In critically ill patients with acute kidney injury (AKI), Continuous Renal Replacement Therapy (CRRT) is a life-sustaining treatment that simulates kidney function over an extended period. This continuous nature, however, significantly alters a patient's pharmacokinetics, requiring a nuanced understanding of how drugs are removed from the body to ensure safe and effective medication dosing. Factors such as the drug's inherent properties and the specific CRRT settings all play a crucial role in determining the extent of drug clearance.
Factors Influencing Drug Clearance by CRRT
The removal of a drug during CRRT is a complex process governed by a combination of pharmacological and technical factors. The characteristics of the medication itself are paramount in predicting whether it will be effectively cleared by the extracorporeal circuit.
Pharmacological Characteristics
- Molecular Weight (MW): A drug's molecular size is a primary determinant of its ability to cross the filter membrane. CRRT filters typically allow solutes with a molecular weight under 50,000 Daltons to pass through. Smaller molecules, like many common antibiotics, are more readily cleared than larger ones, such as therapeutic proteins.
- Protein Binding: A drug's affinity for plasma proteins, particularly albumin, is one of the most critical factors. Only the unbound, or 'free,' fraction of a drug can pass through the CRRT filter membrane. Drugs that are highly protein-bound (e.g., >90%) are poorly cleared by CRRT, even if they have a small molecular weight, because the drug-protein complex is too large to pass through the membrane pores. Conversely, a drug with low protein binding is more easily removed.
- Volume of Distribution (Vd): This pharmacokinetic parameter describes how widely a drug is distributed throughout the body's tissues. Drugs with a large volume of distribution are dispersed throughout the body's fluid compartments and tissues, making them less accessible for removal by CRRT. Drugs with a small volume of distribution, which tend to remain in the vascular space, are more effectively cleared.
- Non-Renal Clearance Pathways: The overall clinical relevance of CRRT clearance must be considered relative to other elimination pathways, primarily hepatic metabolism. A drug with a low non-renal clearance, like vancomycin, will be significantly affected by CRRT, whereas a drug with high hepatic clearance, like acetaminophen, will be less impacted, even with a high CRRT clearance rate.
CRRT Technical and Operating Parameters
- CRRT Modality: Different modalities utilize different primary mechanisms of solute removal. Continuous venovenous hemofiltration (CVVH) uses convection (solvent drag), continuous venovenous hemodialysis (CVVHD) uses diffusion, and continuous venovenous hemodiafiltration (CVVHDF) uses both. These differences influence how effectively drugs are removed.
- Effluent Flow Rate: This is the sum of the dialysate, replacement fluid, and ultrafiltration rates. Increasing the effluent flow rate generally increases the drug clearance, but higher doses are not always associated with better outcomes and may increase the risk of subtherapeutic antibiotic levels.
- Membrane Characteristics: The dialyzer or hemofilter membrane has a specific pore size, or cutoff. The permeability of this membrane, often expressed as a sieving coefficient (SC), dictates how easily drugs can pass through. Generally, more permeable membranes increase drug clearance.
- Predilution vs. Postdilution: In hemofiltration, replacement fluid can be added before (predilution) or after (postdilution) the filter. Predilution dilutes the blood entering the filter, which can reduce the clearance of some drugs compared to postdilution methods.
Specific Examples: What drugs are cleared by CRRT?
Based on these factors, medications can be broadly categorized by their likelihood of being significantly cleared during CRRT. It is vital for clinicians to consult specific dosing protocols for their institution and consider therapeutic drug monitoring (TDM) when available.
Drugs with High CRRT Clearance (May Require Dose Adjustment)
These medications are characterized by low molecular weight, low protein binding, and low non-renal clearance.
- Aminoglycosides: Gentamicin, Tobramycin, Amikacin. These drugs rely heavily on renal elimination and have low protein binding, making them ideal candidates for CRRT clearance.
- Certain Beta-Lactams: Piperacillin/Tazobactam, Cefepime, Ceftazidime, Meropenem. These are generally smaller, water-soluble antibiotics.
- Vancomycin: Its clearance is notably increased by CRRT, requiring dose adjustments based on therapeutic drug monitoring.
- Other Antimicrobials: Fosfomycin, Flucytosine, and Acyclovir. Acyclovir's small size and low protein binding make it readily removed.
- Anticonvulsants: Gabapentin and Levetiracetam.
Drugs with Low CRRT Clearance (Less Likely to Require Adjustment)
These are often characterized by high protein binding or a large volume of distribution, limiting their removal.
- Highly Protein-Bound Drugs: Ceftriaxone, Daptomycin, and Warfarin are examples of drugs with high protein binding that are minimally cleared by CRRT.
- Drugs with Large Volume of Distribution: Lipophilic antibiotics like Linezolid, Macrolides, and Tetracyclines tend to distribute widely into tissues and are not effectively cleared.
- Certain Antifungals: Voriconazole and Amphotericin.
- Others: Azithromycin, Clindamycin, Doxycycline.
Comparison of Drug Clearance Characteristics in CRRT
| Characteristic | Drugs with High CRRT Clearance | Drugs with Low CRRT Clearance |
|---|---|---|
| Molecular Weight | Typically low (<1500 Da) | Can be low or high, but other factors override |
| Protein Binding | Low (<80%) | High (>90%) |
| Volume of Distribution | Low (<0.7 L/kg), primarily in vascular fluid | Large, widely distributed in tissues |
| Elimination Pathways | Primarily renal, low non-renal clearance | Significant non-renal (hepatic) clearance |
| Primary Mechanism | Depends on CRRT modality (diffusion, convection) | Not significantly affected by CRRT |
| Examples | Aminoglycosides, Piperacillin/Tazobactam, Vancomycin | Ceftriaxone, Daptomycin, Linezolid, Warfarin |
Conclusion
Determining what drugs are cleared by CRRT is not a one-size-fits-all problem; it requires a detailed analysis of both the medication's inherent pharmacokinetic properties and the patient's specific CRRT settings. Factors such as molecular size, protein binding, and volume of distribution are the primary determinants of a drug's susceptibility to clearance by CRRT. The CRRT modality and operational parameters, such as flow rates, further modify the extent of drug removal. Given the variability and risk of both underdosing and overdosing, especially with antibiotics in sepsis patients, clinicians should leverage established dosing guidelines, rely on therapeutic drug monitoring whenever feasible, and understand the core pharmacological principles to provide optimal and safe care.
For additional information on optimizing antibiotic dosing in critically ill patients, see this review: Drug Dosing Considerations in Critically Ill Patients Receiving Continuous Renal Replacement Therapy.
