Introduction to Drug Clearance in CRRT
Continuous Renal Replacement Therapy (CRRT) is a cornerstone of managing critically ill patients with acute kidney injury (AKI) [1.4.4]. Unlike intermittent hemodialysis, CRRT runs for 24 hours a day, which provides gentle and continuous fluid and solute control for hemodynamically unstable patients [1.4.4]. However, this continuous process significantly complicates medication management. The central challenge for clinicians is determining which drugs are cleared by the therapy and which are not, as failing to adjust doses correctly can lead to therapeutic failure or toxicity. One study found that changes related to CRRT variables were the most common risk factors for dosing errors, accounting for over 60% of pharmacist interventions [1.11.4]. Antibiotics are the most frequently misdosed class of drugs in this setting [1.11.4].
Core Principles of Drug Removal
Whether a drug is removed by CRRT depends on an interplay between the drug's inherent properties and the specific CRRT settings being used [1.4.3]. The three primary mechanisms of solute transport in CRRT are diffusion, convection, and adsorption [1.2.1, 1.3.1].
- Diffusion (Hemodialysis - CVVHD): Solutes move from an area of higher concentration (blood) to an area of lower concentration (dialysate) across a semipermeable membrane [1.2.1]. This process is most effective for small molecules.
- Convection (Hemofiltration - CVVH): Solutes are dragged across a membrane along with plasma water (ultrafiltrate) in response to a hydrostatic pressure gradient [1.2.1]. This is effective for small and middle-sized molecules.
- Adsorption: Some drugs can stick to the surface of the hemofilter membrane, particularly with certain materials like polyacrylonitrile (PAN/AN69) [1.3.1]. This effect is often unpredictable and can decrease over time as the membrane becomes saturated [1.3.5].
Drug-Related Factors
The intrinsic physicochemical properties of a drug are the most critical determinants of its clearance by CRRT [1.4.5].
- Protein Binding: Only the unbound, or free, fraction of a drug can pass through the hemofilter membrane [1.4.5]. Drugs that are highly protein-bound (>80-90%) will have minimal removal by CRRT, regardless of other factors. For example, ceftriaxone and daptomycin are highly protein-bound, limiting their clearance.
- Molecular Weight (MW): Modern high-flux membranes used in CRRT can remove molecules up to 20,000–50,000 Daltons. Most drugs are well below this threshold (e.g., vancomycin is ~1,450 Da, meropenem is ~383 Da), so MW is less of a limiting factor for diffusion and not a factor for convection for most drugs [1.4.5, 1.5.1]. However, very large molecules like amphotericin B lipid complexes are not significantly removed [1.3.5].
- Volume of Distribution (Vd): This describes how extensively a drug is distributed in body tissues versus plasma. Drugs with a large Vd (>1 L/kg) reside primarily in tissues, meaning only a small portion is in the plasma at any given time to be removed by CRRT [1.4.5]. In contrast, drugs with a low Vd are confined to the bloodstream and are more readily cleared [1.4.5].
- Water Solubility (Hydrophilicity): Water-soluble drugs tend to have a smaller volume of distribution and are more easily removed by the aqueous-based processes of CRRT. Lipophilic (fat-soluble) drugs often have a larger Vd and are less affected.
CRRT-Related Factors
The settings of the CRRT machine also significantly influence drug clearance [1.4.2].
- Modality: As mentioned, CVVH (convection) and CVVHD (diffusion) remove drugs differently. Continuous venovenous hemodiafiltration (CVVHDF) combines both methods [1.4.4]. For most common ICU drugs, the difference in clearance between modalities is often negligible, but convection may be better for larger molecules [1.7.1].
- Effluent Flow Rate: This is the sum of the dialysate and ultrafiltrate (replacement fluid) flow rates. A higher effluent rate generally leads to greater drug clearance [1.4.4]. Dosing recommendations are often stratified based on the effluent rate (e.g., <2 L/hr vs. >2 L/hr) [1.8.2].
- Filter Type: While most modern filters are high-flux, the membrane material can influence clearance through adsorption [1.3.1].
Comparison of Drug Properties and CRRT Clearance
The ideal drug to be removed by CRRT has low protein binding, a low volume of distribution, and a primary reliance on renal clearance [1.5.2].
| Drug Property | Favors Removal by CRRT | Hinders Removal by CRRT | Example of Drug Removed | Example of Drug Not Removed |
|---|---|---|---|---|
| Protein Binding | Low (<80%) | High (>80%) | Gentamicin (<10% bound) | Ceftriaxone (>95% bound) |
| Volume of Distribution | Low (<0.7 L/kg) | High (>1 L/kg) | Vancomycin (~0.7 L/kg) | Propofol (~40 L/kg) |
| Molecular Weight | Small to Medium (<20,000 Da) | Very Large | Levetiracetam (170 Da) | Liposomal Amphotericin B |
| Primary Clearance | Renal | Hepatic / Non-renal | Acyclovir [1.5.5] | Linezolid [1.8.1] |
Practical Dosing Adjustments
For drugs significantly cleared by CRRT, dose adjustments are essential [1.6.4]. A common strategy is to start with a normal loading dose to rapidly achieve therapeutic concentrations, especially for hydrophilic drugs which may have an increased volume of distribution in critically ill patients [1.6.3]. Maintenance doses are then adjusted based on the expected clearance from CRRT and any residual renal function [1.6.3].
- Time-Dependent Antibiotics (e.g., Beta-lactams like Piperacillin/Tazobactam, Meropenem): The goal is to keep the drug concentration above the minimum inhibitory concentration (MIC). This may require more frequent dosing or even continuous infusions to counteract CRRT clearance [1.4.4, 1.6.5].
- Concentration-Dependent Antibiotics (e.g., Aminoglycosides like Gentamicin): The goal is achieving a high peak concentration. A normal or even larger dose may be given, with the knowledge that CRRT will help clear the drug, reducing the risk of trough-related toxicity [1.6.5].
- Antifungals: Fluconazole is significantly cleared and may require doses of 800 mg daily or higher [1.10.2]. In contrast, agents like voriconazole, caspofungin, and amphotericin B are not significantly cleared and typically do not require dose adjustment for CRRT [1.10.2].
- Sedatives and Analgesics: Drugs with high lipophilicity and large volumes of distribution like propofol and fentanyl are not significantly cleared by CRRT. However, some sedatives and their metabolites can be cleared. For example, midazolam is not well cleared, but its active metabolites can accumulate. Dexmedetomidine and ketamine have been shown to be cleared from CRRT circuits [1.9.3]. Dosing for these agents should be titrated to clinical effect [1.4.2].
Conclusion
Determining what drugs are removed by CRRT is a complex but vital aspect of critical care pharmacology. It requires a systematic evaluation of both drug-specific factors—primarily protein binding and volume of distribution—and the operational parameters of the CRRT circuit, especially the effluent rate. For drugs with low protein binding, a small volume of distribution, and primary renal excretion, significant removal is expected, necessitating dose increases or more frequent administration. Conversely, highly protein-bound drugs with large volumes of distribution are largely unaffected. Therapeutic drug monitoring, when available, is invaluable for optimizing therapy and ensuring patient safety in this challenging clinical scenario [1.3.3].
For further reading, consider guidelines from professional societies or comprehensive resources like UpToDate on Drug Removal in CKRT [1.3.4].
