By
Dr Sahar Karimpour
Internal medicine resident
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Rhabdomyolysis is a syndrome
characterized by muscle necrosis
and the release of intracellular
muscle constituents into the
circulation.
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Rhabdomyolysis is characterized
clinically by myalgias, red to
brown urine due to
myoglobinuria, and elevated
serum muscle enzymes
(including creatine kinase) . The
degree of muscle pain and other
symptoms varies widely.
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The characteristic triad of
complaints in rhabdomyolysis is
muscle pain, weakness, and dark
urine .
more than half of patients may not
report muscular symptoms in
contrast, occasional others may
experience very severe pain.
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Muscle pain, when present, is
typically most prominent in
proximal muscle groups, such as the
thighs and shoulders, and in the
lower back and calves . Other
muscle symptoms include stiffness
and cramping.
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Additional symptoms that are more
common in severely affected
patients include malaise, fever,
tachycardia, nausea and vomiting,
and abdominal pain .
Altered mental status may occur
from the underlying etiology (eg,
toxins, drugs, trauma, or electrolyte
abnormalities).
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Muscle tenderness and swelling may be seen
Muscle weakness may be present, depending
upon the severity of muscle injury.
Limb induration is occasionally present.
Skin changes of ischemic tissue injury, such as
discoloration or blisters, may also be seen but
are present in less than 10 percent of patients
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The hallmark of rhabdomyolysis is an
elevation in creatine kinase and other serum
muscle enzymes.
The other characteristic finding is the reddishbrown urine of myoglobinuria, but because this
may be observed in only half of cases, its
absence does not exclude the diagnosis.
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Serum creatine kinase (CK) levels at
presentation are usually at least five times the
upper limit of normal, but range from
approximately 1500 to over 100,000
international units/L.
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The CK is generally of the MM or skeletal
muscle fraction; a small proportion of the total
CK may be from the MB or myocardial
fraction.
The presence of MB reflects the small amount
found in skeletal muscle rather than the
presence of myocardial disease.
Elevations in serum aminotransferases are
common and can cause confusion if attributed
to liver disease.
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The serum CK begins to rise within 2 to 12
hours following the onset of muscle injury and
reaches its maximum within 24 to 72 hours.
A decline is usually seen within three to five
days of cessation of muscle injury.
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CK has a serum half-life of about 1.5 days and
declines at a relatively constant rate of about 40
to 50 percent of the previous day’s value.
In patients whose CK does not decline as
expected, continued muscle injury or the
development of a compartment syndrome may
be present.
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Myoglobin, a heme-containing respiratory
protein, is released from damaged muscle in
parallel with CK.
Myoglobin is a monomer that is not
significantly protein bound and is, rapidly
excreted in the urine, often resulting in the
production of red to brown urine.
It appears in the urine when the plasma
concentration exceeds 1.5 mg/dL
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Visible changes in the urine only occur once
urine levels exceed from about 100 to 300
mg/dL, although it can be detected by the
urine (orthotolidine) dipstick at concentrations
of only 0.5 to 1 mg/dL .
Myoglobin has a half-life of only two to three
hours, much shorter than that of CK.
Because of its rapid excretion and metabolism
to bilirubin, serum levels may return to normal
within six to eight hours.
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Both hemoglobin and myoglobin can be
detected on the urine dipstick as “blood”
microscopic evaluation of the urine generally
shows few red blood cells (less than five per
high-powered field) in patients with
rhabdomyolysis whose positive test results
from myoglobinuria .
Such testing is not a reliable method for rapid
detection of myoglobin if red blood cells are
present or in patients with hemolysis due to its
lack of specificity for myoglobin.
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Proteinuria may also be seen, due to the release
of myoglobin and other proteins by the
damaged myocytes .
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fluid and electrolyte abnormalities, many of
which precede or occur in the absence of
kidney failure, and hepatic injury
cardiac dysrhythmias and risk of cardiac arrest
may result from the severe hyperkalemia that
occurs with significant myonecrosis .
Later complications include acute kidney
injury, compartment syndrome, and, rarely,
disseminated intravascular coagulation.
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Hypovolemia results from “third-spacing” due to
the influx of extracellular fluid into injured
muscles and increases the risk of acute kidney
injury
Hyperkalemia and hyperphosphatemia result from
the release of potassium and phosphorus from
damaged muscle cells.
Levels of potassium may increase rapidly, but the
levels of potassium and phosphate decrease as
they are excreted in the urine. Hyperkalemia is
more common in patients with oliguric acute
kidney injury
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Hypocalcemia, which can be extreme, occurs in the
first few days because of entry into damaged
myocytes and both deposition of calcium salts in
damaged muscle and decreased bone
responsiveness to parathyroid hormone.
During the recovery phase, serum calcium levels
return to normal and may rebound to significantly
elevated levels due to the release of calcium from
injured muscle, mild secondary
hyperparathyroidism from the acute renal failure,
and an increase in calcitriol (1,25dihydroxyvitamin D)
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Severe hyperuricemia may develop because of
the release of purines from damaged muscle
cells and, if acute kidney injury occurs, reduced
urinary excretion.
Metabolic acidosis is common, and an
increased anion gap may be present.
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Acute kidney injury (AKI, acute renal failure)
is a common complication of rhabdomyolysis.
The reported frequency of AKI ranges from 15
to over 50 percent .
The risk of AKI is lower in patients with CK
levels at admission less than 15 to 20,000
units/L;
risk factors for AKI in patients with lower
values include dehydration, sepsis, and
acidosis .
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Volume depletion resulting in renal ischemia,
tubular obstruction due to heme pigment casts,
and tubular injury from free chelatable iron all
contribute to the development of renal
dysfunction.
Reddish-gold pigmented casts are often
observed in the urine sediment.
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A compartment syndrome exists when
increased pressure in a closed anatomic space
threatens the viability of the muscles and
nerves within the compartment .
Compartment syndrome is a potential
complication of severe rhabdomyolysis that
may develop after fluid resuscitation, with
worsening edema of the limb and muscle .
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Infrequently, severe rhabdomyolysis may be
associated with the development of
disseminated intravascular coagulation due to
the release of thromboplastin and other
prothrombotic substances from the damaged
muscle .
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Indications for diagnostic testing:
Both myalgias and pigmenturia
Either myalgias or pigmenturia, with a
history suggesting the presence or recent
exposure to a potential cause or event
The diagnosis should be suspected following
prolonged immobilization, in any stuporous
or comatose patient or in a patient who is
otherwise unable to provide a medical
history and has one or more of the following:
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Muscle tenderness
Evidence of pressure necrosis of the skin
Signs of multiple trauma or a crush injury
Blood chemistry abnormalities suggesting the
possibility of increased cell breakdown, such as
hyperkalemia, hyperphosphatemia, and /or
hypocalcemia
Evidence of acute kidney injury
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Creatine kinase
Urinalysis, including dipstick and microscopic
evaluation
Complete blood count, including differential
and platelet count
Blood urea nitrogen, creatinine, and routine
electrolytes including potassium
Calcium, phosphate, albumin, and uric acid
Electrocardiography
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Additional testing, such as evaluation of
suspected metabolic myopathy or toxicology
screening for drugs of abuse, depends upon the
clinical context.
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We make the diagnosis of rhabdomyolysis in a
patient with either an acute neuromuscular illness
or dark urine without other symptoms, plus a
marked acute elevation in serum creatine kinase
(CK).
The CK is typically at least five times the upper
limit of normal, and is usually greater than 5000
international units/L.
No absolute cut-off value for CK elevation can be
defined, and the CK should be considered in the
clinical context of the history and examination
findings
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Other muscle enzymes in addition to CK are
typically elevated (eg, aldolase,
aminotransferases, lactate dehydrogenase), but
such testing is not usually necessary to make
the diagnosis.
In patients with dark urine, but without
elevation in the CK, additional diagnostic
considerations should be explored.
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A muscle biopsy is generally not required.
Findings on biopsy include loss of normal crossstriations and cell nuclei and the absence of
inflammatory cells .
Electromyography (EMG) is generally not
required. Findings are most often normal and are
only mild when present.
Magnetic resonance imaging (MRI) is generally not
required. Findings in affected muscle include
increased signal intensity on T2-weighted images
and good contrast between normal and abnormal
muscles on STIR images.
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There are recurrent episodes of
rhabdomyolysis after exertion or in association
with fasting or a viral illness. The last two
associations occur most commonly with
carnitine palmitoyltransferase deficiency and
the other disorders of lipid metabolism.
There is a history of exercise intolerance,
recurrent cramps, and fatigue beginning in
childhood, and episodes of pigmenturia
occurring in adolescence.
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There is a family history of rhabdomyolysis or
exercise intolerance, particularly in siblings,
thereby suggestive of an autosomal recessive
inheritance pattern.
The individual has normal strength and muscle
enzymes during interictal periods. One
exception is muscle phosphorylase deficiency,
a disorder in which chronic muscle weakness
may develop after repeated episodes and CK
levels do not return to normal between attacks
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Myocardial infarction
Inflammatory myopathy
Immune-mediated necrotizing myopathy
Deep vein thrombosis
Renal colic
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Recognition and management of fluid and
electrolyte abnormalities, which should be
initiated regardless of renal function and which
may prevent severe metabolic disturbances and
acute kidney injury.
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Identification of the specific causes and the use
of appropriate countermeasures directed at the
triggering events, including discontinuation of
drugs or other toxins that may be etiologic
factors
Prompt recognition, evaluation, and treatment
of compartment syndrome in patients in whom
it is present.
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In addition to treating the underlying
rhabdomyolysis or hemolysis, the general goals
for preventive therapy in all patients at risk for
heme pigment-induced AKI are twofold:
Correction of volume depletion, if present
Prevention of intratubular cast formation
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The goals of volume repletion are to maintain
or enhance renal perfusion, minimizing
ischemic injury, and to increase the urine flow
rate which will limit intratubular cast
formation, wash out partially obstructing
intratubular casts, and increase urinary
potassium excretion.
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Intravenous isotonic saline should be
administered as soon as possible after the onset
of injury or detection of hemolysis, and
continued until the muscle injury or hemolysis
has resolved.
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The optimal fluid and rate of repletion are
unclear. In addition, the total amount and rate
of volume repletion will vary depending on the
underlying cause of rhabdomyolysis and
hemolysis.
For patients who are at risk for hemeassociated AKI due to rhabdomyolysis from
any cause, we suggest initial fluid resuscitation
with isotonic saline at a rate of 1 to 2 L/hour.
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The plasma creatinine kinase (CK) concentration
correlates with the severity of muscle injury and
concentrations >5000 U/L identify patients who
are at risk for the development of AKI.
All patients should be initially treated with
vigorous fluid repletion until it is clear from
sequential laboratory values that the plasma CK
level is stable and not increasing. Patients who
have a stable plasma CK level less than 5000 U/L
do not require intravenous fluid since studies have
shown that the risk of AKI is low among such
patients .
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The initial rate is continued until the systemic
blood pressure normalizes and urine output is
established, or there is evidence of volume
overload.
If a diuresis is established, fluids are titrated to
maintain a urine output of 200 to 300 mL/hour.
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Among patients with rhabdomyolysis, fluid
repletion should be continued until plasma CK
levels decrease to less than 5000 U/L and urine
is dipstick negative for hematuria.
Among patients with hemolysis, LDH and
hemoglobin levels should be monitored to
guide intravenous fluid therapy.
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A forced alkaline diuresis, in which the urine pH
is raised to above 6.5, may diminish the renal
toxicity of heme.
In theory, urine alkalinization prevents hemeprotein precipitation with Tamm-Horsfall protein,
and therefore intratubular pigment cast formation.
Alkalinization may also decrease the release of free
iron from myoglobin and the formation of F2isoprostanes, which may enhance renal
vasoconstriction and decrease the risk for tubular
precipitation of uric acid.
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In addition to a lack of clear evidence of
benefit, maintaining the urine pH above 6.5 is
difficult in patients with AKI.
There are also potential risks to alkalinization
of the plasma, such as promoting calcium
phosphate deposition (which is more likely if
hyperphosphatemia is present), and inducing
or worsening the manifestations of
hypocalcemia by both a direct membrane effect
and a reduction in ionized calcium levels .
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Despite these limitations, patients who are
appropriately monitored may benefit from bicarbonate
therapy.
We generally administer a bicarbonate infusion to
patients who have severe rhabdomyolysis, such as
those with a serum CK above 5000 U/L, or clinical
evidence of severe muscle injury (eg, crush injury) and
a rising serum CK, regardless of the initial value. In
such patients, bicarbonate may be given, providing the
following conditions are met:
Severe hypocalcemia is not present
Arterial pH is less than 7.50
Serum bicarbonate is less 30 meq/L
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We infuse 130 meq/L of sodium bicarbonate
(150 mL [3 amps] of 8.4 percent sodium
bicarbonate mixed with 1 L of 5 percent
dextrose or water) via an intravenous line
separate from that used for the isotonic saline
infusion. The initial rate of infusion is 200
mL/hour; the rate is adjusted to achieve a
urine pH of >6.5.
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If bicarbonate is given, the arterial pH and serum
calcium should be monitored every two hours
during the infusion.
The bicarbonate infusion should be discontinued if
the urine pH does not rise above 6.5 after three to
four hours, if the patient develops symptomatic
hypocalcemia, if the arterial pH exceeds 7.5 or if
the serum bicarbonate exceeds 30 meq/L.
If the bicarbonate solution is discontinued,
volume repletion should be continued with
isotonic saline.
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The benefit of loop diuretics or mannitol in
rhabdomyolysis is not established.
Experimental studies suggested that mannitol
might be protective by causing a diuresis,
which minimizes intratubular heme pigment
deposition and cast formation, and/or by
acting as a free radical scavenger, thereby
minimizing cell injury.
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mannitol can lead to both volume depletion and,
since free water is lost with mannitol,
hypernatremia
Mannitol administered in very high doses, or to
patients with reduced renal excretion can cause
hyperosmolality, volume expansion and
hyperosmolar hyponatremia.
The increase in plasma osmolality can also cause
passive movement of potassium out of cells and
raise the plasma potassium concentration.
Acute renal failure may occur if patients are
treated with more than 200 g of mannitol per day.
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The use of mannitol administration may be of
benefit in patients with marked elevations in CK
(>30,000 U/L), however, even in these patients
with severe rhabdomyolysis, the true benefit
associated with mannitol administration remains
undefined.
If mannitol is given, providing the urinary flow is
adequate (defined as >20 mL/hour), adding 50 mL
of 20 percent mannitol (1 to 2 g/kg per day [total,
120 g], given at a rate of 5 g per hour) to each liter
of fluid is suggested.
Mannitol is contraindicated in patients with
oligoanuria.
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If mannitol is given, the plasma osmolal gap
should be measured, and mannitol
discontinued if the osmolal gap rises above 55
mosmol/kg
Mannitol should be discontinued if the desired
diuresis of approximately 200 to 300 mL/hour
cannot be achieved, since there is a risk of
hyperosmolality, volume overload, and
hyperkalemia with continued mannitol
administration under these conditions.
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Loop diuretics have no impact on outcome in
AKI
In the context of rhabdomyolysis, loop
diuretics may worsen the already existing
trend for hypocalcemia, since they induce
calciuria and may increase the risk of cast
formation
judicious use of loop diuretics may be justified
in patients with rhabdomyolysis or hemolysis
if there is evidence of volume overload.
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Patients who remain oliguric or anuric despite
aggressive volume resuscitation should be
considered to have established AKI.
Among such patients, the rate of fluid
administration should be decreased to a rate
sufficient to maintain circulatory support. Such
patients should be closely followed for
indications to initiate dialysis.
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The use of dialysis to remove myoglobin,
hemoglobin or uric acid in order to prevent the
development of renal injury has not been
demonstrated .
The initiation of dialysis may be necessary for
control of volume overload, hyperkalemia,
severe acidemia, and uremia in established
AKI.
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Patients should be closely followed for the
development of metabolic abnormalities
including hyperkalemia, hypocalcemia,
hyperphosphatemia, and hyperuricemia.
To minimize the late occurrence of
hypercalcemia, calcium supplementation for
hypocalcemia should be avoided unless
significant signs and symptoms of
hypocalcemia develop or calcium
administration is required for the management
of hyperkalemia.
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Hyperkalemia should be anticipated and may
occur even in the absence of severe renal failure.
Hyperkalemia should be aggressively treated.
Dialysis may be required to treat severe
hyperkalemia.
Patients who develop hyperuricemia should be
treated with allopurinol . Allopurinol should be
given orally at 300 mg if uric acid levels are >8
mg/dL (476 micromol/L) or if there is a 25 percent
increase from baseline.
Allopurinol is not indicated in the treatment of
hemolysis in the absence of hyperuricemia.
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Other than maintenance of fluid and electrolyte
balance and tissue perfusion, there is no specific
therapy once the patient has developed AKI.
The initiation of dialysis may be necessary for
control of volume overload, hyperkalemia, severe
acidemia, and uremia.
Peritoneal dialysis may not be sufficient to achieve
adequate metabolic control in patients with severe
rhabdomyolysis, which may necessitate frequent
hemodialysis or the use of high dose continuous
renal replacement therapy
Thanks for your kind attention