CHEST Postgraduate Education Corner

CONTEMPORARY REVIEWS IN CRITICAL CARE MEDICINE

Rhabdomyolysis
Janice L. Zimmerman, MD, FCCP; and Michael C. Shen, MD

Rhabdomyolysis is a well-known clinical syndrome of muscle injury associated with myoglobinu-

ria, electrolyte abnormalities, and often acute kidney injury (AKI). The pathophysiology involves
injury to the myocyte membrane and/or altered energy production that results in increased intra-
cellular calcium concentrations and initiation of destructive processes. Myoglobin has been iden-
tified as the primary muscle constituent contributing to renal damage in rhabdomyolysis. Although
rhabdomyolysis was first described with crush injuries and trauma, more common causes in hos-
pitalized patients at present include prescription and over-the-counter medications, alcohol, and
illicit drugs. The diagnosis is confirmed by elevated creatine kinase levels, but additional testing
is needed to evaluate for potential causes, electrolyte abnormalities, and AKI. Treatment is aimed
at discontinuation of further skeletal muscle damage, prevention of acute renal failure, and rapid
identification of potentially life-threatening complications. Review of existing published data
reveals a lack of high-quality evidence to support many interventions that are often recommended
for treating rhabdomyolysis. Early and aggressive fluid resuscitation to restore renal perfusion
and increase urine flow is agreed on as the main intervention for preventing and treating AKI.
There is little evidence other than from animal studies, retrospective observational studies, and
case series to support the routine use of bicarbonate-containing fluids, mannitol, and loop
diuretics. Hyperkalemia and compartment syndrome are additional complications of rhabdomy-
olysis that must be treated effectively. A definite need exists for well-designed prospective studies
to determine the optimal management of rhabdomyolysis. CHEST 2013; 144(3):1058–1065

Abbreviations: AKI 5 acute kidney injury; CK 5 creatine kinase; CRRT 5 continuous renal replacement therapy;
IVF 5 IV fluid

Rhabdomyolysis is defined as injury of the skeletal

muscle, which results in the release of intracel-
lular contents into the circulation. Skeletal muscle
comprises 40% of body mass, and a large insult can
result in the accumulation of cellular contents in the
extracellular space such that elimination mecha-
nisms are overwhelmed. The resulting effects are
recognized as a clinical syndrome of muscle injury
that is associated with the development of myoglobi-
nuria, electrolyte abnormalities, and often acute kid-
ney injury (AKI).
Rhabdomyolysis has long been recognized as a pri-
mary condition or comorbidity in hospitalized and
critically ill patients. The initial understanding of the
syndrome originated from experiences of warfare
during and following World War II, as well as from
natural disasters. Rhabdomyolysis was caused pri-
marily by crush injury or other physical trauma in
these circumstances. Any form of therapy that pre-
vented renal failure or avoided death was deemed
successful because experience suggested that the out-
comes from rhabdomyolysis were generally poor.1,2
However, in the mostly civilian setting of current health
care, the characteristics of rhabdomyolysis are dif-
ferent. Pharmaceutical agents, alcohol, and illicit drugs
are now significant causes of rhabdomyolysis, in addi-
tion to trauma.3-6 This article focuses on the causes of
rhabdomyolysis likely to be encountered in hospital-
ized patients, current diagnosis and evaluation of the
syndrome and its associated complications, and treat-
ment of rhabdomyolysis, with an emphasis on pre-
vention of AKI.
Pathophysiology
The common pathway leading to muscle injury and
death in rhabdomyolysis is an increase in cytoplasmic
ionized calcium.7 The major mechanisms that result
in increased intracellular calcium are injury to the
myocyte membrane and altered energy production.
Direct disruption of the muscle cell membrane results
in an influx of calcium, with further release of calcium

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 from the damaged sarcoplasmic reticulum and mito-
chondria. Impaired metabolism (production, use, or
consumption) of adenosine triphosphate disrupts the
function of sodium-potassium and sodium-calcium
ion pumps, leading to intracellular calcium accumu-
lation. The increase in calcium activates multiple
destructive processes, resulting in the eventual lysis
of the cell and release of contents. High concentra-
tions of muscle cell contents are absorbed into the
bloodstream; these include electrolytes (potassium,
calcium, and phosphates), enzymes (creatine kinase
[CK], lactate dehydrogenase, aspartate transaminase,
and aldolase), proteins (myoglobin), and purine metab-
olites (uric acid).
Myoglobin, an iron-containing protein in skeletal
muscle that stores oxygen for aerobic mitochondrial
metabolism, is an important factor in rhabdomyoly-
sis. Myoglobin is excreted by the kidneys, and a urine
concentration . 100 mg/dL is responsible for the red
or brown staining of urine that can occur in rhab-
domyolysis.8 The term myoglobinuria is essentially
synonymous with rhabdomyolysis; the latter term is
preferred because it describes the pathophysiologic
process more accurately. Myoglobin has been impli-
cated consistently as the primary nephrotoxin in rhab-
domyolysis, with proposed mechanisms of toxicity
that include tubular obstruction, oxidant injury, and
vasoconstriction.9-11 Animal studies suggest that myo-
globin alone may not be nephrotoxic in the absence
of hypovolemia and acidosis,12 but acute renal fail-
ure has been described in patients without signifi-
cant hypovolemia.13,14 Myoglobin is readily filtered
by glomeruli in the kidneys and concentrated in the
renal tubules. Myoglobin can then be precipitated
out of solution in the acidic environment of the renal
tubules through interaction with Tamm-Horsfall pro-
tein. Myoglobin precipitation can be exacerbated by
intravascular volume depletion and systemic acidosis,
but hypovolemia leading to renal hypoperfusion may
be a more important factor in AKI than tubular
obstruction. Oxidant injury can result from dissocia-
tion of the iron in myoglobin, resulting in the release
of free radical species and oxidative damage to the
renal parenchyma.15 Studies also suggest that myo-
globin can induce lipid peroxidation, resulting in the
generation of isoprostanes. These molecules are potent
Manuscript received August 12, 2012; revision accepted January 31,
2013.
Affiliations: From The Methodist Hospital (Drs Zimmerman
and Shen), Houston, TX; and Weill Cornell Medical College
(Dr Zimmerman) New York, NY.
Correspondence to: Janice L. Zimmerman, MD, FCCP, 6550
Fannin, Ste 1001, Houston, TX 77030; e-mail: janicez@tmhs.org
© 2013 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians. See online for more details.
DOI: 10.1378/chest.12-2016
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vasoconstrictors and can contribute to renal arteriolar
dysregulation and hypoperfusion.11,15-17 Homeostatic
activation of the sympathetic nervous system and the
renin-angiotensin system due to intravascular hypov-
olemia can also contribute to vasoconstriction. Despite
the significant contribution of myoglobin to AKI, coex-
isting factors found in patients with rhabdomyolysis,
such as hypovolemia, other injuries, metabolic abnor-
malities, and drug effects, also impact renal function.
Cause
Rhabdomyolysis has numerous and diverse causes,
and Table 1 contains a listing of some of the most rel-
evant. A useful approach is to consider the mechanisms
of skeletal muscle damage. The insult can usually be
categorized into one of four mechanisms: hypoxic,
physical, chemical, or biologic. Many patients have
multiple factors that contribute to the development of
rhabdomyolysis, and a significant number of patients
may have no cause identified.3,4
Skeletal muscle is more prone to hypoxic injury
and vascular compromise because of its peripheral
location. Limbs are at increased risk of prolonged
pressure during an unconscious state, leading to vas-
cular occlusion and ischemia. Pressure-related muscle
injury causing rhabdomyolysis is now recognized in
obese patients as a complication of bariatric surgery,
as well as in nonobese patients undergoing prolonged
surgeries.18-21 A higher BMI and longer operating
times may increase the risk of rhabdomyolysis. Arte-
rial and venous thrombosis, as well as diffuse occlu-
sion of the microvasculature (eg, sickle cell trait,
vasculitis), can result in ischemic muscle injury and
rhabdomyolysis.22,23
The physical causes of rhabdomyolysis can be due
to external factors such as trauma or internal factors
such as exertion. Trauma results in overt muscle injury,
but rhabdomyolysis can also be precipitated by less
obvious injury. Internal factors can result from vol-
untary and involuntary injury. Common voluntary
injuries causing rhabdomyolysis follow overstrenu-
ous or prolonged exertion during military, recrea-
tional, and sports events.24 Exertional rhabdomyolysis
has also occurred as a result of prolonged electronic
gaming.25 Genetic polymorphic variations may play a
role in the variable susceptibility to exertion-related
muscle injury.26 Involuntary muscle overuse usually
stems from some predisposing medical condition
such as seizures or status asthmaticus.27
Chemical causes now account for most cases of
rhabdomyolysis.3,4 This category includes prescrip-
tion and over-the-counter medications, illicit drugs,
inorganic toxins, and electrolyte abnormalities. Table 2
lists selected drugs implicated as a cause of rhab-
domyolysis. Psychiatric medications (eg, quetiapine,
CHEST / 144 / 3 / SEPTEMBER 2013 1059
 Table 1—Causes of Rhabdomyolysis
Hypoxic Physical
External External
Carbon monoxide exposure Crush injury
Cyanide exposure Trauma
Internal Burns
Compartment syndrome Electrocution
Vascular compression Hypothermia
Immobilization Hyperthermia (heat stroke)
Bariatric surgery Internal
Prolonged surgery Prolonged and/or extreme exertion
Sickle cell trait Seizures
Vascular thrombosis Status asthmaticus
Vasculitis Severe agitation (delirium tremens,
psychosis)
Neuroleptic malignant syndrome
Malignant hyperthermia
aripiprazole) rank as one of the most frequent precip-
itants, with a portion related to neuroleptic malignant
syndrome.4 Statins are also implicated frequently.
Fewer than 1% of those taking statins alone will
develop rhabdomyolysis resulting in hospitalization
or kidney injury, but the risk increases to 6% when
used concomitantly with a fibrate.28 The risk of rhab-
domyolysis is also higher when statins are combined
with drugs that inhibit statin metabolism by cyto-
chrome P450 isoenzymes (cyclosporine, warfarin,
amiodarone, azole antifungals, and calcium channel
blockers). Genetic polymorphisms of transporter pro-
teins that facilitate hepatic uptake of statins, the
cytochrome P isoenzyme system, and enzymes of
the coenzyme Q10 synthetic pathway have been
associated with a higher risk of statin-associated
myopathy.29
Although less common, rhabdomyolysis can also
result from medications administered to hospital-
ized patients. Rhabdomyolysis can accompany the
development of propofol-related infusion syndrome,
a potentially fatal complication of prolonged or high-
dose propofol use.30 Daptomycin, often used to treat
serious hospital-acquired infections, has also been
associated with clinically significant rhabdomyolysis.13,14
Illicit drugs are well-described precipitants of rhab-
domyolysis.6,31 Few of these drugs have direct cyto-
toxic effects on myocytes; instead, multiple factors
coincide to inflict muscle damage. Stimulants such
as cocaine, methamphetamines, amphetamines, and
bath salts (mephedrone, methylenedioxypyrovalerone)
can increase physical activity to deleterious levels,
precipitate seizures or hyperthermia, and produce
ischemia from arterial vasoconstriction.31-33
Alcohol may act as a direct toxin to muscles and
cause rhabdomyolysis via other effects.34 Intoxica-
tion can lead to immobilization associated with com-
pression and ischemic injury. In addition, the diuretic
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Chemical Biologic
External External
Alcohol Bacterial, viral, and parasitic
Prescription medications myositis
Over-the-counter medications Organic toxins
Illicit drugs Snake venom
Internal Spider bites
Hypokalemia Insect stings (ants, bees, wasps)
Hypophosphatemia Internal
Hypocalcemia Dermatomyositis, polymyositis
Hypo-/hypernatremia Endocrinopathies
Adrenal insufficiency
Hypothyroidism
Hyperaldosteronism
Diabetic ketoacidosis
Hyperosmolar state
effect of alcohol can lead to dehydration and increase
the risk of AKI. Chronic alcoholism also predisposes
to rhabdomyolysis because of malnutrition, limited
energy stores, electrolyte abnormalities, and enzyme
deficiencies.
Biologic causes make up the last category of causes
of rhabdomyolysis. Although almost any bacteria can
cause myositis, gram-positive organisms predominate,
and the most common viruses associated with myo-
sitis are influenza A and B, enteroviruses, and HIV.35
Organic toxins that affect skeletal muscles via stings
and bites have been reported for bees, wasps, hor-
nets, ants, centipedes, scorpions, and brown recluse
spiders.36-38 Genetic inborn errors of metabolism and
muscular dystrophies can present with rhabdomy-
olysis later in life, and additional evaluation should
be considered in patients with recurrent episodes of
rhabdomyolysis.39
Clinical Evaluation and Diagnosis
Rapid recognition of rhabdomyolysis is important to
implement timely, appropriate treatment. Evaluation
requires an assessment of risk factors for rhabdomy-
olysis, a thorough history and physical examination,
and laboratory testing. The history should elicit infor-
mation on prior exertional activities; environmental
exposures; prolonged immobilization; trauma; pre-
scription and over-the-counter medication use; illicit
drug or alcohol use; symptoms of infection, rash, or
arthralgias; and change in urine color or quantity. The
physician should be aware that intoxicated, psychotic,
agitated, and unconscious patients are at high risk
of rhabdomyolysis. Psychiatric patients are also con-
sidered higher risk because of use of antipsychotic
and antidepressant medications.
The variable clinical manifestations in rhabdomyoly-
sis may result from the precipitating cause (ie, influenza,
Postgraduate Education Corner
 Table 2—Selected Drugs Associated With have medications reviewed and diagnostic testing ini-
Rhabdomyolysis tiated. Laboratory monitoring may be indicated in
Drugs
patients with risk factors such as obesity, prolonged
surgery, statin use, alcohol abuse, prolonged seizure
Medications activity, severe agitation, propofol use, unexplained
Lipid-lowering agents
Statins
hyperkalemia, and deterioration of renal function.
Fibrates Less commonly, patients may present with mani-
Psychiatric medications festations due to complications of rhabdomyolysis.
Neuroleptics/antipsychotics (including haloperidol, The edema and inflammation resulting from muscle
atypical antipsychotics) damage in the limbs can secondarily increase local
Selective serotonin reuptake inhibitors
Lithium
pressure and compromise circulatory flow, resulting
Valproic acid in compartment syndrome. Circulation should be
Antimicrobial agents evaluated periodically in any severely affected limb,
Antiretroviral medications (protease inhibitors) especially after volume resuscitation. Some patients,
Trimethoprim-sulfamethoxazole especially those with extensive crush injuries, may
Daptomycin
Macrolide antibiotics
present with arrhythmias or sudden death resulting
Quinolones from hyperkalemia. Urine output may be decreased
Amphotericin B on presentation if AKI has already developed.
Anesthetics/paralytics Diagnostic laboratory testing for rhabdomyolysis
Succinylcholine is straightforward (Table 3); serum should be sent for
Propofol
Antihistamines
measurement of CK, which is more specific for the
Doxylamine diagnosis of rhabdomyolysis than are other markers
Diphenhydramine that may also be elevated. Normal CK levels are usu-
Appetite suppressants ally , 100 IU/L. The CK level for clinical concern is
Phentermine uncertain; an arbitrary value of 500 to 1,000 IU/L, or
Ephedra
Others
five to 10 times the upper limit of normal is frequently
Sunitinib, erlotinib used to define rhabdomyolysis. Higher CK levels cor-
Narcotics relate with a greater degree of muscle injury, but levels
Colchicine correlate marginally with the development of AKI or
Vasopressin mortality.3,4,6,40-43 A reasonable consensus recommen-
Amiodarone
dation suggests close monitoring of renal function in
Aminocaproic acid
Illicit drugs patients with CK levels . 5,000 IU/L and creati-
Cocaine nine . 1.5 mg/dL.44 Some studies suggest that patients
Amphetamines/methamphetamines with CK levels , 5,000 IU/L are not at risk of devel-
Hallucinogens oping AKI42,44; otherwise, it is difficult to use the mag-
Heroin
nitude of the CK value to estimate the risk of kidney
Methylenedioxypyrovalerone, mephedrone (bath salts)
Phencyclidine injury. Serial CK measurements should be monitored;
increasing levels, or failure of levels to decline despite
therapy, suggest ongoing muscle injury or the devel-
opment of renal failure.
trauma), the muscle injury (direct or indirect), and Serum myoglobin levels are not needed for the
the complications associated with rhabdomyolysis. diagnosis or management of rhabdomyolysis. Myo-
Muscle injury may manifest as pain, swelling, tender- globin is cleared more rapidly than CK, and therefore
ness, or weakness, but such findings may be absent or is less sensitive for detecting rhabdomyolysis, espe-
may be overshadowed by other conditions. Signifi- cially when presentation is delayed.3 When initially
cant limb pain in the setting of trauma should raise evaluating a patient with dark-colored urine, a posi-
the suspicion for compartment syndrome. Nonspecific tive urine dipstick test for blood without evidence
symptoms may include fatigue, nausea, vomiting, and of RBCs on microscopy is a clue to the presence of
fever. Red or brown urine suggests significant myo- rhabdomyolysis, because myoglobin will also react
globin excretion but its absence does not preclude with the orthotolidine test reagent. Urine myoglobin is
the presence of rhabdomyolysis. not a sensitive test for rhabdomyolysis, nor is it specific
Detection of rhabdomyolysis that develops during for the development of AKI; therefore, it is not neces-
hospitalization may be more difficult, because it may sary for routine testing.
not be suspected and patients may not be able to Additional laboratory testing is needed to deter-
communicate complaints. Patients who do complain mine the potential precipitating factors and compli-
of myalgias or develop a change in urine color should cations resulting from rhabdomyolysis. A metabolic

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 Table 3—Selected Laboratory Testing for Initial Evaluation
Test Abnormal Value for Rhabdomyolysis
CK . 500 IU/L
Potassium . 6.0 mmol/L
, 2.0 mmol/L
Phosphorous . 6.0 mg/dL
, 2.0 mg/dL
Calcium Decreased (, 8.0 mg/dL)
Creatinine Increased
BUN:creatinine , 10:1, often , 6:1
Anion gap Increased
Blood alcohol level Elevated
Urine blood dipstick Positive
Urine drug screen Positive
BUN 5 blood urea nitrogen; CK 5 creatine kinase.
panel that includes electrolytes (potassium, calcium,
phosphorous) and renal function should be obtained
routinely. The results screen for hypokalemia and
hypophosphatemia as potential causes and identify
potentially life-threatening hyperkalemia. Calcium
levels are often low initially, secondary to precipita-
tion of calcium with phosphates in damaged muscles.3,45
Calcium mobilization from damaged muscles in the
recovery phase of rhabdomyolysis and AKI may sub-
sequently result in hypercalcemia.45 An elevated cre-
atinine level with a blood urea nitrogen-to-creatinine
ratio , 10:1 is often noted on presentation.3 The dis-
proportionate increase in creatinine early in rhab-
domyolysis is possibly due to metabolism of released
muscle creatine. The anion gap in rhabdomyolysis is
often increased more than expected for the degree of
AKI and may be due to phosphates and organic acids
released from muscle.3 Hyperuricemia resulting from
the release of muscle purines is common. A coagula-
tion panel should be assessed for evidence of the dis-
seminated intravascular coagulation that can occur
with rhabdomyolysis. An ECG can be obtained quickly
to screen for conduction abnormalities and evidence
of hyperkalemia (P-R interval prolongation, peaked
T waves, and widened QRS complex). A urine drug
screen may be indicated to confirm exposure to spe-
cific drugs.
Therapy
There are no randomized, controlled trials in rhab-
domyolysis that offer definitive guidance for treatment.
Only a few interventional clinical trials in rhabdomy-
olysis have been reported in the past 10 years. The
lack of high-quality evidence must be acknowledged
and considered when reviewing recommendations for
interventions. Most recommendations are based on
retrospective observational studies with small num-
bers of patients, animal models, case reports or series,
and opinion. The treatment of rhabdomyolysis usu-
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Comments
Diagnostic for rhabdomyolysis; increased risk of kidney injury if . 5,000 IU/L
Marker of severity of muscle injury and renal dysfunction
Potential cause of rhabdomyolysis
Marker of severity of muscle injury and renal dysfunction
Potential cause of rhabdomyolysis
Deposition in damaged muscle
Marker of decreased renal function
Increased conversion of muscle creatine to creatinine
Increased organic acids due to muscle injury or renal dysfunction
Potential cause of rhabdomyolysis
Detects myoglobinuria in absence of RBCs in urine
Potential drug-related cause of rhabdomyolysis
ally involves three components: discontinuation of
further skeletal muscle damage, prevention of acute
renal failure, and rapid identification of potentially
life-threatening complications. Specific measures to
stop ongoing muscle injury will vary with the cause
of the rhabdomyolysis. Interventions may include
control of agitation, discontinuation of medications,
treatment of infection, correction of metabolic abnor-
malities, cooling or warming, surgery, and others.
The major effort in the treatment of rhabdomy-
olysis is directed toward prevention of renal failure.
AKI has been observed in 10% to 60% of patients
presenting with rhabdomyolysis,3,4,6,40,42,43,46 and 10%
of AKI has been attributed to rhabdomyolysis.10 The
cause of muscle injury, intravascular volume status,
patient comorbidities, and initial laboratory results
may be helpful in determining the risk of progression
to AKI. Although CK, myoglobin, potassium, bicar-
bonate, albumin, lactate dehydrogenase, and creati-
nine levels at presentation have been evaluated, no
single marker or predictive model has been able to
reliably assess the risk of AKI. The reason for this dif-
ficulty is at least twofold: the multifactorial nature of
kidney injury, with rhabdomyolysis being only one of
the contributing factors, and the heterogeneity in
the causes of rhabdomyolysis. Suggested markers and
models of AKI are derived from the results of single-
center retrospective studies and are difficult to gen-
eralize. Serial trends of laboratory markers may be
more appropriate than single results to assess the risk
of AKI.
Patients with elevated CK levels secondary to chronic
myositis due to statins, HIV infection, or inflamma-
tory myopathies may be at a lower risk of developing
AKI.4 Patients with exertional rhabdomyolysis also
appear to be at a much lower risk of AKI.47 Trauma
patients and those with comorbidities such as chronic
alcoholism or drug use may be at a higher risk.
There is complete agreement that early and aggres-
sive volume resuscitation to restore adequate renal
Postgraduate Education Corner
 perfusion and increase urine flow is the mainstay for
preventing and treating AKI in rhabdomyolysis.9,10,44,48,49
The administration of IV fluid (IVF) dilutes nephro-
toxins and promotes renal tubule flow, which may
prevent the accumulation of myoglobin and toxic
products in the renal parenchyma. More controversy
exists regarding the type and volume of fluid and the
use of diuretics. When a patient is suspected or rec-
ognized to have rhabdomyolysis, IVF should be admin-
istered rapidly as an initial bolus. Isotonic saline is
preferred because it is readily available and does not
contain potassium. In disaster situations, prompt IVF
administration prior to or during extrication of crush
victims may help prevent later renal complications.48
IVF is continued by infusion until resolution of rhab-
domyolysis or until the development of oliguric AKI
limits further fluid administration. A prospective,
randomized trial compared the effects of lactated
Ringer’s vs 0.9% saline administered at 400 mL/h in
patients with mild rhabdomyolysis secondary to doxy-
lamine.50 At the end of 12 h of infusion, the serum
and urine pH were higher in the lactated Ringer’s
group; however, the clinical significance of this out-
come is unclear.
Large amounts of IVF within the first 24 h are
associated with improved outcomes.1 No specific rate
of infusion or target urine output has been demon-
strated to be superior to another. For the first 24 h
after presentation, as little as 3 L to as much as 24 L
have been administered effectively. A target of 6 to
12 L within 24 h is a reasonable goal, as long as com-
plications from volume overload can be avoided. Tra-
ditionally, urine output goals of 200 to 300 mL/h have
been recommended. There has been minimal inves-
tigation of fluid administration in high-risk patients
to prevent the development of rhabdomyolysis prior
to injury. A prospective, randomized trial of intraop-
erative isotonic fluids in bariatric surgery patients at
15 mL/kg vs 40 mL/kg total body weight did not find
any difference in the incidence of rhabdomyolysis.51
Alkalinization of the urine is also a common inter-
vention in rhabdomyolysis, but evidence of a clinical
benefit is lacking. The concept of urine alkalinization
derives from the precipitation of myoglobin in an
acidic environment, and therefore, urinary alkaliniza-
tion (pH . 6.5) theoretically can decrease the depo-
sition of myoglobin in renal tubules. Alkalinization
therapy was shown to be more effective than IVF
alone in animal models, and two small retrospective
observational case series (27 patients in total) are often
cited to suggest the benefit of bicarbonate and man-
nitol administration in rhabdomyolysis.1,2 However,
several other retrospective studies were not able to
show that bicarbonate coadministered with mannitol
was more effective than volume infusion with isotonic
saline.42,52 The largest retrospective study of bicar-
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bonate and mannitol therapy vs no use of this therapy
in trauma patients did not find any difference between
groups in the incidence of renal failure, need for dial-
ysis, or mortality.42 A current consensus statement sug-
gests that sodium bicarbonate administration is not
necessary and not superior to normal saline diuresis
in increasing urine pH.44 Urine alkalinization is gen-
erally accomplished by the administration of bicar-
bonate, either by direct infusion or by adding it to
IVF. Alkalinization of the urine may be difficult to
achieve without causing a systemic metabolic alka-
losis. Conversely, some bicarbonate-containing fluids
may be helpful if 0.9% saline administration causes a
dilutional metabolic acidosis. If the decision is made
to alkalinize urine, care must be taken to ensure that
other electrolytes remain balanced.
Forced diuresis with mannitol and loop diuretics
has also been used to promote urine output and pre-
vent AKI. Theoretically, diuresis may prevent the
accumulation of debris in the renal tubules, thereby
decreasing the risk of obstruction contributing to
AKI. Mannitol also acts as an intravascular volume
expander and vasodilator, which may ameliorate renal
injury, along with other proposed protective mecha-
nisms.9,53 A variety of dosing regimens using intermit-
tent bolus and continuous infusion of mannitol have
been reported. Mannitol has not been evaluated as a
sole intervention in a controlled trial of rhabdomyoly-
sis. The same small retrospective studies of bicar-
bonate administered with mannitol in rhabdomyolysis
are cited to suggest treatment success with mannitol.1,2
Routine use of mannitol is not recommended for
rhabdomyolysis, and it should not be administered
to hypovolemic or anuric patients.
Use of loop diuretics has been advocated to “con-
vert” oliguria or anuria to nonoliguria, but with very
limited published experience. Care must be taken
not to exacerbate hypokalemia or hypocalcemia if
loop diuretics are used; conversely, use may be bene-
ficial to treat hyperkalemia before renal recovery or
hemodialysis.
Anecdotal use of corticosteroids, acetazolamide,
and various antioxidants has been reported, but these
agents cannot be recommended.54,55 Laboratory studies
have suggested that acetaminophen and l-carnitine
may be able to ameliorate nephrotoxicity from myo-
globin, but more clinical research is needed.17,56,57
If AKI develops, or fails to reverse despite aggres-
sive fluid administration, renal replacement therapy
may be required to manage the complications of
rhabdomyolysis. Indications for hemodialysis include
hyperkalemia, metabolic acidosis, volume overload,
and azotemia.9,44 Hyperkalemia tends to be the major
indication for early renal replacement therapy because
of the potassium load released from muscle. Currently,
there are no data to support the use of continuous
CHEST / 144 / 3 / SEPTEMBER 2013 1063
 renal replacement therapy (CRRT) over intermit-
tent hemodialysis in rhabdomyolysis, but CRRT
may be better tolerated in patients with hypotension
or in those at risk of hypotension. CRRT using con-
ventional high-flux filters has been found to remove
myoglobin despite its large molecular weight, and
experimental super-high-flux filters may be even more
effective.58 However, it is not clear that removal of
myoglobin prevents or alters the clinical course of AKI,
and CRRT is not advocated for myoglobin removal.9,44
At the same time that IVF is initiated, the phy-
sician should assess the likelihood of electrolyte
complications with laboratory testing and an ECG.
Significant hyperkalemia should be treated accord-
ing to standard management principles.59 Treatment of
hypocalcemia is not recommended because of the
high intracellular concentrations in injured muscle and
the potential for precipitation. Exceptions are con-
comitant hyperkalemia with significant ECG changes
and symptomatic hypocalcemia (tetany). Calcium
levels should be monitored throughout the hospital
course to detect later development of hypercalcemia.
Oral phosphate binders can be considered for signif-
icant hyperphosphatemia. If compartment syndrome
is suspected, surgical consultation should be obtained
for measurement of intracompartment pressures and/or
fasciotomy.60
Outcome
Outcomes from rhabdomyolysis vary considerably
with the type of patient population, cause, and comor-
bidities. A consistent finding is that the mortality of
patients with rhabdomyolysis and acute renal failure
is higher than in patients with no renal failure.1,42 It is
not surprising that hospital length of stay is noted to
be longer in patients with significant renal compro-
mise.6 Most patients with acute renal failure from
rhabdomyolysis recover function within a few months.
Mortality in rhabdomyolysis also ranges from 1.7% to
46%, and the variability is likely due to differing
causes, coexisting conditions, and improved treatment
over time (especially for trauma patients).1,2,6,42,43,47
Conclusions
Rhabdomyolysis continues to be a significant syn-
drome leading to hospitalization or developing in
hospitalized patients. The prominent role of medi-
cations, alcohol, and illicit drugs as causes of rhabdomy-
olysis requires careful consideration when evaluating
patients. Aggressive fluid resuscitation with isotonic
fluids is probably sufficient to prevent AKI in the
majority of patients with rhabdomyolysis. There is
little evidence to support the routine use other inter-
ventions with bicarbonate, mannitol, and loop diuret-
ics. Prospective well-designed trials in rhabdomyolysis
1064
Downloaded From: http://journal.publications.chestnet.org/ by David Kinnison on 09/03/2013
are sorely needed to provide more definitive guidance
on treatment interventions.
Acknowledgments
Financial/nonfinancial disclosures: The authors have reported
to CHEST that no potential conflicts of interest exist with any
companies/organizations whose products or services may be dis-
cussed in this article.
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