Pharmacotherapy and Supportive Care of Rhabdomyolysis

1. Introduction

Massive muscle breakdown (rhabdomyolysis) releases myoglobin, potassium, phosphate, and other intracellular contents into the circulation. This cascade precipitates renal vasoconstriction, direct oxidative tubular injury, and mechanical obstruction from myoglobin cast formation. Early, protocolized escalation of fluids, electrolyte management, and adjunctive therapies is critical to maximize renal salvage and improve patient outcomes.

Clinical Pearl: Proactive Management is Key

The cornerstone of management is anticipation. Begin aggressive fluid resuscitation and monitoring before overt AKI develops, as defined by rising creatinine or falling urine output. Delaying intervention significantly increases the risk of requiring dialysis and is associated with higher mortality.

2. Fluid Resuscitation

The primary goal of fluid resuscitation is to restore intravascular volume, optimize renal perfusion, and dilute circulating nephrotoxins. Isotonic crystalloids remain the first-line therapy, with the specific fluid type and rate tailored to the patient’s volume and electrolyte status.

Mechanism & Goals

Volume Expansion: Aggressive hydration expands plasma volume, which improves glomerular filtration rate (GFR) and helps dilute myoglobin concentrations.
Vasoconstriction Suppression: Adequate volume resuscitation helps suppress the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system drive, mitigating renal vasoconstriction.
Urine Output Target: Aim for a target urine output of ≥200 mL/h (approximately 2–3 mL/kg/h) to ensure adequate renal flushing.

Agent Selection & Dosing

Initial Bolus: Start with a 20 mL/kg bolus of isotonic crystalloid over 1–2 hours.
Maintenance Infusion: Continue with an infusion at 200–300 mL/h, titrating frequently based on hourly urine output, vital signs, and signs of volume overload.

Comparison Table: Fluid Choice in Rhabdomyolysis
Feature	Normal Saline (0.9% NaCl)	Lactated Ringer’s (LR)
Na⁺ (mEq/L)	154	130
Cl⁻ (mEq/L)	154	109
K⁺ (mEq/L)	0	4
Risk of Hyperchloremia	High	Low–Moderate
Impact on Acid-Base	May cause non-anion gap metabolic acidosis	More physiologic; lactate is metabolized to bicarbonate
Clinical Tip	Preferred initial choice if significant hyperkalemia is present or suspected.	A reasonable choice to mitigate acidosis, but monitor serum K⁺ closely.

Clinical Pearl: Fluid Selection in Hyperkalemia

Avoid potassium- or lactate-containing fluids (like Lactated Ringer’s) when serum potassium is ≥5.5 mEq/L or rising rapidly. In these cases, normal saline is the safer initial choice despite its risk of hyperchloremic acidosis.

3. Urine Alkalinization with Sodium Bicarbonate

The theory behind urine alkalinization is that maintaining a higher urine pH (6.5–7.0) reduces the formation of myoglobin casts and minimizes free-radical injury. However, its use is controversial and should be reserved for select severe cases.

Indications & Dosing

Indications: Consider for patients with very high CK levels (>5,000 U/L) or persistent metabolic acidosis (pH < 7.2) despite fluid resuscitation.
Dosing: Add 50–100 mEq of sodium bicarbonate to 1 liter of D5W and infuse at 150–200 mL/h.
Monitoring: Check urine pH every 2–4 hours. Closely monitor serum sodium, pH, and volume status for complications.

Controversy: Limited Evidence for Bicarbonate

Sodium bicarbonate has not been shown to provide a clear benefit in preventing AKI over aggressive saline hydration alone. Its use introduces risks of hypernatremia, volume overload, metabolic alkalosis, and exacerbation of hypocalcemia. Therefore, it should not be used routinely and only considered selectively after euvolemia is achieved.

4. Electrolyte Management

Rapid identification and correction of life-threatening electrolyte derangements—particularly hyperkalemia, hypocalcemia, and hyperphosphatemia—are essential to prevent cardiac arrhythmias and further renal injury.

Hyperkalemia with ECG Changes

1. Stabilize Cardiac Membrane (Immediate)

Calcium Gluconate 10 mL of 10% IV over 2-5 min

2. Shift K⁺ Intracellularly (Minutes to Hours)

Insulin 10 units IV + D50W 25g • Albuterol 10-20 mg Nebulized

3. Remove K⁺ from Body (Hours)

Loop Diuretics (if responsive) • Potassium Binders • Renal Replacement Therapy

Figure 1. Stepwise Management of Severe Hyperkalemia. Prioritization is critical: first, protect the heart; second, temporarily shift potassium into cells; third, facilitate its removal from the body.

B. Hypocalcemia

Hypocalcemia is common due to calcium binding with released phosphate. Treatment should be reserved for specific situations to avoid later rebound hypercalcemia.

Treatment Indications: Treat only if the patient is symptomatic (e.g., tetany, seizures, arrhythmias) or in the setting of severe hyperkalemia where calcium is needed for membrane stabilization.
Dosing: Administer calcium gluconate 1–2 g IV over 10–20 minutes.

C. Hyperphosphatemia

Elevated phosphate levels contribute to hypocalcemia and can cause calcium-phosphate deposition in the kidneys.

Treatment: Consider non-calcium-based phosphate binders (e.g., sevelamer 800–1,600 mg TID with meals) if serum phosphate is persistently >7 mg/dL or the calcium-phosphate product (Ca × PO₄) exceeds 55 mg²/dL².

Clinical Pearl: Prioritize and Be Cautious

Always stabilize the cardiac membrane with calcium before administering therapies to shift potassium. Additionally, treat hypocalcemia sparingly, as aggressive correction can lead to dangerous rebound hypercalcemia during the recovery phase of AKI when phosphate levels normalize.

5. Pharmacokinetic & Dosing Adjustments

The massive fluid shifts and development of AKI in rhabdomyolysis significantly alter drug volume of distribution (Vd) and clearance. Careful dose adjustments are necessary to avoid therapeutic failure or toxicity.

Expanded Volume of Distribution: Large-volume resuscitation can dilute hydrophilic drugs (e.g., beta-lactams, vancomycin). Loading doses may be required to achieve therapeutic concentrations.
Renal Dosing: Adjust maintenance doses or extend dosing intervals for all renally cleared medications based on estimated GFR. For drugs like vancomycin, prefer AUC-guided dosing over trough-only monitoring.
Renal Replacement Therapy (RRT) Impact: Drug clearance is highly dependent on the RRT modality and prescription. Use validated nomograms for dosing during continuous (CRRT) or intermittent (IHD) hemodialysis.

Clinical Pearl: Collaborate with Pharmacy

Active collaboration with a clinical pharmacist is invaluable. Pharmacists can assist with calculating appropriate loading doses, adjusting for renal dysfunction, interpreting therapeutic drug monitoring (TDM) results, and providing dosing recommendations during RRT, significantly improving therapeutic outcomes.

6. Renal Replacement Therapy (RRT)

RRT is a supportive measure reserved for managing the complications of severe AKI. There is no established role for prophylactic dialysis purely to clear myoglobin from the blood.

Indications

Initiate RRT for standard, life-threatening indications of AKI:

Acidosis: Severe metabolic acidosis (pH < 7.1) refractory to bicarbonate therapy.
Electrolytes: Refractory hyperkalemia (>6.5 mEq/L) or rapidly rising potassium.
Ingestions: (Not typically relevant in rhabdomyolysis).
Overload: Refractory volume overload causing respiratory compromise.
Uremia: Symptomatic uremia (e.g., pericarditis, encephalopathy).

Modalities

Continuous Renal Replacement Therapy (CRRT): Preferred for hemodynamically unstable patients. Target an effluent dose of 20–25 mL/kg/h.
Intermittent Hemodialysis (IHD): Suitable for hemodynamically stable patients who require rapid clearance of solutes and volume.

Controversy: Timing of RRT Initiation

Multiple large clinical trials (e.g., AKIKI, STARRT-AKI) have shown no clear mortality benefit for “early” RRT initiation compared to a “delayed” or watchful-waiting strategy. The current consensus is to base the decision to start RRT on urgent clinical criteria rather than on CK or myoglobin levels alone.

7. Drug Interactions & Nephrotoxic Agents

A critical step in management is to identify and withhold all medications that could either exacerbate the underlying rhabdomyolysis or worsen the acute kidney injury.

High-Risk Medications to Avoid or Discontinue

Statins: Discontinue immediately in any patient with acute rhabdomyolysis. The decision to rechallenge later should be made on an individual basis after recovery.
NSAIDs: Strictly avoid, as they cause afferent arteriolar vasoconstriction, which can severely compromise renal blood flow in a vulnerable kidney.
Other Nephrotoxins: Avoid or use with extreme caution and intensive monitoring. This includes aminoglycosides, amphotericin B, and intravenous contrast dye.

Clinical Pearl: Medication Reconciliation is a Priority

Perform a comprehensive medication reconciliation immediately upon admission. Early identification and discontinuation of nephrotoxic agents can be as impactful as any active therapy and may prevent the progression from mild kidney injury to severe, dialysis-dependent AKI.

8. Adjunctive Pharmacotherapies

Diuretics and vasopressors are supportive therapies used to manage volume status and perfusion pressure, respectively. They do not prevent AKI but are essential tools in the overall management plan.

Diuretics

Mannitol: An osmotic diuretic (0.25–1 g/kg IV bolus) that may theoretically reduce tubular swelling and act as a free-radical scavenger. However, it should only be considered after volume repletion is complete, as it can worsen AKI in hypovolemic patients. Its routine use is not recommended.
Furosemide: A loop diuretic (20–40 mg IV bolus) used to manage fluid overload once the patient is euvolemic or hypervolemic. It has no proven role in preventing AKI and can be harmful if used in a volume-depleted state.

Vasopressors

Norepinephrine: The first-line vasopressor for persistent hypotension despite adequate fluid resuscitation. Titrate to a mean arterial pressure (MAP) of ≥65 mmHg.
Phenylephrine: A pure alpha-agonist that can be used as an adjunct if norepinephrine causes significant tachycardia or arrhythmias.

Clinical Pearl: Fluids First, Then Pressors

Never initiate vasopressors in a patient who has not been adequately fluid resuscitated. “Pressing a dry tank” will worsen end-organ perfusion, including to the kidneys, and accelerate organ injury. Ensure volume status is optimized before concluding that vasopressor support is needed.

9. Monitoring Plan

Frequent, serial assessments are crucial to guide the escalation and de-escalation of therapies and to detect complications early.

Laboratory Monitoring

Creatine Kinase (CK): Check every 6–12 hours until a clear downward trend is established. The peak value helps stratify risk, while the rate of decline signals recovery.
Renal Panel & Electrolytes: Monitor creatinine, BUN, potassium, calcium, and phosphate every 4–6 hours initially, then daily once stable.

Clinical & Hemodynamic Monitoring

Intake and Output: Strict hourly intake and output measurement is mandatory to guide fluid therapy.
Daily Weights: The most reliable indicator of net fluid balance.
Vital Signs: Continuous monitoring of heart rate, blood pressure, and MAP. Invasive monitoring (e.g., CVP) may be needed in complex cases or if there is a poor response to initial therapy.

Clinical Pearl: Dynamic Reassessment

Rhabdomyolysis is a dynamic process. A patient’s fluid needs and electrolyte status can change rapidly. Frequent reassessment of clinical and laboratory data is the only way to ensure timely and appropriate therapy adjustments, which directly correlates with improved outcomes.

References

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Escalating Pharmacotherapy Strategies in Rhabdomyolysis-Induced AKI

Learning Objective