RHABDOMYOLYSIS

Overview (Davidson’s and Kumar and Clark)

• Rhabdomyolysis occurs when there is an injury to a large volume • Rhabdomyolysis, or ‘crush syndrome’, occurs when skeletal
of skeletal muscle, usually because a single limb or muscle muscle injury provokes the release of intracellular myoglobin, a
compartment has been ischaemic for a prolonged period. direct tubular toxin leading to ATN.
• It can also occur following trauma and crush injury or a>er over- • Causes include trauma, compartment syndrome, excessive
exerAon of muscles. Over-exerAon can occur a>er intense exerAon (marathon runners), status epilepAcus and muscle
physical exercise or as part of a medical condiAon that causes toxins (staAns, malaria and anAmalarials, and snake and insect
widespread muscular acAvity, such as malignant hyperpyrexia or venom).
neurolepAc malignant syndrome. • Rapid rises in potassium, phosphate and lactate accompany
• A CK level of > 1000 U/L is highly suggesAve, although it can rise elevated muscle enzymes (AST); characterisAcally, creaAne
to tens of thousands in severe cases. phosphokinase (CK) is massively elevated.
• Management should focus on idenAficaAon and correcAon of • Early and vigorous fluid resuscitaAon is vital (injured muscle
the underlying cause and support for mulA-organ dysfuncAon. sequesters large amounts of fluid, causing hypovolaemic shock).
• Forced alkaline diuresis (using IV bicarbonate infusion and • Inflamed, injured muscle may become ischaemic in
furosemide) can be used to maintain a good flow of less acidic compartments, and a careful examinaAon for typical ‘woody-
fluid within the renal tubules and reduce myoglobin hard’ muscle compartments may suggest a need for
precipitaAon. fasciotomies to release at-risk muscle.
• Sodium bicarbonate used to alkalinize the urine may limit
myoglobin-induced injury.
• A similar syndrome can arise with massive haemolysis, where
the tubular toxin is haemoglobin rather than myoglobin.
• As cell breakdown is on a far smaller scale, the biochemical
derangements seen with muscle injury may be absent.

INTRODUCTION

• Rhabdomyolysis is a syndrome characterized by muscle necrosis • The severity of illness ranges from asymptomaAc elevaAons in
and the release of intracellular muscle consAtuents into the serum muscle enzymes to life-threatening disease associated
circulaAon. with extreme enzyme elevaAons, electrolyte imbalances, and
• CreaAne kinase (CK) levels are typically markedly elevated, and acute kidney injury.
muscle pain and myoglobinuria may be present.
CLINICAL MANIFESTATIONS

• Rhabdomyolysis is characterized clinically by myalgias, red to

brown urine due to myoglobinuria, and elevated serum muscle
enzymes (including CK).
• The degree of muscle pain and other symptoms varies widely.

Symptoms

• The characterisAc triad of complaints in rhabdomyolysis is

muscle pain, weakness, and dark urine.
• However, more than half of paAents may not report muscular
symptoms; by contrast, occasional others may experience very
severe pain.
• 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 sAffness and cramping.
• AddiAonal symptoms that are more common in severely affected
paAents include malaise, fever, tachycardia, nausea and
vomiAng, and abdominal pain.
• Altered mental status may occur from the underlying eAology
(eg, toxins, drugs, trauma, or electrolyte abnormaliAes).

Physical findings

• Muscle tenderness and swelling may be seen, but detectable • Limb induraAon is occasionally present.
muscle swelling in the extremiAes generally develops, when it • Skin changes of ischemic Assue injury, such as discoloraAon or
occurs, with fluid repleAon. Such swelling is much less common blisters, may also be seen but are present in <10% of paAents.
on hospital admission.
• Muscle weakness may be present, depending upon the severity
of muscle injury.
Laboratory findings

• The hallmark of rhabdomyolysis is an elevaAon in CK and other • InfecAons and crush injuries are associated with marked
serum muscle enzymes. elevaAon of the acute phase reactants and peripheral WBC
• The other characterisAc finding is the reddish-brown urine of count, while these markers of inflammaAon would likely be
myoglobinuria, but because this may be observed in only half of normal or only minimally raised in paAents with other eAologies,
cases, its absence does not exclude the diagnosis. such as drug-induced or electrolyte derangements.
• RouAne lab tests, including complete blood count, ESR, and CRP,
vary greatly depending on the underlying cause of
rhabdomyolysis.

Crea%ne kinase

• Serum CK levels at presentaAon are usually at least five Ames • ElevaAons in serum aminotransferases are common and can
the upper limit of normal, but range from ~1500 to over 100,000 cause confusion if agributed to liver disease. In one study,
internaAonal units/L. aspartate aminotransferase (AST) was elevated in 93.1% and
• The mean peak CK reported for each of a variety of different alanine aminotransferase (ALT) in 75% of rhabdomyolysis cases
causes and for paAents with both single and mulAple causes in which the CK was greater than or equal to 1000 units/L. In
ranged from ~10,000 to 25,000 in the largest series; excepAons only one instance was the ALT greater than the AST, although the
were the three paAents with malignant hyperthermia, whose AST declines faster than the ALT as the rhabdomyolysis resolves,
values averaged almost 60,000. such that the two may equalize a>er a few days.
• The CK is generally enArely or almost enArely of the MM or • The serum CK begins to rise within 2 to 12 hours following the
skeletal muscle fracAon; a small proporAon of the total CK may onset of muscle injury and reaches its maximum within 24 to 72
be from the MB or myocardial fracAon. The presence of MB hours. A decline is usually seen within three to five days of
reflects the small amount found in skeletal muscle rather than cessaAon of muscle injury. CK has a serum half-life of about 1.5
the presence of myocardial disease. days and declines at a relaAvely constant rate of about 40 to 50%
of the previous day's value. In paAents whose CK does not
decline as expected, conAnued muscle injury or the
development of a compartment syndrome may be present.

Urine findings and myoglobinuria

• Myoglobin, a heme-containing respiratory protein, is released • As above, rhabdomyolysis does not occur unless CK is elevated
from damaged muscle in parallel with CK. five Ames or more above the upper limit of normal.
• Myoglobin is a monomer that is not significantly protein-bound • RouAne urine tesAng for myoglobin by urine dipsAck evaluaAon
and is therefore rapidly excreted in the urine, o>en resulAng in may be negaAve in up to half of paAents with rhabdomyolysis.
the producAon of red to brown urine. • Pigmenturia will be missed in rhabdomyolysis if the filtered load
• It appears in the urine when the plasma concentraAon exceeds of myoglobin is insufficient or has largely resolved before the
1.5 mg/dL. Visible changes in the urine only occur once urine paAent seeks medical agenAon due to its rapid clearance.
levels exceed from about 100 to 300 mg/dL, although it can be • Both hemoglobin and myoglobin can be detected on the urine
detected by the urine (orthotolidine) dipsAck at concentraAons dipsAck as "blood"; microscopic evaluaAon of the urine generally
of only 0.5 to 1 mg/dL. shows few RBCs (<5 per high-powered field) in paAents with
• Myoglobin has a half-life of only two to three hours, much rhabdomyolysis whose posiAve test results from myoglobinuria.
shorter than that of CK. Because of its rapid excreAon and Such tesAng is not a reliable method for rapid detecAon of
metabolism to bilirubin, serum levels may return to normal myoglobin if RBC are present or in paAents with hemolysis due
within six to eight hours. to its lack of specificity for myoglobin.
• Thus, it is not unusual for CK levels to remain elevated in the • Hemoglobin, the other heme pigment capable of producing
absence of myoglobinuria. pigmented urine, is much larger (a tetramer) than myoglobin
• In rhabdomyolysis, myoglobin appears in the plasma before CK and is protein-bound. As a result, much higher plasma
elevaAon occurs and disappears while CK is sAll elevated or concentraAons are required before red to brown urine is seen,
rising. Therefore, there is no CK threshold for when myoglobin resulAng in a change in plasma color.
appears.
Other manifesta%ons

• Other manifestaAons of rhabdomyolysis include fluid and • Later complicaAons include acute kidney injury, compartment
electrolyte abnormaliAes, many of which precede or occur in the syndrome, and, rarely, disseminated intravascular coagulaAon.
absence of kidney failure, and hepaAc injury; addiAonally,
cardiac dysrhythmias and risk of cardiac arrest may result from
the severe hyperkalemia that occurs with significant
myonecrosis.

Fluid and electrolyte abnormaliAes Acute kidney injury (AKI, acute renal failure)
• Hypovolemia and abnormaliAes in serum electrolytes and uric • AKI is a common complicaAon of rhabdomyolysis.
acid are common in paAents with rhabdomyolysis. • The risk of AKI is lower in paAents with CK levels at admission
• Hypovolemia results from "third-spacing" due to the influx of <15 to 20,000 units/L; risk factors for AKI in paAents with lower
extracellular fluid into injured muscles and increases the risk of values include dehydraAon, sepsis, and acidosis.
acute kidney injury. • Volume depleAon resulAng in renal ischemia, tubular
• Hyperkalemia and hyperphosphatemia result from the release of obstrucAon due to heme pigment casts, and tubular injury from
potassium and phosphorus from damaged muscle cells. Levels of free chelatable iron all contribute to the development of renal
potassium may increase rapidly, but the levels of potassium and dysfuncAon. Reddish-g
phosphate decrease as they are excreted in the urine.
Hyperkalemia is more common in paAents with oliguric acute Compartment syndrome
kidney injury. • A compartment syndrome exists when increased pressure in a
• Hypocalcemia, which can be extreme, occurs in the first few days closed anatomic space threatens the viability of the muscles and
because of entry into damaged myocytes and both deposiAon of nerves within the compartment.
calcium salts in damaged muscle and decreased bone • Compartment syndrome is a potenAal complicaAon of severe
responsiveness to parathyroid hormone. During the recovery rhabdomyolysis that may develop a>er fluid resuscitaAon, with
phase, serum calcium levels return to normal and may rebound worsening edema of the limb and muscle.
to significantly elevated levels due to the release of calcium from • Lower extremity compartment syndrome can also be a cause of
injured muscle, mild secondary hyperparathyroidism from the rhabdomyolysis, as may occur a>er Abial fractures.
acute renal failure, and an increase in calcitriol (1,25-
dihydroxyvitamin D) Disseminated intravascular coagulaAon
• Severe hyperuricemia may develop because of the release of Infrequently, severe rhabdomyolysis may be associated with the
purines from damaged muscle cells and, if acute kidney injury development of disseminated intravascular coagulaAon due to the
occurs, reduced urinary excreAon. release of thromboplasAn and other prothromboAc substances
• Metabolic acidosis is common, and an increased anion gap may from the damaged muscle.
be present.
EVALUATION AND DIAGNOSIS
IndicaGons for diagnosGc tesGng

• DiagnosAc tesAng should be performed in individuals with: • The diagnosis should be suspected following prolonged
- Both myalgias and pigmenturia. immobilizaAon, in any stuporous or comatose paAent or in a
- Either myalgias or pigmenturia, with a history suggesAng the paAent who is otherwise unable to provide a medical history and
presence or recent exposure to a potenAal cause or event. has one or more of the following:
• The absence of myalgias or pigmenturia in a clinical seqng - Muscle tenderness
associated with increased risk for rhabdomyolysis, as symptoms - Evidence of pressure necrosis of the skin
may be vague or absent in up to 50% of paAents. - Signs of mulAple trauma or a crush injury
- Blood chemistry abnormaliAes suggesAng the possibility of
increased cell breakdown, such as hyperkalemia,
hyperphosphatemia, and /or hypocalcemia
- Evidence of acute kidney injury

DiagnosGc evaluaGon
Crea%ne kinase

• FracAonaAon of the CK is generally not required but may be • Other muscle enzymes in addiAon to CK are typically elevated
helpful, in addiAon to the clinical history and examinaAon, in (eg, aldolase, aminotransferases, LDH), but such tesAng is not
excluding other potenAal causes of CK elevaAon such as acute usually necessary to make the diagnosis. However, elevaAons in
myocardial infarcAon, stroke, and other diseases of the heart aminotransferases or LDH may suggest the need for CK tesAng if
and brain. it has not been performed in a paAent in whom such
abnormaliAes may potenAally be due to muscle injury rather
than hepaAc injury or another cause.

Urinalysis (dips%ck and microscopic evalua%on)

• Evidence of myoglobinuria should be sought by rouAne urine • In paAents with persistent red to reddish-brown urine,
dipsAck evaluaAon combined with microscopic examinaAon. myoglobinuria is suggested when the urine tests posiAve for
• TesAng of the unspun urine or the supernatant of the heme by dipsAck a>er centrifugaAon, while the plasma has a
centrifuged urine will be posiAve for "heme" on dipsAck if normal color and tests negaAve for heme.
myoglobinuria is present, even if red to reddish brown urine is • Myoglobinuria lacks sensiAvity as a test for rhabdomyolysis; it
not evident macroscopically. may be absent in 25 to 50% of paAents with rhabdomyolysis due
• The visual and microscopic examinaAon of the sediment from a to the more rapid clearance of myoglobin, compared with CK,
fresh urine specimen is required to exclude the presence of RBC following muscle injury. Myoglobin also decreases rapidly in a
as the cause of posiAve tesAng; RBC in an older specimen may similar fashion in paAents with renal failure, suggesAng a role for
hemolyze over Ame, confounding the results. extrarenal metabolism and clearance in such paAents.

Diagnosis

• We make the diagnosis of rhabdomyolysis in a paAent with • AddiAonal tesAng, such as electromyography (EMG), MRI, and
either an acute neuromuscular illness or dark urine without muscle biopsy, is not required for the diagnosis of
other symptoms, plus a marked acute elevaAon in serum CK. rhabdomyolysis. These studies are generally reserved for
• The CK is typically at least five Ames the upper limit of normal, paAents in whom an underlying inflammatory myopathy is
and is usually >5000 internaAonal units/L. No absolute cut-off suspected.
value for CK elevaAon can be defined, and the CK should be
considered in the clinical context of the history and examinaAon
findings.
DIFFERENTIAL DIAGNOSIS
• The differenAal diagnoses of myalgia, elevated CK and other muscle enzymes, and dark urine are fairly extensive. However, when
present together, and if the CK elevaAon is acute and myoglobinuria is present, the diagnosis of rhabdomyolysis can generally be made
with confidence.
• The following condiAons may be considered, depending upon the combinaAon of findings that are present, but disAncAons can usually
be made with readily available informaAon from the medical history as well as the physical and laboratory examinaAons:

(a) Myocardial infarc;on – Although serum CK also rises (d) Immune-mediated necro;zing myopathy – PaAents on staAn
acutely with myocardial infarcAon, paAents with medicaAons may develop an immune-mediated necroAzing
rhabdomyolysis alone do not have ischemic chest pain or myopathy with markedly elevated levels of CK and weakness
ECG signs of myocardial infarcAon. AddiAonally, the CK- that does not improve with disconAnuaAon of staAns but that
MM fracAon is elevated, while ligle or no CK-MB is does respond to aggressive immunosuppressive therapy.
present. Assays for cardiac troponins (both the I and T These paAents can be disAnguished from paAents with
isoforms) are highly sensiAve and specific for cardiac rhabdomyolysis by the persistence of symptoms and findings,
muscle injury, although both isoforms can someAmes be including the elevaAon in CK, in the absence of treatment with
elevated in paAents with rhabdomyolysis. immunosuppressives and by their histopathologic changes.

(b) Hematuria and hemoglobinuria – Both hematuria and (e) Renal colic – In paAents presenAng with back pain,
hemoglobinuria (due to hemolysis) may result in red to rhabdomyolysis may be confused with renal colic. AddiAonally,
reddish-brown urine and may be confused with urine dipsAck tesAng may be posiAve for blood. However,
myoglobinuria. Careful examinaAon of the urine for RBCs urolithiasis is not associated with marked elevaAons of the CK,
(present in hematuria, by definiAon), of serum for and myoglobinuria is not present.
evidence of hemolysis, and of the CK (which is not
elevated in hemolysis, or most paAents with hematuria)
will help disAnguish these condiAons. Other causes of red
to brown urine include various foods and drugs, but such
paAents lack evidence of skeletal muscle injury, including
CK elevaAon.

(c) Inflammatory myopathy – PaAents with inflammatory

myopathy can also exhibit myalgias and elevated CK and
may exhibit myoglobinuria. These paAents can be
differenAated from paAents with rhabdomyolysis by the
chronicity of disease, usually symmetric proximal muscle
weakness developing over weeks to months, relaAve
stability of the laboratory abnormaliAes compared with
paAents with rhabdomyolysis, and the systemic features
associated with the inflammatory myopathies, such as
dermatomyosiAs.