N E U R O M US C ULA R N O T E S

Rhabdomyolysis
A practical approach to diagnosis and management.
By Farah El-Sadi, MD and Aaron Izenberg, MD, FRCPC

Rhabdomyolysis is a descriptive TABLE. RHABDOMYOLYSIS ETIOLOGIES

term used in reference to stri- Nonexertional nontraumatic
ated muscle breakdown with Alcohol and recreational drugs: ethanol, methanol, narcotics,
subsequent leakage of cellular amphetamines, lysergic acid
content into the circulation.1
Once released into the blood- Electrolyte disturbances: hypo- or hypernatremia, hypo- or
stream, muscle cellular components (eg, myoglobin, creatine hyperkalemia, hypophosphatemia, hypocalcemia
kinase, phosphate, and potassium) induce a cascade of Endocrine disorders: hypo- or hyperthyroidism, hyperglycemic
reactions, resulting in end-organ damage. Renal failure may states
be caused by tubular obstruction, tubular necrosis, or renal Environmental toxins: snake venom, spider venom, carbon
vasoconstriction. It is estimated that 15% to 33% of individu- monoxide
als with rhabdomyolysis develop acute renal failure.2
Hypo- or hyperthermia
Clinically, the defining features of rhabdomyolysis
include a triad of myalgia, weakness, and myoglobinuria. Inflammatory myopathies (rare presentation)
The biochemical hallmark of rhabdomyolysis is an eleva- Medications: statins, fibric acid derivatives, salicylates
tion of serum creatinine kinase (CK), at least 5 times the Neuroleptic malignant syndrome
upper limit of normal. Presentations range from asymp-
tomatic to severe myalgias, limb weakness, and fulminant Nonexertional traumatic
renal failure requiring dialysis. Compartment syndrome
The incidence of rhabdomyolysis is difficult to estimate, Crush injury
because some cases may be mild, and not everyone presents
Electrical injury
for medical attention. Hospital admissions secondary to rhab-
domyolysis over a 7-year period were reported as 0.074% of Infections
all admissions.3 Other estimates are provided by studies of Immobilization
specific causes of rhabdomyolysis, rather than rhabdomyolysis Surgery
as a whole. For example, the incidence of exertional rhabdo-
myolysis is reported as 22.2 cases per 100,000 per year.4 Exertional acquired
Extreme physical activity and exertion
Etiologies Hyperkinetic state
Although there are multiple approaches to categorizing
Sickle cell disease or trait (strenuous exercise)
etiologies of rhabdomyolysis, in clinical practice it is useful
to separate these into exertional vs nonexertional (Table).5 Seizure
Extreme physical activity may cause exertional rhabdomy- Exertional genetic
olysis in otherwise healthy individuals. People with under-
Congenital myopathies: ryanodine receptor 1 (RYR1) deficiency
lying myopathies (eg, mitochondrial disorders, metabolic
diseases, and muscular dystrophies) subjected to an addi- Disorders of lipid metabolism: carnitine palmitoyltransferas II
tional stressor may also develop exertional rhabdomyolysis. (CPT2) deficiency, carnitine deficiency
Nonexertional causes include drugs, toxins, inflammatory Glycogenoses: myophosphorylase deficiency (McArdle’s dis-
or autoimmune disease, infections, metabolic derange- ease), phosphofructokinase deficiency
ments, and direct muscle trauma. Muscle compression dur- Mitochondrial diseases
ing prolonged immobility (eg, from stroke, after surgery, or
because of altered consciousness after drug/alcohol intoxi- Muscular dystrophies: dystrophinopathies, limb-girdle
cation) is a common frequent cause for rhabdomyolysis. muscular dystrophies

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Pathophysiology
Regardless of the initial mechanism of muscle injury, the final
common pathway involves a rapid influx of calcium into myo-
cyte cytoplasm and mitochondria. Normally, the sarcolemma
maintains a low intracellular calcium concentration via a Ca2+-
Na+ exchanger, which is powered by a Na+-K+ ATPase pump.
Similarly, the sarcoplasmic reticulum relies on a Ca2+-ATPase
membrane pump. Both of these mechanisms require a con-
stant supply of adenosine triphosphate (ATP).6
Trauma can cause rupture of the sarcolemma, resulting
in passive calcium diffusion intracellularly. Alternatively, the
depletion of ATP—whether from intense exercise, sustained
muscle contraction, or electrolyte derangement—can induce
Na+-K+ ATPase dysfunction, reversing the Na+-Ca2+ exchanger
and thereby depolarizing the sarcolemma. A disrupted sarco-
lemma, in turn, can promote further calcium secretion from
the sarcoplasmic reticulum.7
Ultimately, increased intracellular calcium concentration
activates calcium-dependent proteases and phospholipases,
leading to muscle fiber necrosis and release of intracellular con-
tents into the circulation.

Clinical Presentation
The classic presentation of rhabdomyolysis includes myal-
gias; weakness; dark red or brown urine; elevated serum
CK; and, in more severe cases, renal failure. The full triad of
myalgia, muscle weakness, and pigmenturia, however, is seen
only in 10% of cases.8 Elevated CK is typically seen within 2 to
12 hours and often peaks within 3 days, but elevated CK alone
does not necessarily mean rhabdomyolysis has occurred. Some
degree of hyperCKemia is not uncommon in the context of
high-intensity exercise (eg, CK levels can be 22 times the upper
limit of normal in male marathon runners after a race).9 Levels
of CK that lead to renal failure are not well established; some
studies suggest values as low as 5000 U/L are sufficient to
cause renal failure.5 Rhabdomyolysis becomes clinically signifi-
cant when CK elevation is sufficiently high to cause end-organ
damage, such as renal failure.
Neurologists are often called on to determine if some-
one with rhabdomyolysis harbors an underlying myopathy.
This distinction is critical, because it informs counselling for
future activity levels and other important aspects of man-
agement (Figure).
Figure. Diagnostic algorithm for suspected rhabdomyolysis.
Several important clues raise suspicion for an underlying
Abbreviations: CK, creatinine kinase; EMG, electromyography;
myopathy. Recurrent episodes of rhabdomyolysis, including
NCS, nerve conduction studies.
recurrent episodes of pigmenturia, are suggestive of muscle
disease. The circumstances triggering rhabdomyolysis, such
as a viral illness or fasting, may also indicate the presence of 50 times the upper limit of normal at initial presentation sug-
an inherited myopathy. A family history of rhabdomyolysis gests a metabolic disorder. A continued CK elevation for more
may also indicate presence of an inherited myopathy. The than 8 weeks should raise suspicion for myopathy.5
degree and duration of CK elevation can also be helpful when The clinical picture beyond the acute phase is also
considering the differential diagnosis. Levels of CK more than extremely important. Individuals with persistent muscle

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weakness in between distinct episodes are more likely to tions during a fixed time interval. There have been growing
have a primary myopathy. concerns regarding the overall safety of these programs,
especially because some practitioners may be novice or inex-
Diagnostic Studies perienced athletes. Overall, ECP-induced rhabdomyolysis has
The diagnostic approach to rhabdomyolysis needs to be been reported in fit young individuals who are experienced
tailored to the suspected etiology. An initial common path- athletes, in deconditioned athletes, and in novices. The inci-
way, however, can be followed for all cases.6 Elevated serum dence of serious complications such as acute renal failure
CK may be the only indication of rhabdomyolysis in sub- as a result of exercise-induced rhabdomyolysis, however, is
clinical cases. Myoglobinuria is visible only when more than considerably lower than from other causes.12
100 g of muscle has been destroyed.6 The half-life of myo-
globin is 2 to 4 hours, and it is excreted into the urine only Management
when it overwhelms the serum protein-binding capacity.10 Management of rhabdomyolysis should involve treat-
These features make myoglobinuria a reliable marker only in ment of the renal and metabolic sequelae and an attempt
the hyperacute phase of rhabdomyolysis. to clarify the presence of any potential triggers or underly-
Detection of an electrolyte derangement (eg, hypoka- ing precipitating conditions. Electrolytes must be checked
lemia, hypophosphatemia, and hyper- or hyponatremia), frequently, and derangements corrected accordingly. If
which can be either a trigger or a consequence of rhabdo- any drugs are identified as possible triggers, they should
myolysis, is essential. A drug and toxin screen is indicated be promptly discontinued. The management of the renal
if a clear exertional or traumatic etiology is not established complications is dependent on the severity of the injury and
by the clinical history. Similarly, an endocrine work up is may involve diuresis with aggressive intravenous hydration
required, especially in the presence of an unexplained elec- or possibly dialysis. When possible, a nephrologist should be
trolyte derangement, with or without systemic features.11 consulted. Urine output of more than 200 mL/hr is recom-
If the presentation suggests an underlying myopathy, mended as a target for hydration therapy. Routine use of
additional investigations need to be considered. During urinary alkalinisation, with mannitol or sodium bicarbonate,
the resting period, an elevated serum lactate can indicate has not been shown effective in preventing renal failure.13
the presence of an underlying mitochondrial myopathy. A Admission to an intensive care unit for close monitoring
nonischemic forearm exercise test can be used to diagnose may be required if there are significantly elevated CK levels
McArdle’s disease. Mass spectrometry to determine an acyl- or evidence of end-organ damage.
carnitine profile can diagnose fatty acid oxidation disorders. There are currently no clear guidelines on returning to exer-
Muscle biopsy is an essential investigation for individuals cise after an episode of rhabdomyolysis. A risk stratification
with suspected myopathy who cannot be diagnosed with approach has been suggested that classifies individuals as hav-
genetic testing. The timing of the biopsy is crucial because ing high or low risk for recurrence.14 Factors associated with
features of an inherited myopathy can be obscured by a high risk of recurrence include personal or family history of
muscle necrosis during the acute phase of rhabdomyolysis. exertional rhabdomyolysis, persistent elevation in CK despite
Electrodiagnostic testing (ie, EMG) can provide further sup- rest for 2 weeks, serum CK peak more than100,000 UL, rhab-
port if the findings reveal myopathic features, although such domyolysis complicated by acute kidney injury of any degree,
testing should also be deferred until after the acute phase. and personal or family history of malignant hyperthermia.
Genetic screening for inherited myopathies can be done via Those who are considered at high risk for recurrence are also
single gene testing, panel tests, targeted or whole exome more likely to have an underlying myopathy. For these indi-
sequencing, or mitochondrial genome testing. The choice of viduals, a thorough work up is recommended including an
test depends on specific clinical features and the pattern of EMG, laboratory investigations for metabolic disease, and pos-
inheritance suggested by family history. Often, genetic test- sibly a muscle biopsy and/or genetic testing.
ing can obviate the need for a muscle biopsy and EMG. For People who are considered at low risk of recurrence
example, individuals with classic features of McArdle’s disease may return to exercise over 3 phases. Phase 1 consists of a
(eg, exercise intolerance, rhabdomyolysis, and second-wind 72-hour rest period with oral hydration in a thermally con-
phenomenon) can readily be diagnosed with genetic testing. trolled environment. The CK level and urinalysis should be
repeated at 72 hours. If these values are less than 5 times the
Rhabdomyolysis and High-Intensity Exercise upper limit of normal, then phase 2 can begin. In phase 2,
Recently, there has been a marked rise in the popular- the individual may do light exercise at their own pace. If this
ity of extreme conditioning programs (ECPs), such as is well tolerated with no return of symptoms, then phase 3
CrossFit. These activities are characterised by high-intensity can be commenced with a gradual return to regular sport-
functional movements performed as a number of repeti- ing activities.

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Summary
The clinical presentation of rhabdomyolysis is varied,
and not all individuals exhibit the classic triad of weakness,
myalgia, and myoglobinuria. Accurate diagnosis facilitates
the prompt initiation of management, including removal
of triggers and the correction of metabolic derangements.
Although most cases of rhabdomyolysis are benign, some
individuals harbor an occult myopathy. In selected cases
further workup, including electrodiagnostic studies, muscle
biopsy, and genetic testing is required. n
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Farah El-Sadi, MD
Division of Neurology
Department of Medicine
University of Toronto
St. Michael’s Hospital
Toronto, ON Canada

Aaron Izenberg, MD, FRCPC

Division of Neurology
Department of Medicine
University of Toronto
Sunnybrook Health Sciences Center
Toronto, ON Canada

Disclosures
FE-S and AI report no disclosures.

column editor
William S. David, MD, PhD
Associate Professor of Neurology
Harvard University School of Medicine
Neuromuscular Division Chief
Director of EMG Laboratory
Massachusetts General Hospital
Boston, MA

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