I. Pharmacokinetic Principles in RRT

Renal replacement therapy (RRT) profoundly alters drug clearance based on the specific modality employed, effluent rate, and inherent characteristics of the drug. A thorough understanding of factors such as molecular weight, protein binding, and volume of distribution (Vd) is crucial for guiding appropriate dosing regimens.

A. Drug Properties Influencing Removal

B. Modality and Effluent Rate Effects

II. Antimicrobial Dosing Strategies

RRT significantly alters the clearance of many antimicrobials. Dosing regimens must be carefully adjusted to balance efficacy (e.g., achieving target %fT>MIC for beta-lactams or AUC/MIC for vancomycin) with the avoidance of toxicity.

A. Vancomycin

Mechanism/Indication:

A glycopeptide antibiotic primarily used for infections caused by Methicillin-Resistant Staphylococcus aureus (MRSA) and other susceptible Gram-positive organisms.

Dosing:

• Loading Dose: Typically 15–20 mg/kg based on actual body weight.
• Maintenance Dose (CRRT at 20–25 mL/kg/hr effluent rate): 10–15 mg/kg every 24–48 hours. The frequency should be increased (e.g., to every 24 hours or even more frequently with higher doses) with higher effluent rates.

Monitoring:

Target an AUC/MIC ratio of 400–600 for optimal efficacy. Trough concentrations alone are often suboptimal for guiding therapy, especially in CRRT, but may be used in conjunction with AUC calculations.

Pearls:

• Extended or continuous infusion of vancomycin may help stabilize serum concentrations and achieve pharmacodynamic targets, particularly in high-volume CRRT.
• Carefully track the cumulative daily dose of vancomycin against the total daily effluent volume to anticipate changes in clearance.

B. Beta-Lactams (e.g., piperacillin-tazobactam, meropenem)

Mechanism:

Exhibit time-dependent killing, where efficacy is primarily linked to the percentage of the dosing interval that the free drug concentration remains above the Minimum Inhibitory Concentration (%fT>MIC).

Dosing:

• Prolonged or continuous infusions are often preferred to maximize %fT>MIC (e.g., meropenem 2 g administered over 3 hours every 8 hours, or as a continuous infusion).
• The total daily dose may need to be adjusted upward in high-effluent CRRT settings to compensate for increased clearance.

Pitfalls:

• Ensure filter compatibility, as some beta-lactams may adsorb to certain filter membranes or, rarely, crystallize.
• In the absence of routine therapeutic drug monitoring for beta-lactams, clinical response and microbiological cure are key guides for therapy adequacy.

C. Antifungals

• Fluconazole: Being water-soluble and having low protein binding, fluconazole is readily cleared by RRT. Standard dosing (e.g., 400–800 mg IV daily) is generally maintained in CRRT. A supplemental dose should be given after each IHD session.
• Voriconazole: Exhibits variable clearance via RRT and has a narrow therapeutic index. Therapeutic drug monitoring (TDM) is strongly recommended to optimize efficacy and avoid toxicity (e.g., neurotoxicity, hepatotoxicity).
• Amphotericin B Lipid Formulations (e.g., LAmB): Due to their large size and lipophilic nature, these formulations undergo negligible removal by RRT. No dose adjustment is typically required, but renal function (nephrotoxicity) should still be monitored closely.

III. Sedative, Analgesic, and Neuromuscular Blocker Adjustments

The impact of RRT on sedatives, analgesics, and neuromuscular blockers is determined by their lipophilicity, degree of protein binding, and the presence of active metabolites that may be cleared or accumulate.

A. Sedatives

• Propofol: The parent drug is highly lipophilic and protein-bound, resulting in minimal clearance by RRT. However, its water-soluble glucuronide metabolites can accumulate, particularly with prolonged infusions in patients with renal failure, though their clinical significance is debated.
• Midazolam: Highly protein-bound, limiting its direct removal. However, its active metabolite, 1-hydroxymidazolam, is water-soluble and renally cleared. This metabolite can accumulate significantly in patients on RRT, leading to prolonged sedation. Dose reduction and careful monitoring of sedation depth are advised.

B. Analgesics

• Fentanyl: Due to its high lipophilicity and extensive protein binding, fentanyl undergoes minimal removal by RRT. Routine dose adjustments are generally not necessary based on RRT alone.
• Hydromorphone: The parent drug is moderately cleared by RRT. However, its active metabolite, hydromorphone-3-glucuronide (H3G), is renally excreted and can accumulate significantly, potentially causing neurotoxicity (e.g., myoclonus, hyperalgesia). Consider dose reduction and monitor for signs of neurotoxicity.

C. Neuromuscular Blockers

• Cisatracurium: Undergoes Hoffman elimination (spontaneous degradation in plasma) and ester hydrolysis, which are independent of renal or hepatic function. It is the preferred neuromuscular blocker in patients with renal failure or on RRT.
• Vecuronium/Rocuronium: These aminosteroidal agents undergo partial renal clearance. Their duration of action may be prolonged in renal impairment and with RRT. Monitor neuromuscular blockade closely (e.g., with train-of-four monitoring) and consider extending dosing intervals or reducing doses.

IV. Management of Dialyzable Drug Toxicities

Prompt initiation of RRT can be a lifesaving intervention in certain drug poisonings. The choice of RRT modality influences the rate of toxin clearance and the potential for rebound phenomena.

V. Nutritional Support Considerations

Continuous renal replacement therapy (CRRT) can lead to significant losses of amino acids, water-soluble vitamins, and trace elements. Nutritional support must be tailored to account for these losses and meet the increased metabolic demands of critically ill patients.

A. Amino Acid and Protein Losses

• CRRT can result in losses of up to 10–15 grams of amino acids per day, and sometimes higher depending on the effluent rate and filter type.
• Protein intake targets should generally be increased to 1.2–1.5 g/kg/day, and potentially higher in hypercatabolic states. Enteral nutrition is preferred whenever feasible; parenteral supplementation may be necessary if enteral targets cannot be met.

B. Vitamins and Trace Elements

• Water-soluble vitamins (e.g., B-complex vitamins, Vitamin C) are readily cleared by CRRT due to their small molecular size. Routine daily replacement is often necessary.
• Trace elements such as zinc and selenium can also be depleted during CRRT. Supplementation should be provided according to institutional protocols or based on measured levels if available.
• Fat-soluble vitamins (A, D, E, K) are generally not significantly affected by RRT due to their lipophilicity and protein binding.

VI. Medications Largely Unaffected by RRT

Drugs that are highly protein-bound, have a large volume of distribution, or are primarily metabolized by non-renal pathways (e.g., hepatic metabolism) are generally not significantly removed by RRT. Dose adjustments for these medications are typically not required based on RRT alone, though underlying organ dysfunction (e.g., liver failure) may still necessitate changes.

• Warfarin: Highly protein-bound; no dose adjustment needed due to RRT.
• Phenytoin: Highly protein-bound; monitor free levels if hypoalbuminemia is present, but RRT itself has minimal impact on clearance.
• Hepatically Metabolized Agents: Many drugs, such as clopidogrel and numerous psychotropic medications, are primarily cleared by the liver. While RRT has minimal direct impact, underlying critical illness and hepatic function should guide dosing.
• Large Molecules / Biologics: Monoclonal antibodies and other very large therapeutic proteins are generally not cleared by standard RRT modalities.

VII. Therapeutic Drug Monitoring and Resources

Effective pharmacotherapy in patients on RRT often requires a combination of applying pharmacokinetic principles, utilizing evidence-based guidelines, and employing therapeutic drug monitoring (TDM) when available and indicated.

A. Evidence-Based Guidelines

Consulting established guidelines provides a foundational framework for initial dosing decisions:

• KDIGO (Kidney Disease: Improving Global Outcomes) Guidelines: Offer recommendations for various aspects of kidney disease management, including some drug dosing considerations.
• ASHP (American Society of Health-System Pharmacists) Consensus Guidelines and Resources: Provide valuable information on medication use in renal impairment and RRT.
• FDA Labeling (Package Inserts): Often contain specific dosing recommendations for patients with renal impairment and, in some cases, for those on RRT.

B. TDM Strategies

For drugs with a narrow therapeutic index and significant RRT-induced clearance variability, TDM is crucial:

• Draw drug levels at steady state, if possible, and ensure timing is appropriate relative to the RRT session (e.g., pre-dialysis, post-dialysis, or during CRRT).
• In high-clearance RRT modalities (e.g., high-effluent CRRT, high-flux IHD), consider increasing the frequency of monitoring.
• Adjust doses based on a combination of the measured drug level, the specific pharmacodynamic target (e.g., AUC/MIC, %fT>MIC), and the patient’s clinical response.