I. Framework for Escalating Pharmacotherapy

Begin with precise assessment of perfusion and volume status to guide therapy escalation and avoid inappropriate interventions.

• Goals: Restore renal perfusion, prevent further injury, support recovery.
• Assess: Hemodynamics (MAP, pulse pressure variation), volume status (ultrasound, CVP, fluid responsiveness), AKI etiology (pre-renal, intrinsic, post-renal).
• Integrate lab data: Serum creatinine trends, urine output, lactate clearance.

II. Tier 1 – Volume Resuscitation

Initial therapy targets hypovolemia with judicious fluid administration and close monitoring to avoid overload.

A. Crystalloids

• Mechanism: Expand intravascular volume via hydrostatic shift.
• Indication: Hypovolemia or pre-renal AKI.
• Choice: Balanced solutions (lactated Ringer’s, Plasma-Lyte) over 0.9% saline.
• Dosing: 20 mL/kg bolus; reassess after each bolus for fluid responsiveness.
• Monitoring: Urine output (>0.5 mL/kg/h), CVP or ultrasound indices, lactate.
• Pitfalls: Hyperchloremia from saline, fluid overload, pulmonary edema.

B. Colloids (Albumin)

• Mechanism: Oncotic expansion draws interstitial fluid into vasculature.
• Indications: Hypoalbuminemia with refractory volume deficit, particularly in settings like sepsis or cirrhosis.
• Dosing: 20–25 g infusion (e.g., 100 mL of 20-25% albumin) over 30 minutes to 4 hours, titrate to hemodynamic response.
• Monitoring: Colloid oncotic pressure (if available), hemodynamics, signs of fluid overload (pulmonary edema, worsening oxygenation).
• Pros/Cons: Less total volume needed for similar intravascular expansion compared to crystalloids vs. higher cost and potential (though rare) risk of allergic reactions.

III. Tier 2 – Vasopressor and Inotropic Support

When fluids fail to restore perfusion, escalate to vasoactive agents to maintain target MAP and renal blood flow.

A. Norepinephrine

• Mechanism: Potent α₁-mediated vasoconstriction, modest β₁ cardiac support; increases MAP with minimal direct effect on heart rate.
• Indication: Persistent hypotension after adequate fluid resuscitation (e.g., in septic or vasodilatory shock). First-line vasopressor.
• Dosing: Start 0.01–0.1 µg/kg/min; titrate to achieve target MAP (typically 65–75 mm Hg).
• Monitoring: Continuous invasive arterial pressure, ECG, peripheral perfusion (capillary refill, skin temperature, mottling), urine output, lactate.
• Pitfalls: Risk of digital or splanchnic ischemia at high doses, arrhythmias (less common than with dopamine), extravasation injury (requires central line administration).
• Advantage: Lower risk of tachyarrhythmias compared to dopamine.

B. Vasopressin

• Mechanism: V₁ receptor–mediated vasoconstriction, relatively independent of adrenergic pathways; may be catecholamine-sparing.
• Indications: Adjunct to norepinephrine in refractory vasodilatory shock (e.g., septic shock) to help decrease norepinephrine requirements or achieve MAP target.
• Dosing: Fixed infusion, typically 0.03 units/min (up to 0.04 units/min). Not typically titrated.
• Monitoring: Serum sodium levels (risk of hyponatremia, though less common with V1-specific effects), signs of splanchnic and digital perfusion.
• Pitfalls: Potential for hyponatremia, ischemic complications (especially coronary, splanchnic, digital) at higher doses or in susceptible patients.

C. Adjunctive Agents

• Angiotensin II: For refractory vasodilatory shock despite high-dose catecholamines and vasopressin. High cost, potential thrombotic risk.
• Phenylephrine: Selective α₁ agonist; may be considered in specific situations like tachyarrhythmias limiting norepinephrine use, or neurogenic shock. Can significantly reduce cardiac output.
• Dopamine: Generally avoided as a primary vasopressor for AKI due to higher rates of arrhythmogenicity and potentially worse outcomes compared to norepinephrine in septic shock. “Renal-dose” dopamine is not effective and not recommended.

IV. Avoidance and Adjustment of Nephrotoxic Agents

Prevent further injury by eliminating or modifying exposures to known nephrotoxins.

A. NSAIDs (Non-Steroidal Anti-Inflammatory Drugs)

• Mechanism: Inhibit prostaglandin synthesis, leading to reduced prostaglandin-mediated afferent arteriolar dilation, thereby decreasing GFR, especially in states of renal hypoperfusion.
• Strategy: Use alternative analgesics like acetaminophen or opioids. Strictly avoid NSAIDs in patients with hypovolemia, significant CKD, heart failure, or cirrhosis.

B. Aminoglycosides

• Mechanism: Accumulate in proximal tubule cells causing direct cytotoxicity and acute tubular necrosis.
• Strategy: Prefer non-nephrotoxic alternatives whenever possible. If required, use once-daily (extended-interval) dosing.
• Dosing: Adjust dose and/or interval based on estimated creatinine clearance (CrCl) or other markers of renal function. Monitor drug levels.
• Monitoring: Target trough concentrations <1 mg/L for gentamicin/tobramycin (or per institutional guidelines). Monitor daily serum creatinine and urine output.

C. Contrast Media

• Risk: Contrast-induced AKI (CI-AKI) can occur due to direct tubular toxicity and renal medullary hypoxia from vasoconstriction.
• Prevention: Ensure adequate isotonic hydration (e.g., 0.9% saline or balanced crystalloid) before and after the study. Use low-osmolar or iso-osmolar contrast agents. Minimize the volume of contrast administered.
• Clinical decision: Carefully weigh the diagnostic yield of the contrast study against the risk of AKI, especially in high-risk patients (pre-existing CKD, diabetes, dehydration, concomitant nephrotoxins).

V. Pharmacokinetic (PK) / Pharmacodynamic (PD) Considerations in AKI

AKI significantly alters drug distribution and elimination, demanding individualized dosing strategies to ensure efficacy and avoid toxicity.

• Volume of distribution (Vd): Often increased for hydrophilic drugs (e.g., β-lactams, aminoglycosides) due to fluid accumulation and capillary leak, potentially requiring larger loading doses to achieve therapeutic concentrations.
• Hypoalbuminemia: Common in critical illness and AKI, leading to an increased free fraction of highly protein-bound drugs (e.g., phenytoin, ceftriaxone, warfarin), which can enhance their pharmacologic effect or toxicity.
• Lipophilic agents: Generally less affected by Vd changes in AKI but may accumulate active or toxic metabolites if their clearance pathways (hepatic or renal) are impaired.

VI. Drug Dosing Adjustments in AKI and Renal Replacement Therapy (RRT)

A. Principles of Renal Dosing

• Use serial serum creatinine (SCr) and urine output trends rather than relying on a single SCr value or estimated GFR, as renal function can change rapidly in critically ill patients.
• Adjust dosing regimens (dose, frequency, or both) to both current and projected renal function to avoid underdosing or accumulation.

B. RRT-Related Clearance

• Continuous Renal Replacement Therapy (CRRT): Provides continuous drug clearance. Dosing should generally be based on the effluent flow rate (typically targeting 20–25 mL/kg/h for solute clearance). Some drugs may require supplemental doses.
• Intermittent Hemodialysis (IHD): Results in intermittent, high-flux drug removal. For drugs significantly cleared by IHD, administer doses after the dialysis session to avoid premature removal.
• Sustained Low-Efficiency Dialysis (SLED): A hybrid option. Drug dosing adjustments depend on the duration of the SLED session, blood and dialysate flow rates, and filter characteristics.

C. Antimicrobial Examples

VII. Route and Delivery Device Considerations

• Central venous catheters: Essential for the administration of vasopressors (e.g., norepinephrine, vasopressin) and hyperosmolar or irritant infusions to prevent extravasation and tissue injury.
• Continuous infusion pumps: Ensure stable plasma concentrations for drugs with narrow therapeutic windows or short half-lives, such as vasopressors and some antimicrobials (e.g., continuous infusion β-lactams).
• Enteral route: Only consider for medication administration after gut perfusion and function are confirmed (e.g., presence of bowel sounds, tolerance of enteral nutrition). AKI and shock can impair drug absorption from the GI tract.

VIII. Monitoring Plan for Efficacy and Toxicity

• Hemodynamics: Target MAP ≥65 mm Hg (or individualized target), urine output >0.5 mL/kg/h, lactate clearance, improvement in peripheral perfusion.
• Laboratory parameters: Daily (or more frequent) monitoring of SCr, blood urea nitrogen (BUN), electrolytes (especially potassium, magnesium, phosphorus), acid-base status, and fluid balance.
• Therapeutic Drug Monitoring (TDM): For drugs with narrow therapeutic indices and variable PK in AKI, such as vancomycin and aminoglycosides. Obtain levels according to institutional protocols or clinical indication.

IX. Pharmacoeconomics and Resource Utilization

• Fluids: Balanced crystalloids may have a higher acquisition cost than 0.9% saline but could potentially reduce overall AKI-related healthcare costs by mitigating complications like hyperchloremic acidosis or further renal injury.
• Vasopressors: Norepinephrine is generally considered a cost-effective first-line vasopressor. More expensive agents like angiotensin II are typically reserved for refractory cases due to higher costs and specific indications.
• Therapeutic Drug Monitoring (TDM): While resource-intensive (laboratory costs, pharmacist time), TDM can be cost-saving in the long run by preventing drug toxicity (and associated complications/length of stay) and ensuring therapeutic efficacy, thereby reducing treatment failure.

X. Case-Based Algorithm and Decision Pathway