dosing for meropenem in CRRT typically uses 3-6g/day, which achieves much higher steady-state levels.

Let me recalculate more carefully:

• If clearance is 55 mL/min = 3.3 L/h, and we infuse 3,000 mg/day = 125 mg/h:

C_{ss} = \frac{125 \text{ mg/h}}{3.3 \text{ L/h}} = 38 \text{ mg/L}

This is above target (8-16 mg/L), which is acceptable for severe sepsis with resistant organisms.

Revised answer:

• 3-4g/day continuous infusion (125-167 mg/h) → predicted Css 30-50 mg/L (well above 4× MIC).
• Measure level at 24 hours (steady state) to confirm therapeutic.

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Examiner: Let's now discuss aminoglycosides. The same patient has Pseudomonas added to their infection. You want to add gentamicin. How do you dose it in CRRT?

Expected Answer (4 marks):

Pharmacodynamics: [0.5 marks] Gentamicin exhibits concentration-dependent killing. Target Cmax/MIC ≥8-10 for Gram-negative bacteria.

Dosing: [2 marks]

1. Calculate dosing weight: [0.5 marks]

   • Patient: 90 kg actual body weight, height 175 cm.
   • IBW (male) = 50 + 2.3 × (height in inches - 60) = 50 + 2.3 × (69 - 60) = 70.7 kg.
   • Adjusted body weight (if obese): AdjBW = IBW + 0.4 × (TBW - IBW) = 70.7 + 0.4 × (90 - 70.7) = 78.4 kg.
   • Use AdjBW = 78 kg for dosing (gentamicin distributes into adipose tissue but not as much as hydrophilic drugs).

2. Loading dose: [0.5 marks]

   • 7 mg/kg AdjBW = 7 × 78 = 546 mg (round to 560 mg or 7 mg/kg × 80 kg = 560 mg).
   • Infuse over 30-60 minutes.

3. Maintenance dose and interval: [1 mark]

   • 5-7 mg/kg q24-48h based on TDM.
   • Initial interval: q24h (assuming high CRRT clearance 30 mL/kg/h).
   • If effluent dose is lower (20-25 mL/kg/h), may need q36-48h.

Therapeutic Drug Monitoring (ESSENTIAL): [1.5 marks]

1. Peak level (1 hour post-infusion): [0.5 marks]

   • Target 20-30 mg/L (to achieve Cmax/MIC ≥10 for Pseudomonas MIC typically 1-2 mg/L).

2. Trough level (pre-dose): [0.5 marks]

   • Target below 1 mg/L to minimize nephrotoxicity and ototoxicity.
   • If trough greater than 1 mg/L, extend interval (q36-48h).

3. Extended-interval dosing nomogram: [0.5 marks]

   • Measure mid-interval level (e.g., 12 hours post-dose for q24h dosing).
   • Use Hartford nomogram to adjust interval based on mid-interval level.

Toxicity monitoring:

• Daily serum creatinine (assess for nephrotoxicity; difficult to interpret in AKI on CRRT).
• Baseline audiometry if prolonged therapy (ototoxicity is irreversible).

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Examiner: The patient is also on levetiracetam for seizure prophylaxis (post-cardiac arrest). Standard dosing is 500 mg q12h in renal impairment. Does this need adjustment in CRRT?

Expected Answer (3 marks):

Levetiracetam pharmacokinetics: [1 mark]

• MW 170 Da (small molecule)
• Protein binding below 10% (almost entirely free)
• 60% renally eliminated unchanged → significantly cleared by CRRT
• Sieving coefficient 0.9-1.0 (freely crosses membrane)

CRRT clearance: [0.5 marks]

• CRRT clearance ~15-30 mL/min at standard effluent doses.
• Higher in this patient (effluent 30 mL/kg/h) → clearance ~25-35 mL/min.

Dosing adjustment: [1 mark]

• Standard renal dosing (CrCl below 30 mL/min): 500 mg q12h.
• CRRT dosing: 500-1,000 mg q12h (CRRT clears levetiracetam more efficiently than expected from standard renal dosing charts).
• For this patient with high-effluent CRRT, recommend 1,000 mg q12h.

Therapeutic Drug Monitoring: [0.5 marks]

• Measure trough (if available; not routinely measured in many centers).
• Target 12-46 mg/L (therapeutic range).
• If trough below 12 mg/L, increase dose (1,500 mg q12h or 1,000 mg q8h).
• If trough greater than 46 mg/L, reduce dose (risk of neurotoxicity: somnolence, behavioral changes, psychosis).

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Examiner: Finally, does regional citrate anticoagulation affect drug metabolism or clearance?

Expected Answer (2 marks):

Short answer: Citrate anticoagulation does not significantly alter drug clearance in CRRT. [0.5 marks]

Mechanism: [1 mark]

• Citrate chelates ionized calcium in the circuit (pre-filter), preventing coagulation.
• Citrate-calcium complexes are removed by CRRT.
• Citrate entering systemic circulation is metabolized by the liver (Krebs cycle) to bicarbonate + calcium.
• Systemic ionized calcium is maintained via calcium chloride infusion → calcium-dependent enzyme activity (e.g., calcium channel blockers) is unaffected.

Theoretical concerns (limited evidence): [0.5 marks]

• Citrate metabolism generates acetyl-CoA → potential upregulation of hepatic CYP450 enzymes → theoretical increase in hepatic drug metabolism. However, this has not been demonstrated clinically for antibiotics or common ICU drugs.
• Filter lifespan is longer with citrate (48-72 hours vs 24-36 hours with heparin) → more consistent drug clearance over time (less downtime).

Clinical recommendation: Use standard CRRT-based drug dosing regardless of citrate vs heparin anticoagulation.

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Closing Prompt: "Excellent, thank you. That completes this station."

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Summary

This comprehensive topic covers CRRT pharmacology at a depth suitable for CICM Fellowship Written and Viva examinations. Key takeaways:

1. Drug removal mechanisms: Convection (solute drag), diffusion (concentration gradient), adsorption (membrane binding).
2. Sieving coefficient and extraction ratio quantify drug clearance efficiency.
3. CRRT modality matters: CVVHDF > CVVH > CVVHD for most drugs.
4. Antibiotic dosing:
   • Vancomycin: 25-30 mg/kg loading, 15-20 mg/kg q12-24h, AUC-guided TDM.
   • Beta-lactams: Extended/continuous infusion to maximize fT>MIC.
   • Aminoglycosides: 5-7 mg/kg q24-48h with mandatory TDM.
5. Regional citrate anticoagulation does NOT significantly alter drug clearance.
6. Therapeutic drug monitoring is essential for narrow therapeutic index drugs and when treatment failure is suspected.
7. Australian/NZ context: 20-25 mL/kg/h standard effluent dose (RENAL trial), CVVHDF preferred, citrate first-line.