CONTENTS

• Rapid Reference 🚀
• Preamble: Trust No One
• Causes of rhabdomyolysis
• Signs & symptoms
• Diagnosis
  • Lab clues to rhabdomyolysis
  • Creatine kinase (CK)
  • McMahon Score
  • Problems in defining rhabdomyolysis
• Treatment
  • Basics
  • Volume & pH management
  • Dialysis
• Podcast
• Questions & discussion
• Pitfalls

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rapid reference

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diagnosis:

McMahon Score (≧6 indicates risk of renal failure):

• Age
  • <50 = zero points.
  • 51-70 = 1 point.
  • 71-80 = 2 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.

treatment:

1. Manage any underlying causes (e.g., compartment syndrome).
2. Discontinue any nephrotoxic medications.
3. Discontinue any myotoxic medications.
4. Follow electrolytes and manage as needed (e.g., hyperkalemia).
5. Manage acute kidney injury if present.
6. Volume resuscitation as below:

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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 creatinine kinase (if any) predicts renal injury. There are precisely zero 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 (most notable offenders listed below, but this is not exhaustive)(Wijdicks, 2019)

• Statins & fibrates.
  • 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.📄
• Colchicine.
• Psychiatric medications
  • Antidepressants: tricyclics, venlafaxine, sertraline, escitalopram.
  • Antipsychotics: aripiprazole, clozapine, haloperidol, risperidone, quetiapine.
• Antimicrobials (32532456)
  • Antibiotics: daptomycin, quinolones, trimethoprim-sulfamethoxazole
  • Antifungals: amphotericin B
  • Antiretrovirals: tenofovir/abacavir, raltegravir, zidovudine
• Propofol (sometimes via propofol infusion syndrome).
• Antihistamines.
• Interferon alpha.
• Toxicology:
  • Sympathomimetics (especially in combination with hyperactivity).
  • Alcohol (acute or chronic).
  • Venoms (snake, spider).

physical injury

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

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 (e.g., serotonin syndrome, neuroleptic malignant syndrome).

dysthermia

• Hyperthermia of any etiology (especially hyperthermic rigidity syndromes, such as neuroleptic malignant syndrome).
• Hypothermia.

electrolyte abnormalities

• hypoPhosphatemia.
• hypoCalcemia.
• hypoKalemia.
• hypernatremia or hyponatremia.
• hyperosmolarity due to diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic syndrome (HHNS).
• hypothyroidism.

infections (numerous, perhaps most commonly associated with)

• Viral infections (e.g., influenza, adenovirus, herpes simplex, Epstein-Barr, Cytomegalovirus, VZV, HIV, coxsackievirus, enterovirus)
• Legionella, Mycoplasma pneumoniae.
• Clostridium spp.
• Toxic shock syndrome.

other

• Hyperthyroidism or hypothyroidism.
• Sickle cell disease.
• Dermatomyositis, polymyositis.

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signs & symptoms of rhabdomyolysis

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symptoms

• Overall in the literature, symptoms of rhabdomyolysis are uncommon:(30617905)
  • Muscle pain (23% of patients), swelling, or cramping.
  • Muscle weakness (12% of patients).
  • Muscle swelling.
• Symptoms are usually absent in critically ill patients (e.g., due to sedation or altered sensorium).

signs

• True signs of rhabdomyolysis:
  • 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.
• Red flags of possible muscle damage:
  • Patients who were comatose for prolonged periods may develop focal pressure ulceration or blistering on dependent skin. This should raise alertness for the possibility of underlying muscle damage.
  • Other signs of muscle damage (e.g., compartment syndrome or ischemic limb).

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lab clues to the diagnosis of rhabdomyolysis

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Aside from creatinine kinase levels, three lab patterns may suggest rhabdomyolysis. None of these patterns are 100% sensitive, so they cannot be relied upon to diagnose rhabdomyolysis. However, if you happen to come across them, further investigation is warranted.

pattern #1: tumor lysis syndrome pattern

• Necrosis of large quantities of tissue may cause the following constellation of electrolyte changes. This is similar to tumor lysis syndrome:
  • Hyperkalemia
  • Hyperphosphatemia
  • Hypocalcemia (calcium enters damaged muscle cells, and also forms complexes with phosphate)
  • Elevated uric acid & lactate dehydrogenase levels (although these aren't routinely measured)

pattern #2: isolated AST (aspartate aminotransferase) elevation

• 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.

pattern #3: urinalysis with positive “heme” but no red blood cells.

• Free myoglobin released in the urine creates a paradoxical mismatch:
  • Myoglobin cross-reacts with the dipstick test for heme pigments. This will cause the urinalysis to be positive for “heme” or “blood.”
  • Microscopic urinalysis shows no red blood cells (0-5 erythrocytes per high-powered field).
• Performance of urinalysis for diagnosis of rhabdomyolysis:
  • The sensitivity of a heme-positive urine is good (>90%).(22082877, 24332910) Patients with myoglobinuria may have heme-negative dipstick results (false-negative) due to highly concentrated urine, high nitrite concentrations, or ascorbic acid.(28235546) Of course, the specificity of heme-positive urine is low.
  • The combination of heme-positive plus erythrocyte-negative urinalysis is seen only in ~35% of patients with rhabdomyolysis.(22082877, 24332910)
• Clinical use of urinalysis to evaluate for rhabdomyolysis:
  • If you see the heme-positive, erythrocyte-negative pattern, then evaluate further for rhabdomyolysis or hemolysis.
  • If the urinalysis is heme-negative, this argues against rhabdomyolysis (without excluding it). Further evaluation may be indicated depending on your pre-test probability.

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creatine kinase

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Creatine kinase (CK) is the standard biomarker for rhabdomyolysis. The following categorization scheme is consistent with the majority of current literature.(30617905)

creatine kinase level has major problems:

• (1) Using CK levels may delay the diagnosis of rhabdomyolysis:
  • 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 creatinine 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 creatinine 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 moderately elevated 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).
  • It's unclear whether ongoing measurement of CK is helpful to guide the treatment of established rhabdomyolysis.

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McMahon Score

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McMahon score basics

• This is a prognostic score generated from epidemiological data and labs available on admission.
• A score of six or greater indicates risk of acute kidney injury or dialysis, suggesting a possible benefit from treatment:

calculating the McMahon score [MDCalc link]

• Age:
  • <50 = zero points.
  • 51-70 = 1 point.
  • 71-80 = 2 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.

advantages of McMahon score compared to CK level alone

• The McMahon score can facilitate treatment without waiting for the CK level to rise above 5,000 U/L.
• The McMahon score is based on superior evidence than purely CK-based definitions of rhabdomyolysis:
  • The McMahon score was validated in two studies at different institutions. (24000014, 27259093)
  • In one validation study, a McMahon score of 6 or greater 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 may be a more scientific approach than arbitrarily defining rhabdomyolysis based on a single cutoff value.

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treatment basics

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evaluate & treat any underlying problem(s)

• Focused physical examination to evaluate for causes (e.g. compartment syndrome, ischemic limb).
• Discontinue any potentially causative medications.

electrolyte management

• Hyperkalemia due to renal failure and muscle breakdown may require urgent treatment.
  • More on treatment for hyperkalemia here.
• 🛑 Avoid treatment of hypocalcemia if at possible (giving calcium may theoretically worsen muscle injury).
• Treat electrolyte abnormalities which may be contributing to rhabdomyolysis (especially hypokalemia and hypophosphatemia). However, once established rhabdomyolysis occurs, hypokalemia and hypophosphatemia will generally disappear, due to potassium and phosphate release from muscle tissue.

discontinue any nephrotoxic medications

• The primary concern with rhabdomyolysis is the development of acute kidney injury.
• 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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volume & pH management

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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.
  • These fluids have relatively neutral effects on pH.
  • Many studies suggest that balanced crystalloids reduce the risk of acute kidney injury, as compared to normal saline.
• For patients with a non-anion-gap metabolic acidosis or uremic acidosis, administration of isotonic bicarbonate is sensible:
  • Administration of isotonic bicarbonate to patients with non-anion-gap metabolic acidosis makes physiologic sense in general and is usually accepted as therapy for this abnormality.
  • 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 for days – 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 causing harm. 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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podcast

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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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