Rhabdomyolysis

Contents

Overview

Rhabdomyolysis is breakdown of skeletal muscle with release of intracellular contents — myoglobin, creatine kinase (CK), potassium, phosphate, and uric acid — into the systemic circulation. Acute kidney injury (AKI) is the most important complication, occurring in approximately 15–50% of cases. Aggressive early fluid resuscitation is the cornerstone of management and can prevent progression to dialysis-dependent renal failure.

Causes

Traumatic:

  • Crush injury (earthquake, entrapment, road traffic accident)
  • Prolonged immobility ("found lying") — pressure necrosis of dependent muscles
  • Compartment syndrome
  • Burns and electrical injury

Exertional:

  • Extreme physical exertion (marathon running, military training, heat stroke)
  • Seizures (prolonged or status epilepticus)

Drugs and toxins:

  • Statins (particularly at high doses, in combination with CYP3A4 inhibitors, or with genetic predisposition)
  • Alcohol (direct myotoxicity, falls causing crush)
  • Cocaine and amphetamines (hyperthermia, seizures, direct toxicity)
  • MDMA (ecstasy) — hyperthermia, serotonin syndrome
  • Suxamethonium in susceptible patients (undiagnosed myopathy, Duchenne's)
  • Carbon monoxide poisoning

Inflammatory and infective:

  • Bacterial myositis (Staphylococcal, Streptococcal, Clostridial)
  • Viral myositis (influenza, COVID-19, Legionella — classic cause)
  • Inflammatory myopathies (polymyositis, dermatomyositis)

Metabolic and genetic:

  • Hypokalaemia, hypophosphataemia (severe depletion impairs muscle energy metabolism)
  • Hypothyroidism
  • McArdle's disease (glycogen phosphorylase deficiency) and other glycogen storage disorders
  • Carnitine deficiency, mitochondrial myopathies

Other:

  • Neuroleptic malignant syndrome (NMS)
  • Serotonin syndrome
  • Hyperthermia

Pathophysiology

Muscle cell death — regardless of cause — leads to failure of the Na⁺/K⁺-ATPase pump and sarcolemmal disruption. Calcium floods intracellularly, triggering mitochondrial dysfunction, activation of proteases and phospholipases, and irreversible cell death. Intracellular contents are released into the circulation.

Mechanism of AKI in rhabdomyolysis:

Myoglobin is freely filtered at the glomerulus. In acidic, concentrated urine (the conditions of dehydration and metabolic acidosis), myoglobin precipitates in the tubular lumen and co-precipitates with Tamm-Horsfall protein (uromodulin) to form tubular casts. These obstruct tubular flow and cause:

  • Direct tubular toxicity: the ferrihemate released from myoglobin in acidic conditions generates reactive oxygen species, causing oxidative tubular cell injury
  • Tubular obstruction: cast formation and tubular blockage
  • Afferent arteriolar vasoconstriction: mediated by haem-induced vasoconstriction and reduced nitric oxide availability

The combination of direct toxicity, cast obstruction, and renal ischaemia causes AKI, which may be severe and require renal replacement therapy.

Clinical Features and Investigations

Clinical features: Muscle pain, swelling, and weakness in the distribution of the injured muscles; dark brown or red urine (myoglobinuria). In traumatic or found-lying patients, the clinical picture may be dominated by the precipitating cause. Many patients with rhabdomyolysis have no localising symptoms.

CK: The key diagnostic marker. A CK >1,000 IU/L defines rhabdomyolysis in most consensus definitions; most clinically significant cases have CK >5,000–10,000 IU/L. Very high CK (>100,000 IU/L) indicates severe muscle injury and highest AKI risk. Serial CK should be measured 4–6-hourly until the trend is clearly downward.

Urinalysis: Dipstick positive for haem (blood) but microscopy shows no red blood cells — this discordance strongly suggests myoglobinuria. Myoglobin is not detected by standard urine dipstick; the haem signal is false-positive for blood.

Urine myoglobin: Can be measured but clears rapidly from serum (half-life ~2 hours); CK is more reliable for tracking disease course.

Electrolytes: Hyperkalaemia (massive release from muscle cells — can be life-threatening); hyperphosphataemia; hypocalcaemia (calcium enters necrotic muscle early; may paradoxically rise during recovery as it is released); elevated creatinine and urea.

LFTs: AST and ALT elevated due to muscle-related enzyme release (AST is not liver-specific); does not indicate hepatocellular injury unless very high or LDH markedly elevated out of proportion.

Management

Fluid Resuscitation

Aggressive IV fluid resuscitation is the single most important intervention and should begin immediately.

Target: Urine output 200–300 mL/hour (approximately 1–3 mL/kg/hour) until the CK trend is clearly falling.

Fluid type: Isotonic crystalloid is the standard initial fluid. 0.9% sodium chloride is commonly used, but prolonged large-volume saline can cause hyperchloraemic acidosis; balanced crystalloids are reasonable where local practice supports them. Total fluid requirements may be very large in severe cases, but fluid should be titrated to urine output, haemodynamics, electrolytes, and pulmonary oedema risk rather than given to a fixed volume target.

Urinary alkalinisation: Sodium bicarbonate is not routine rhabdomyolysis treatment. The theoretical aim is to increase urine pH and reduce myoglobin precipitation, but evidence for clinical benefit is weak and observational. Consider only after senior/nephrology discussion in selected patients, such as severe metabolic acidosis, and avoid if hypocalcaemia, alkalosis, volume overload, or failure to alkalinise the urine occurs.

Monitor: Hourly urine output, serum electrolytes 4–6-hourly, fluid balance. ECG monitoring for hyperkalaemia.

Electrolyte Management

Hyperkalaemia: The most immediately life-threatening complication. Manage with IV calcium gluconate for cardiac membrane stabilisation, dextrose/insulin infusion, and escalate to CRRT if severe, refractory, or rising despite conservative measures.

Hypocalcaemia: Do not treat unless the patient is symptomatic (neuromuscular irritability, tetany, significant ECG changes) or calcium is severely low (<1.7 mmol/L). Calcium given early deposits in necrotic muscle and causes soft tissue calcification; paradoxical hypercalcaemia during recovery is common if calcium has been replaced.

Phosphate: Hyperphosphataemia worsens hypocalcaemia via calcium-phosphate precipitation. Avoid phosphate-containing fluids.

Renal Replacement Therapy

CRRT is required for:

  • Persistent or worsening AKI despite aggressive fluid resuscitation
  • Refractory hyperkalaemia
  • Fluid overload
  • Uraemia or acidosis

Myoglobin is a relatively small molecule (17 kDa) and may be cleared by high-cutoff membranes (HCO-HD) or CRRT, though the clinical benefit of enhanced myoglobin clearance has not been established.

Treat the Underlying Cause

Identify and address the precipitant: fasciotomy for compartment syndrome; antibiotics and source control for bacterial myositis; cooling for hyperthermia; cessation of offending drug; treatment of NMS or serotonin syndrome.

Compartment Syndrome

Compartment syndrome should be suspected in any patient with:

  • Crush injury or prolonged limb compression
  • Swollen, tense limb with pain disproportionate to injury
  • Pain on passive stretch of the muscles within the compartment
  • Weakness or paraesthesia distal to the compartment

Diagnosis: Clinical ± compartment pressure measurement. Pressure >30 mmHg or within 30 mmHg of diastolic pressure (delta pressure <30 mmHg) indicates impending or established compartment syndrome.

Treatment: Urgent fasciotomy. Do not delay for imaging if clinical signs are clear. Fasciotomy releases the pressure, restoring perfusion and preventing muscle necrosis. Delayed fasciotomy results in permanent muscle necrosis and nerve injury.

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Viva Questions

Explain the mechanism by which myoglobin causes acute kidney injury.

Myoglobin causes AKI through three overlapping mechanisms. First, direct tubular toxicity: in the acidic, concentrated urine of a dehydrated, acidotic patient, ferrihemate released from myoglobin generates reactive oxygen species that directly injure proximal tubular cells. Second, tubular obstruction: myoglobin co-precipitates with Tamm-Horsfall protein to form casts that physically obstruct tubular flow and back-pressure the glomerulus, reducing GFR. Third, renal vasoconstriction: haem compounds cause afferent arteriolar vasoconstriction and reduce nitric oxide bioavailability, reducing renal blood flow. All three mechanisms converge to produce AKI. The acidic urine environment is critical: myoglobin is soluble at physiological pH but precipitates at pH below 5.6. Aggressive fluid resuscitation dilutes tubular myoglobin, increases urine flow to flush precipitated casts, and — if combined with urinary alkalinisation — raises urine pH to keep myoglobin in solution. The target urine output of 200–300 mL/hour reflects the need to maintain a brisk tubular flow rate to prevent cast accumulation. If urine output cannot be maintained despite aggressive fluid resuscitation, the patient likely already has established AKI and may require renal replacement therapy.

A 35-year-old man is found lying on the floor at home having been collapsed for 18 hours. His CK is 85,000 IU/L. How do you manage him?

The immediate priority is early isotonic crystalloid resuscitation, titrated to haemodynamics and a urine output of 200–300 mL/hour while avoiding fluid overload. A urinary catheter should be inserted for accurate hourly monitoring. ECG monitoring is essential — with a CK of 85,000 IU/L and muscle necrosis of this scale, significant hyperkalaemia is likely, and I would check electrolytes urgently. If hyperkalaemia is present or the ECG shows peaked T waves or broad complexes, IV calcium gluconate should be given immediately for cardiac membrane stabilisation, followed by dextrose/insulin. I would monitor CK, electrolytes, creatinine, and urea every 4–6 hours. If urine output responds to fluid loading, I would continue aggressive resuscitation until CK is clearly falling and urine output is maintained. I would not use sodium bicarbonate routinely; I would discuss it with nephrology only if there is severe metabolic acidosis or another specific indication, and monitor carefully for worsening hypocalcaemia or volume overload. Hypocalcaemia should not be treated unless symptomatic, as administered calcium deposits in necrotic muscle. The underlying cause must be identified: toxicology screen, metabolic panel, assessment for compartment syndrome in the dependent limbs (tense swollen compartments, pain on passive stretch, neurological deficit distally). If compartment pressures are elevated (>30 mmHg or delta pressure <30 mmHg), urgent surgical fasciotomy is required regardless of other management. If renal function deteriorates despite adequate fluid resuscitation, or if hyperkalaemia becomes refractory, CRRT should be initiated promptly.

How does rhabdomyolysis from statins occur and which patients are at highest risk?

Statin-associated myopathy ranges from asymptomatic CK elevation through myalgia to life-threatening rhabdomyolysis. Statins inhibit HMG-CoA reductase, blocking the mevalonate pathway and reducing synthesis of cholesterol but also of ubiquinone (coenzyme Q10), a critical component of the mitochondrial electron transport chain. Reduced CoQ10 impairs mitochondrial ATP production in skeletal muscle cells, causing energy failure and cell death. Risk factors for statin-induced rhabdomyolysis include: high-dose statin therapy; concurrent use of drugs that inhibit CYP3A4 (the enzyme that metabolises simvastatin, atorvastatin, and lovastatin) — particularly macrolide antibiotics (clarithromycin, erythromycin), azole antifungals, diltiazem, verapamil, and ciclosporin; renal or hepatic impairment, which reduces statin clearance; hypothyroidism; and genetic predisposition. The SLCO1B1 gene encodes a hepatic transporter that takes statins up into hepatocytes; patients with the SLCO1B1*5 variant have reduced hepatic uptake, resulting in higher plasma statin concentrations and greater muscle exposure. Genetic predisposition to myopathy (undiagnosed mitochondrial myopathy, carnitine palmitoyltransferase II deficiency) also markedly increases rhabdomyolysis risk. In hospital patients, the commonest precipitant of statin rhabdomyolysis is drug interaction — typically adding a CYP3A4 inhibitor (often clarithromycin) to an existing statin prescription without dose adjustment or temporary statin suspension.