CONTENTS

• Rapid Reference 🚀
• Preamble: Trust No One
• Causes of rhabdomyolysis
• Signs & symptoms
• Diagnosis
  • [1] Urinalysis
  • [2] Creatine kinase (CK)
  • [3] McMahon Score
  • Problems in defining rhabdomyolysis
  • (Other lab clues)
    • Cellular lysis electrolyte pattern
    • Lone AST elevation
• Complete treatment package
  • [1] Underlying disorders
  • [2] Discontinue myotoxins
  • [3] Discontinue nephrotoxins
  • [4] Electrolyte management
  • [5] Volume & pH management
• Dialysis
• Podcast
• Questions & discussion
• Pitfalls

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rapid reference

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diagnosis

• Check urinalysis (chemical + sediment) to evaluate for myoglobin.
• Check full electrolytes (including Ca/Mg/Phos).
• Check creatine kinase (CK) level.

McMahon Score (≧6 indicates risk of renal failure)

• Age:
  • <50 = zero points.
  • 51-70 = 1.5 point.
  • 71-80 = 2.5 points.
  • >80 = 3 points.
• Female sex: 1 point.
• Initial creatinine:
  • <1.4 mg/dL (<124 uM) = 0 points.
  • 1.4-2.2 mg/dL (124-195 uM) = 1.5 points.
  • >2.2 mg/dL (195 uM) = 3 points.
• Initial calcium <7.5 mg/dL (1.88 mM) = 2 points.
• Initial phosphate:
  • <4 mg/dL (1 mM) = zero points.
  • 4-5.4 mg/dL (1-1.4 mM) = 1.5 points.
  • >5.4 mg/dL (>1.4 mM) = 3 points.
• Initial bicarbonate <19 mM = 2 points.
• Initial CK >40,000 U/L = 2 points.
• Rhabdomyolysis NOT caused by seizure, syncope, exercise, statins, or myositis: 3 points.

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preamble

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Rhabdomyolysis is a riddle wrapped in a mystery inside an enigma. The definition of rhabdomyolysis is debatable, specifically regarding which level of creatine kinase (if any) predicts renal injury. There are no RCTs showing benefit of any treatment for rhabdomyolysis. So from diagnosis to treatment, there is no solid evidence on this disease. This chapter attempts to cut a path through the confusion, but please be warned – little in this chapter is certain.

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causes of rhabdomyolysis

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medications / toxins, especially: 

• Statins & fibrates:
  • Especially with P450 inhibitors that increase statin levels (e.g., amiodarone, azole antifungals, calcium channel blockers). (Koyner 2021)
  • Statins commonly cause rhabdomyolysis that resolves after stopping the medication. However, statins can also trigger statin-associated necrotizing autoimmune myopathy, which persists after stopping the statin. 📄
• Propofol (sometimes via propofol infusion syndrome).
• Antimicrobials:
  • Antibiotics: daptomycin, quinolones, trimethoprim-sulfamethoxazole.
  • Antifungals: amphotericin B.
  • Antiretrovirals: tenofovir/abacavir, raltegravir, zidovudine. (32532456)
• Colchicine.
• Psychiatric medications:
  • Antidepressants: tricyclics, venlafaxine, sertraline, escitalopram.
  • Antipsychotics: aripiprazole, clozapine, haloperidol, risperidone, quetiapine.
• Antihistamines.
• Interferon alpha.
• Toxicology:
  • [1] Sympathomimetics (especially in combination with hyperactivity).
  • [2] Alcohol (acute or chronic, especially causing obtundation and pressure injury).
  • [3] Any coma-inducing medication that can cause pressure injury (e.g., opioids).
  • [4] Venoms (e.g., snake, bees, wasps, hornets, ants, brown recluse spiders). (Wijdicks, 2019; Koyner 2021)

metabolic abnormalities

• Electrolyte abnormalities:
  • HypoPhosphatemia.
  • HypoCalcemia.
  • HypoKalemia.
  • Hyponatremia.
  • Hyperosmolarity (including hypernatremia).
• Endocrinopathies:
  • Adrenal insufficiency.
  • Hypothyroidism or hyperthyroidism.
  • Hyperaldosteronism.
  • DKA (diabetic ketoacidosis).
  • HHS (hyperosmolar hyperglycemic state).

excessive muscle activity

• Status epilepticus.
• Status asthmaticus.
• Psychotic agitation.
• Marathon running.
• Eccentric exercise against high resistance (prolonged muscle contraction while the muscle is lengthening).
• Muscle tone disorders:
  • Serotonin syndrome.
  • Neuroleptic malignant syndrome.

physical injury

• Stupor/coma with prolonged immobility.
• Trauma (especially crush injury).
• Compartment syndrome.
• Surgery (especially vascular or orthopedic).
• Ischemic limb.
• Electrical injury.
• Burns.

dysthermia

• Hyperthermia of any etiology, especially:
  • Neuroleptic malignant syndrome.
  • Malignant hyperthermia.
• Hypothermia.

infections, most notably:

• Viral infections, including:
  • Influenza A and B.
  • COVID.
  • Adenovirus.
  • Herpesviruses (HSV, EBV, CMV, VZV).
  • HIV.
  • Coxsackievirus.
  • Enterovirus.
• Legionella.
• Mycoplasma pneumoniae.
• Clostridium spp.
• Toxic shock syndrome.
• Salmonella.

primary myopathies

• Dermatomyositis.
• Polymyositis.
• Genetic metabolic disorders.

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signs & symptoms of rhabdomyolysis

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symptoms are uncommon

• Muscle pain (23% of patients), swelling, or cramping.
• Muscle weakness (12% of patients).
• Muscle swelling. (30617905)
• ⚠️ Symptoms are usually absent in critically ill patients (e.g., due to sedation or altered sensorium).

signs of rhabdomyolysis or probable muscle injury

• [1] Brownish urine (“tea-colored”) is generally described as being reported in 5-10% of cases. (30630682) However, this finding might be more noticeable among patients with foley catheters, in whom urine color is clinically apparent.
  • Brown urine reflects the presence of toxic myoglobin within the urine, so this is a concerning sign for clinically relevant kidney injury.
  • Brown urine usually correlates with a urine myoglobin level >57,000 nM (>100 mg/dL). (34276082)
• [2] Pressure ulceration or blistering of dependent skin may occur following prolonged coma prior to admission. This should raise alertness for the possibility of underlying muscle damage.
• [3] Compartment syndrome.
• [4] Ischemic limb.

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urinalysis for the diagnosis of rhabdomyolysis

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urinalysis as a screening test for rhabdomyolysis

• Urinalysis lacks specificity but is arguably the best front-line screening test for rhabdomyolysis.
• Advantages of urinalysis:
  • [1] Urinalysis detects myoglobin, which will be elevated much earlier than creatine kinase.
  • [2] Urinalysis is universally available with rapid turn-around times.
• Drawbacks of urinalysis: a positive result is poorly specific, so this requires careful consideration within the context of overall patient management.
• If there is a high index of concern for rhabdomyolysis, both urinalysis and serial creatinine kinase levels should be followed.

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urinalysis results in rhabdomyolysis

urinalysis with positive “heme”

• Myoglobin cross-reacts with the dipstick test for heme pigments. This will cause the chemical urinalysis to be positive for “heme” or “blood.”
• Sensitivity for rhabdomyolysis:
  • The sensitivity of a heme-positive urine is good (>90%). (22082877, 24332910)
  • False-negative results may occur due to:
    • Highly concentrated urine.
    • High nitrite concentrations.
    • Timing of the urine collection (myoglobin levels increase 1-3 hours after injury, peak ~8-12 hours, and often normalize within 24 hours). (34276082)
    • Ascorbic acid. (28235546)
• Specificity is poor (may be caused by hematuria, or hemolysis).
• Sensitivity might be increased by repeating the urinalysis after 6 hours.

heme-positive, RBC-negative

• The specificity of a positive “heme” result is increased if there are no erythrocytes seen in the urine sediment (i.e., 0-5 red blood cells per high-powered field).
• The combination of heme-positive plus erythrocyte-negative urinalysis is seen only in ~35% of patients with rhabdomyolysis. (22082877, 24332910)

other findings on urinalysis

• Proteinuria may occur (due to myoglobin and other myocyte proteins).
• Coarse, granular red-brown myoglobin casts may occasionally be seen. (34276082)

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creatine kinase

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rough classification of rhabdomyolysis based on CK level

• Normal CK (CK ~40-200 U/L).
• Mild rhabdomyolysis (CK 1,000-5,000 U/L)
  • Low risk for kidney injury.
  • Need for treatment depends on context.
• Moderate rhabdomyolysis (CK 5,000-15,000 U/L).
  • Increased risk of kidney injury.
  • Treatment is indicated.
• Severe rhabdomyolysis (CK >15,000 U/L)
  • Increased risk of dialysis.
  • Treatment is indicated. (30617905)

creatine kinase level has major problems:

• [1] Using CK levels may delay the diagnosis of rhabdomyolysis:
  • CK starts to rise 2-12 hours after muscle injury. (34276082)
  • CK levels usually peak ~1-3 days after the initial injury.
  • Myoglobin (which is the true nephrotoxin) peaks earlier and may normalize before the creatine kinase level rises substantially.
  • Therefore, waiting to treat rhabdomyolysis until the creatine kinase level is extremely elevated may delay treatment until the actual nephrotoxin (myoglobin) is already gone!
• [2] CK levels correlate poorly with the risk of acute kidney injury and dialysis.

do we need a repeat creatine kinase level?

• Normal kinetics:
  • CK levels usually peak within ~24-48 hours and then gradually decline.
  • CK has a half-life of ~36 hours, whereas myoglobin has a half-life of ~2-4 hours. (28235546)
• Serial CK values may be useful in some situations:
  • Initial CK level is <1,000 U/L and there is a high index of suspicion for rhabdomyolysis.
  • The initial CK level is 1,000-5,000 U/L. Further increase could indicate the need for fluid resuscitation (more on this below).
• Failure of the CK to fall may indicate ongoing muscle injury or the development of a compartment syndrome. (34276082)

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McMahon Score

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This is a prognostic score generated from labs available upon admission. It has been validated in two studies at different institutions. (24000014, 27259093) It is superior to simply looking at the CK level.

calculating the McMahon score 🧮

• Age:
  • <50 = zero points.
  • 51-70 = 1.5 point.
  • 71-80 = 2.5 points.
  • >80 = 3 points.
• Female sex: 1 point.
• Initial creatinine:
  • <1.4 mg/dL (<124 uM) = 0 points.
  • 1.4-2.2 mg/dL (124-195 uM) = 1.5 points.
  • >2.2 mg/dL (195 uM) = 3 points.
• Initial calcium <7.5 mg/dL (1.88 mM) = 2 points.
• Initial phosphate:
  • <4 mg/dL (1 mM) = zero points.
  • 4-5.4 mg/dL (1-1.4 mM) = 1.5 points.
  • >5.4 mg/dL (>1.4 mM) = 3 points.
• Initial bicarbonate <19 mM = 2 points.
• Initial CK >40,000 U/L = 2 points.
• Rhabdomyolysis NOT caused by seizure, syncope, exercise, statins, or myositis = 3 points.

interpretation of the McMahon score

• <6 indicates a low risk of acute kidney injury or dialysis.
• ≧6 indicates risk of acute kidney injury or dialysis
  • In one validation study, a score ≧6 had performance superior to CK > 5,000 U/L for the prediction of dialysis (McMahon had sensitivity and specificity of 86% and 68% respectively, whereas CK >5,000 U/L had sensitivity and specificity of only 83% and 55%). (27259093)

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difficulty in defining rhabdomyolysis

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why rhabdomyolysis defies any simple definition:

• Rhabdomyolysis is extremely difficult to define precisely. Despite decades of research on this disease, there is no single consensus definition!
• Rhabdomyolysis rarely occurs alone (e.g., it's usually accompanied with traumatic injuries, shock, or hypoperfusion). This makes it extremely difficult to sort out the independent contribution of rhabdomyolysis to kidney failure.
• Most studies of rhabdomyolysis have used creatinine levels to determine whether there is “renal failure.” However, rhabdomyolysis may itself cause release of creatinine from myocytes and thereby directly increase the creatinine levels! This may create a circular logic loop, wherein elevated creatinine kinase and elevated creatinine are both measuring the same thing (muscle injury).

a reasonable approach to defining rhabdomyolysis?

• In the absence of any single consensus definition, the approach below may be reasonable.
• This approach uses the McMahon score to sort out patients with borderline creatine kinase levels. Given that the McMahon score is evidence-based and validated, this is a more scientific approach than arbitrarily defining rhabdomyolysis based on a single cutoff value.

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other laboratory clues that may support rhabdomyolysis

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The following abnormalities are neither sensitive nor rapidly responsive for the diagnosis of rhabdomyolysis. Therefore, they are not recommended for diagnosis of rhabdomyolysis. However, it may be worth having some awareness of them.

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cellular lysis electrolyte pattern

• HyperKalemia.
• HyperMagnesemia.
• HyperPhosphatemia.
• HypoCalcemia (calcium enters damaged muscle cells, and also forms complexes with phosphate).
• Hyperuricemia.
• Elevated LDH (lactate dehydrogenase).
• Elevated anion gap (due to lactic acid, phosphates, and other organic anions). (Koyner 2021)

Differential diagnosis: necrotic tissue of any etiology may cause this pattern of findings (e.g., tumor lysis syndrome).

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lone isolated AST (aspartate aminotransferase)

• Most elevations of AST (aspartate aminotransferase) reflect liver injury, and they are generally accompanied by an elevation of the ALT (alanine aminotransferase).
• Elevation of AST alone (or a dramatically elevated AST with minimally elevated ALT) raises a question of AST release from the muscle due to rhabdomyolysis.

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complete treatment of rhabdomyolysis: more than just fluid

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[1] evaluate and treat any underlying disorder(s) 

• Focused physical examination to evaluate for causes (e.g., compartment syndrome, ischemic limb).
  • ⚠️ Low threshold to consult surgery if there is any concern for compartment syndrome.  Some compartment syndromes may be challenging to diagnose.

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[2] discontinue any potentially myotoxic mediations

• Medications to discontinue:
  • Statins.
  • Fibrates.
  • Colchicine.
  • Daptomycin.
• Other potentially myotoxic medications are listed above. ⚡️

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[3] discontinue nephrotoxic medications

• Stop any nephrotoxic medications (listed here).
• Consider holding or dose-reducing medications that may decrease renal perfusion (e.g. beta-blockers).

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[4] electrolyte management

• 🚨 Hyperkalemia: 📖
  • Hyperkalemia may represent an emergent life-threat.
  • Early dialysis should be considered if there is ongoing myonecrosis that continues to release potassium into the blood.
• Hypocalcemia: 📖
  • Avoid treatment if at all possible.
  • Giving calcium may theoretically worsen muscle injury.
  • Later in the phase of illness calcium is released from muscle tissue, so there is a risk of rebound hypercalcemia.
• Hypokalemia & hypophosphatemia:
  • Severe hypokalemia and/or hypophosphatemia may cause rhabdomyolysis.
  • Once established rhabdomyolysis develops, these abnormalities will generally disappear (due to potassium and phosphate release from muscle tissue).

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[5] volume & pH management 

when is fluid potentially indicated?

• This can be roughly categorized as above.
• The most confusing box are patients with CK >5,000 U/L, yet a McMahon score <6.
  • These patients are at low, yet finite risk of renal injury (the validation study by Simpson found that the McMahon score was only 86% sensitive for dialysis). (27259093)
  • Some fluid therapy should be considered for these patients, but the benefit may be relatively lower.
• Some patients may have a CK of 1,000-5000 IU/L with a McMahon score of 6 or greater:
  • This can occur early in the course of rhabdomyolysis, before the CK level has peaked.
  • Prompt initiation of fluid in these patients is reasonable, especially if myoglobin is detected (e.g., based on urinalysis). Moderate fluid doses may be reasonable (e.g., lactated ringers at 150 ml/hr).
  • If the CK doesn't elevate to >5,000 U/L within 24-48 hours, the fluid therapy may be discontinued (the benefit of ongoing fluid therapy beyond 1-2 days is dubious anyway).

volume of fluid?

• It is generally believed that administration of fluid to flush myoglobin out of the renal tubules is beneficial treatment in rhabdomyolysis. There is probably some truth to this, but unfortunately the concept hasn't been studied prospectively. Most texts and review articles contain strong recommendations regarding precise volumes of fluid, which are completely arbitrary.
  • Three observational studies exist on the volume of fluid: two found that liberal fluid was beneficial whereas the other found that it was harmful! (30644084)
• Blind administration of large volume of fluid can provoke volume overload, which is harmful.
• The algorithm below seems sensible, but it's impossible to really know.

type of fluid?

• Theoretically there may be some benefits to administration of bicarbonate to alkalinize the urine. However, studies haven't shown any benefit of isotonic bicarbonate compared to other fluids among all comers with rhabdomyolysis.
• For patients with relatively normal electrolytes, administration of lactated ringers or plasmalyte seems reasonable.
• For patients with a NAGMA (non-anion-gap metabolic acidosis) or uremic acidosis, administration of isotonic bicarbonate is sensible:
  • Administration of isotonic bicarbonate to patients with NAGMA makes physiologic sense in general and is usually accepted as therapy for this NAGMA.
  • Treatment of uremic acidosis with bicarbonate demonstrated benefit in the BICAR-ICU trial.
  • Isotonic bicarbonate may be administered with a goal of increasing the serum bicarbonate to a high-normal level (e.g., ~24-28 mEq/L).
  • Isotonic bicarbonate may exacerbate hypocalcemia, so caution and monitoring may be required.

when to stop fluid?

• Most guidelines and texts recommend continuing fluid until the CK is below 5,000 U/L. This doesn't really make sense, though, because the CK persists for days after myoglobin is gone (and it is the myoglobin which is nephrotoxic; figure below).
  • Continuing fluid as long as the CK is >5,000 U/L amounts to treating a lab abnormality, rather than a true disease.
  • CK has a half-life of 36 hours. Thus, if the CK is markedly elevated, it will remain above 5,000 U/L long after myoglobin is gone. (28235546)
• Use your judgement regarding when to stop the fluid:
  • If the patient is running an even fluid balance (i.e., excreting all the fluid you give them), then infused fluid isn't causing harm. Continuing the fluid in this scenario is fine.
  • If the patient is running a persistently positive fluid balance, then fluid is accumulating and potentially dangerous. Consider earlier termination of fluid administration.
    • 🛑 Systemic congestion is nephrotoxic. If the patient is retaining the administered fluid and developing volume overload, then continuing to administer fluid will cause harm.

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dialysis

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• Historically, there was interest in using dialysis to remove myoglobin from the blood, but this hasn't been shown to be effective.
  • Dialysis should not be used “prophylactically” to prevent AKI.
• The indications for dialysis in these patients are the same as indications for dialysis in any patient.
  • For more on the use of dialysis in AKI, see the AKI chapter.

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Failure to review the medication list and discontinue all potentially causative drugs.
• Placing the patient on 200 ml/hour, forgetting about it, and discovering on the following day that the patient is five liters positive.
• Failure to discontinue nephrotoxic medications.

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